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
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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.
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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.
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Blood-Brain barrier: prevent the passage of microbes and its
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.
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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).
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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).
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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).
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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.
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Acute Meningitis (bacterial and viral)
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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).
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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.
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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).
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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.
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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.
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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.
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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.
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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.
Slide 21
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.
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Chronic Meningitis
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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.
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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.
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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).
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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).
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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 45.8C. - Exposure to
rivers water (swimming) causes this rare and lethal infection
within 1-2 weeks. - Mortality rate 97%
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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.
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Diagnosis of Meningitis
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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
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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.
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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.
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In Microbiology Laboratory: Direct Microscopy: CSF specimen
should be concentrated by centrifugation; and the pellet will be
used for: Grams 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.
Slide 35
The Grams negative diplococci (N. meningitidis) inside
polymorph- nucleated neutrophils. (Grams stain). Gram positive
lancet shape capsulated diplococci (S. pneumoniae) The Budding
capsulated yeast Cryptococcus neoformans as shown in India ink wet
mount. Mycobacterium (Z.N Stain); lymphocytic infiltration.
Slide 36
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. OPOP
Slide 37
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.
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Isolation of Haemophilus influenzae: (infants and young
children): - Pleomorphic Grams 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.
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Quellung reaction Satellitism of H. influenzae around S. aureus
growth
Slide 40
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.
Slide 41
Isolation of E. coli: - Neonatal meningitis. - Gram negative
bacilli. K1 Capsular antigen. - Lactose fermenters. Indole
positive. - Metallic green sheen on EMB medium.
Slide 42
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 E.coli Control N. meningitidis S.
pneumoniaeH. influenzae b Positive
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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
Slide 44
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). Grams 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.
Slide 45
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?
