Infections of The
Central Nervous
System
CNS Infections:
• Encephalitis: Infection of brain parenchyma.
• Meningitis: Infection of meninges.
• Meningoencephalitis.
• Myelitis: Infection of spinal cord tissue.
• Subdural empyema. Brain abscess.
• Acute disseminated encephalomyelitis:
post viral infection encephalitis that is mediated
by cross reactivity against myelin.
• Bovine spongiform encephalopathy: Prions
Natural defense mechanism of CNS:
• The blood-brain barrier: endothelial cells that line
brain capillaries (with tight junctions), astrocytic
end-feet and thick basement membrane.
• Local immune responses of CNS.
Local Immune Responses of CNS:
The CNS has an intrinsic immunological
surveillance mechanism that depends on:
• Presence of specific antigen presenting cell; the
microglial cells.
• Virchow-Robin spaces (the perivascular sheaths
surrounding the blood vessels) contain lymph-like
system of macrophages and lymphocytes.
Blood-Brain barrier:
prevent the passage of microbes and it’s toxic
substances into the brain and CSF.
However, the blood-brain barrier also:
• Prevents the passage of humoral immune
components (complement and antibodies) to the
site of infection.
• Prevents the cellular infiltration of WBCs to the
site of infection.
• Reduces the penetration of many antimicrobial
drugs.
Neurotropism and Microbial Virulence:
Neurotropism: ability of some pathogenic microbes
to infect the nervous system cells due to presence of
specific virulence factors and specific receptors.
Examples:
Viruses: Poliovirus infects the motor neurons of the
spinal cord and medulla.
Mumps virus invades ependymal cells lining the
ventricles in the fetal brain. (complication: 50% of
patients develop meningitis, but only 5% are
symptomatic).
Bacteria:
Capsules has anti-phagocytic capacity and resist
complement mediated lysis.
K1 capsular antigen (polysaccharide rich in sialic
acid) increase the bacterial adherence ability to the
meninges. In some strains of Escherichia coli and
group B Streptococcus).
Ports of entry to CNS:
One of three routs:
• Hematogenous rout: Respiratory epithelia, bite
of animals (rabies virus) or transplacental
(rubella virus).
• Neural rout: rabies virus, HSV-1 &2 and
Naegleria fowleri.
• Direct inoculation (trauma, surgery or
congenial defects).
Classification of meningitis:
• According to clinical presentation: acute,
subacute and chronic.
• According to etiology: bacterial, viral (aseptic
meningitis), fungal, protozoal.
• Acute meningitis is usually bacterial or viral in
etiology.
• In all cases of suspected bacterial meningitis,
antibiotic therapy must be administrated
immediately.
Acute
Meningitis
(bacterial and viral)
Etiology of acute bacterial meningitis:
varies with the age of the patients:
• Neonates and infants younger than 3 months of
age; group B streptococci (50%), E. coli (20%),
and Listeria monocytogenes and others (up to
10%).
• In infants older than 3 months, children and
adults: Streptococcus pneumonia, Neisseria
meningitides (outbreaks), and Haemophilus
influenzae type b (in non immunized).
Pathogenesis:
• Upper or lower respiratory infection or carrier
state: Neisseria meningitides , Streptococcus
pneumonia & Haemophilus influenzae type b.
• Bacteremia; capsule resist humoral mediated
destruction.
• Reach CNS through choroid plexus, due to lack
of tight junctions between endothelial cells (loss
of blood-brain barrier); direct access to the CSF.
• Blood to the choroid plexus to the ventricular
CSF to ependymal cells lining the ventricles to
periventricular brain tissues.
Damage and Destruction:
• CSF glucose, protein& oxygen content supports
bacterial multiplication (in Pia, arachnoid & CSF).
• Bacterial exotoxins and endotoxin (LPS)
production
cells death.
• Infiltration and proliferation of microglial cells.
Chemotaxis of neutrophils & lymphocytes from
choroid plexus and Virchow-Robin space.
Cytokines produced (edema & damage).
• Increased Intracranial pressure (ICP).
• Increased ICP (Intracranial pressure): due to
hematomas (break BBB), cerebral edema and
decreased CSF reabsorption and increased secretion.
• Reduced cerebral perfusion pressure (blood flow
pressure to the brain) due to:
Increased Intracranial pressure.
Reduced mean arterial pressure secondary to
shock.
This will results in: thrombosis and ischemia, and so
neuronal infarction.

So damage results from: bacterial toxins, cytokines
effects and infarction due to increased ICP, reduced
perfusion and thrombosis.
Clinical presentation of N. meningitides infection:
Meningitis, meningococcemia or meningitis with
meningococcemia. Mortality rate in meningococcemia
is ̴ 70 %.
Symptoms:
General symptoms: Headache, high fever & vomiting.
Meningitis: photophobia, neck stiffness, seizures
(20%), and skin rash (50%).
Meningococcemia: purpuric skin rash (endothelia
necrosis); hypotension, thrombosis causes disseminated
intravascular coagulopathy (DIC); multiple organ
failure and death.
Subdural Empyema
• Collection of pus between the dura mater and
arachnoid mater (usually unilateral).
• In infants, and young children; it occurs as a
complication of meningitis.
• In adults; it occurs as a complication of otitis
media, mastoiditis or paranasal sinusitis (mainly
frontal and ethmoid sinusitis; 2 weeks later).
• Infection spreads intracranial through
thrombophlebitis.
Acute Viral Meningitis (Aseptic Meningitis):
Aseptic meningitis: Negative CSF bacterial culture.
Causes:
• Enteroviruses.
• Mumps virus.
• Arboviruses.
• Herpes viruses.
• Lymphocytic Choriomeningitis virus
• Other viral causes: Adenovirus, Measles, HIV: in
5-10 % of AIDS patients.
Enteroviruses:
Family: Picornaviridae. Enteroviruses: Echoviruses,
Coxsackievirus A and B viruses, Poliovirus.
• Currently more than 85% of viral meningitis are
due to non-polio Enteroviruses.
Coxsackievirus B accounts alone for more than
60% of meningitis in infants younger than 3
months. Enteroviruses 70 and 71 has a strong
neurotropism that results in encephalitis with
polio-like paralysis.
Mumps virus: Paramyxoviridae.
In parts of the world where vaccine is not applicable;
it causes 10% of cases.
Arboviruses: Arthropod-borne infection associated
with 5% of cases.
Herpes viruses:HSV-1 and HSV-2 (account 4% of
the cases).
Lymphocytic Choriomeningitis virus:
Arenaviridae; meningitis with lymphocytic
infiltration of choroid plexuses.
Encountered from hamsters, rats or mice by
inhalation route, ingestion route or contaminated
wound. Mild or asymptomatic except for
immunocompromised.
Chronic
Meningitis
Causes:
Bacteria: Mycobacterium tuberculosis.
Fungi: Cryptococcus neoformans.
CNS Tuberculosis:
• Tuberculous Meningitis.
• Spinal cord tuberculosis.
Tuberculous Meningitis:
• Pathogenesis:
During primary pulmonary infection; tubercle bacilli
may disseminate to the meninges or brain
parenchyma through lymphatics.
• These bacilli are contained within subpial or
subependymal granulomas that remain latent
unless the cellular immunity decreases.
• When immunity decrease the size of foci increases;
ruptures into the CSF & subarachnoid space
causing basilar cisterns meningitis.
• As the cellular immunity returns granulomas
(tuberculoma, caseous abscess, cold abscess) are
reformed.
• Basilar meningitis may lead to:
o Cranial nerves III, VI, VII dysfunction.
o Obstructive hydrocephalus & increased ICP.
Spinal cord tuberculosis:
The earliest lesion are in the lumbar or thoracic
vertebra (vertebral osteomyelitis).
- Might be complicated by spinal epidural abscess;
rupture of abscess may cause spinal meningitis.
- Involvement of the dorsal columns of the spinal
cord results in loss of position sensation. Resemble
tabes dorsalis caused by Treponema pallidum
(neurosyphilis).
Fungal Meningitis: Cryptococcus neoformans:
• Melanin producing yeast reproduce by budding.
In tissues it has a large polysaccharide capsule.
• Found in soil contaminated by birds excreta.
• It causes infection in immunocompetent patients
(20% of cases) and children.
• Primary infection in the lung is usually
asymptomatic.
Due to resistance of phagocytosis and decreased
cell-mediated immunity; carried by bloodstream
to the brain (subacute or chronic meningitis).
Amebic Meningitis or Meningoencephalitis:
-Primary amebic meningitis: Naegleria fowleri;
the freshwater brain-eating amoeba.
-Secondary amebic meningitis: Entamoeba
histolytica.
Naegleria fowleri Meningitis:
- Classified as ameboflagellate. Salt, chlorine &
pH-sensitive microbe. Heat tolerant at 45.8ᵒC.
- Exposure to river’s water (swimming) causes this
rare and lethal infection within 1-2 weeks.
- Mortality rate 97%
Pathogenesis:
-Port of entry: Neural route: through olfactory nerve
endings. Migration through the cribriform plate of
ethmoid bone to parenchymal cells of olfactory bulbs.
-Reach subarachnoid space; meningitis, acute
ependymitis; encephalitis.
Diagnosis of
Meningitis
• Clinical history & examination.
• Laboratory Diagnosis: CSF analysis
o Turbidity and increased opining pressure.
o Hematology analysis: Leukocytes count and
differential count.
o Biochemistry analysis: glucose &protein.
o Microbiology Laboratory:
• Direct Microscopy and culture.
• Detection of microbial genetic material by PCR.
• Rapid tests: serology
In Hematology Laboratory:
Leukocytes count and differential count:
Normal Leukocytes count: 0-6 cells/mm3
(lymphocytes).
- If it is > 1000/cumm : suspect bacterial infection.
- If it is < 300/cumm : suspect viral infection.
Differential count:
- if % neutrophils is >50% : suspected bacterial
infection.
- if % of neutrophils < 50% and lymphocytes
dominates: suspect viral infection.
In Biochemistry Laboratory:
Glucose:
- Decreased level: suspected bacterial infection.
- Normal Level: suspect viral infection.
Protein:
• Increased protein: bacterial infection.
• Increased or normal protein level: Viral infection.
In Microbiology Laboratory:
Direct Microscopy:
CSF specimen should be concentrated by
centrifugation; and the pellet will be used for:
Gram’s stain: gram positive or negative cocci or bacilli.
Z.N stain: for acid-fast bacilli; M. tuberculosis
Capsule stain: for Streptococcus pneumoniae.
India ink wet-mount: for all capsulated microbes
specially Cryptococcus yeasts.
The Budding capsulated yeast Cryptococcus
neoformans as shown in India ink wet
mount .
The Gram’s negative diplococci
(N. meningitidis) inside polymorphnucleated neutrophils. (Gram’s stain).
Gram positive lancet shape capsulated
diplococci (S. pneumoniae)
Mycobacterium (Z.N Stain);
lymphocytic infiltration.
Microbial cultivation and identification:
Isolation of Streptococcus pneumoniae:
(most common cause in adults):
- Gram positive lancet-shaped capsulated cocci.
- Alpha hemolytic on blood agar.
- Optochin sensitive.
O
P
Isolation of Neisseria meningitidis: (most
common between the ages of 2-18 years,
outbreaks).
-Gram negative diplococci inside polymorph
nucleated phagocytes (in CSF).
-Fastidious bacterium grow best on chocolate agar
and at microaerophilic conditions of 5-10 % CO2.
-Oxidase positive.
- Glucose and maltose fermenters.
Isolation of Haemophilus influenzae:
(infants and young children):
- Pleomorphic Gram’s negative coccobacilli.
- Fastidious (similar to N. meningitidis). Only grow
on chocolate agar because it needs hemin and NAD.
- Type b capsule can be examined by Quellung
swelling test or immunofluorescent staining.
Quellung reaction
Satellitism of H. influenzae
around S. aureus growth
Isolation of Group B Streptococci :
(Streptococcus agalactiae):
- The leading cause of neonatal meningitis and
septicemia with high mortality rate.
- Found normally in the vagina and cervix of
female carriers. Transmitted during birth.
- Gram positive cocci in chains.
- Beta hemolytic activity.
- Bacitracin resistant.
Isolation of E. coli:
- Neonatal meningitis.
- Gram negative bacilli. K1 Capsular antigen.
- Lactose fermenters. Indole positive.
- Metallic green sheen on EMB medium.
Detection of microbial genetic material by PCR:
PCR has a significant diagnostic value for: Detection
of Mycobacterium genes in CSF. Detection of viral
genetic material in CSF (RT-PCR).
Serology: direct agglutination:
A-Microbial capsule. B-Microbial exotoxins.
Streptococcus B
N. meningitidis
Positive
H. influenzae b
E.coli
S. pneumoniae
Control
Case Study:
A 32-year-old lady immigrated from India to the
United States 2 years ago. Four weeks following her
arrival, her oldest child returned from child care with
chicken pox. Two weeks later, she developed the
disease.
Over the next week she developed headache, fever
and vomiting and after a week became stupor.
Physical examination: impaired eye movements.
Chest radiography showed lobar pneumonia.
computerized tomography (CT) scan showed
enlarged ventricles suggestive of acute hydrocephalus
Lumbar puncture revealed high elevated opening
pressure, and the CSF showed 350 WBCs/mm3, of
Which 87% were lymphocytes. The CSF protein
was 168 mg/dl (increased), and the glucose was 20
mg/dl(decreased).
Gram’s stain and acid-fast stain of CSF showed
negative results. A positive PCR results confirmed
mycobacterial meningitis.
She was treated with isoniazid, rifampin,
pyrazinamide, and streptomycin with steroids for 2
months. With resolution of symptoms, she was
discharged to receive 10 additional months of
therapy with isoniazid and rifampin.
1-How does chicken pox activate this infection?
2-What is the explanation for eye movement
abnormalities?
3-How do the CSF finding in this case compare with
other viral or bacterial meningitis?
4-Why are multiple drugs required for the treatment
of this case?