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CNS Bacterial Infections
Pediatric Critical Care Medicine
Emory University
Children’s Healthcare of Atlanta
• Infections of the CNS are among the most devastating
infectious diseases
– Cause death and disability worldwide
• Often present as medical emergencies
– Early, appropriate care is critical to reducing morbidity and
CNS Development
CNS Development
• 2 wks: Neural plate forms from ectoderm
– Neural tube completed by day 26-28
• 3-4 wks: Hemispheres form
– Pons/medulla develop at 3-7.5 wks
• 8-18 wks: Neuronal proliferation
– Up to 200,000 new neurons per minute
• > 25 wks: Arborization, synaptogenesis, apoptosis, neural
• 30 wks - adolescence: Continuing myelination
CNS Development
• The mature human brain will have 10 billion neurons
– Most are formed during the period of rapid proliferation (8-18 wks)
– Very little neurogenesis after birth
• 70% of developing neurons will die by apoptosis during
– Bcl-2, Apaf1, cystein-protease caspase
• Pathways are upregulated during development
– Newborn brain more prone to injury-related PCD
Blood-Brain Barrier
Blood-Brain Barrier
• There is debate over whether the infant BBB is ‘leaky’
– Tight junctions in mature BBB form a true zona occludens
– Agree that permeability of macromolecules in the same as in adults
• BBB has both ‘static and dynamic’ properties
– Astrocyte feet have lots of control
• Impermeable to ions, proteins, osmolar agents
– Osmotic (not oncotic) gradients are critical to water movement
through aquaporin channels
• Pathogens must first gain access to CNS to cause disease
– Subarachnoid space (meningitis)
– CNS parenchyma (encephalitis, myelitis, abscess)
• Most are spread through the bloodstream
• May also occur through direct spread
» Adjacent structures (otitis, sinusitis, dental abscess)
» Shunt infections
» Skull fractures
Clinical Syndromes
Signs and Symptoms
Acute Meningitis
Acute onset of fever, HA, vomiting,
meningismus, AMS
Progression over hours to days
Bacteria, viruses
Subacute or Chronic
Gradual onset, lower fever,
progression over weeks
Tuberculous, fungal
Acute Encephalitis
Diffuse: AMS and seizures
Focal: tropism of virus for specific
CNS location (HSV)
Encephalopathy w/
Systemic Infection
Symptoms vary, often AMS.
Shigella, typhoid,
malaria, Rickettsia,
Various, depending on lesion
ADEM, transverse myelitis, optic
neuritis, MS
Viruses, vaccines
 Thorough history and physical exam are very important!
 Note chronicity of symptoms, comorbid conditions, preceding
illnesses, VP shunt
 Travel, surgery, trauma, sick contacts, insect bites, animal contact,
sexual activity
 Lab evaluation: CBC, CMP, CPR, UA, blood culture
 CSF: opening pressure, cultures, cytology
 Fungal, AFB, mycobacterial cx if appropriate
 CSF gram stain, PCR, antigen testing, serology
 Other studies: Imaging, EEG, biopsy, I&D
CSF Findings
Normal (<5) or
raised (10-100)
Raised 100 –
Raised 100 –
Cell type
(CSF: serum)
Normal (<0.6) or Decreased <0.4
decreased (<0.4) (or much lower)
Decreased <0.4
Normal (<50) or
up to 100
Raised 100-500
Raised 100 –
General Management
• Neurologic evaluation
Meningeal signs
Severity of coma
Neuro exam (focal deficits, cranial nerves, bulbar tone)
Increased ICP
• Other sites of infection or injury
– Otitis, sinusitis, PNA
– Rashes or skin lesions
– Trauma
General Management
• Consider intubation if GCS <8 or bulbar hypotonia
– Take care to minimize ICP spikes
– Consider thiopental, propofol, ketamine (becoming more accepted
for high ICP), lidocaine
– Modified RSI, avoid overventilation
• Get antibiotics going early and at high doses!
• Cardiovascular support as needed
General Management
• Consider ICP monitoring for moderate to severe ICP
– Level of consciousness correlates well with decreased cerebral
– M&M are inversely related to CPP
• Control seizures with benzodiazepenes
– About 50% of patients with seizures progress to status
– Status is hard to treat and has poor outcome
General Management
• Electrolyte and fluid derangements are common
– At risk for diabetes insipidus
– Do not fluid restrict empirically
– Prospective RCT by Singhi et al found no outcome improvement
with fluid restriction vs. maintenance
• Correct hyponatremia slowly over 36-48 hrs
– 3% if necessary for seizures
• Also at risk for hypokalemia
– GI losses, hemodilution, osmotherapy, diuretics, sepsis
Etiology, Pathophysiology, Diagnosis, Treatment,
Bacterial Meningitis: Etiology
*There are 3 main bacterial meningeal
1. Haemophilus influenzae
2. Neisseria meningitidis
3. Streptococcus pneumoniae
*Incidence varies by region and age.
Haemophilus influenzae
• Small GN, pleomorphic,
• H. flu type B causes almost
ALL invasive disease
• Nontypeable Hib can
rarely cause meningitis.
• Incidence of Hib decreased
by 97% after vaccine
Neisseria meningitidis
 - GN diplococci
 - Serotypes A,B,C,Y, and
W135 cause most invasive
 - Virulence depends on:
1. Capsular
2. LPS(endotoxin)
3. Pili
4. IgA protease
5. ompS gene
Streptococcus pneumoniae
 * Small, non-motile GPC in
pairs or chains.
 * 8 serotypes cause 90% of
invasive disease.
 1, 4, 6, 9, 14, 18, 19 & 23
 * Virulence depends on
capsular polysaccharides
 * Associated with CSF leak
(skull fractures), asplenia,
HIV, cochlear implants
Other Pathogens: GN bacilli
• Neonatal GN sepsis/meningitis is most commonly due to
– K1 capsular polysaccharide antigen is a marker of neurovirulence
• Outside of neonates, GN meningitis is often nosocomial
– Associated with GI infections, head trauma, NS procedures, immune
– Klebsiella, Salmonella, Enterobacter, and Pseudomonas
Klebsiella Ventriculitis/Abscess
Other Pathogens: GBS
• Still a common cause of invasive neonatal disease
• Six main serotypes: Type III causes most neonatal
• Incidence is down in developed countries due to screening
and treatment of pregnant women
GBS Meningitis with Infarcts
Other Pathogens: Listeria
• Listeria monocytogenes is a Gram positive rod and still an
important cause of neonatal sepsis
• Can also be seen in older children with cellular immune
• Associated with maternal consumption of unpasteurized
cheese or contaminated meats
Other Pathogens: Anaerobes
 * Anaerobic meningitis occurs in only in certain conditions
Rupture of brain abscess
Chronic otitis, mastoiditis, sinusitis
Head trauma, NS procedures
Congenital dural defects
GI infections, suppurative pharyngitis
CSF shunts
Immune suppression
 * Includes Bacteroides fragilis, Fusobacterium spp.,
Clostridum spp
 * With acute CNS infection there is loss of autoregulation:
 Early increase in CBF, followed later by a decrease
 At risk for global cerebral hypoperfusion
 * Focal hypoperfusion can result from vasculitis leading to
 Can occlude large vessels: carotid, MCA, ACA
 * Cerebral edema can be vasogenic, cytotoxic, or interstitial
 Interstitial edema is the main cause of obstructive hydrocephalous in
Cerebral Edema
Clinical Presentation
• Depends on the age of the patient and the offending
– Generally more abrupt onset than viral
• Infants have a variable presentation
– Fever, poor feeding, lethargy, irritability, high-pitched cry, full
• Older children may have acute onset of fever, HA, vomiting,
photophobia, and altered mental status
– +/- Kernig or Brudzinski sign
Clinical Presentation
 *Seizures may be the
presenting feature in nearly 1
in 6 children
 Have a low index of suspicion
with seizures + fever
 *Papilledema is uncommon at
 *Focal signs can be found in
14% of cases
 Sudural epyema, cortical
infarction, cerebritis
 *Rashes are not uncommon
 Petechial or purpuric rash
highly suggests
 * Definitive diagnosis is by analysis and culture of the CSF
 LP should be done at earliest opportunity
 Do not delay antibiotics – may alter culture and gram stain but
chemistry or cells
 * WAIT on the LP if:
 Evidence of raised ICP (pupil changes, cushing’s, kussmaul pattern,
deep coma), focal neuro exam, resp/CV instability, coagulopathy
 Get a head CT if there is focality or question about diagnosis
• CSF findings include high opening pressure, pleocytosis, low
glucose, and high protein
– Cloudy CSF with high opening pressure is diagnostic
– Glucose ratio of 0.4 is 80% sensitive and 98% specific
• CSF WBC (predicted) = CSF RBC x (blood WBC/blood
– Observed CSF WBC/ predicted <0.01 and WBC/RBC ratio of <0.01
are 100% reliable in ruling out bacterial meningitis
• Gram stains are quick, cheap, and accurate
– 90% strep, 86% H. flu, 75% neisseria, 30% Listeria
• CSF culture will be positive in the majority of untreated
• Empiric diagnosis can be made if:
– CSF WBC > 300, with >60% poly’s
– Glucose < 50% of serum
– Absolute glucose < 30
Diagnosis: Viral vs. Bacterial
 * Latex agglutination
 Helpful in partially treated meningitis
 Specific but not that sensitive
 Strep pneumo – 96% specific, 70 -100 % sensitive
 * PCRs are available for neisseria and pneumococcus
 Both are sensitive and specific
 DNA load correlates with mortality for neisseria
 Very expensive
 * CRP may be helpful but only if very high or very low
 * Peripheral WBC, CSF lactate, limulus amebocyte lysate,
procalcitonin, and various cytokines are up in the air
Raised ICP
Subdural empyema
Brain abscess
Hydrocephalous, ventriculitis
Cranial nerve involvement
Sensorineural hearing loss
Treatment: By Age
Common pathogens
Antimicrobial Therapy
< 1 month
GBS, E. coli, Listeria,
Amp + cefotaxime or an
1-23 months
S.pneumoniae, N. meningitidis, Vanc + 3rd gen
GBS, H.flu, E.coli
2-50 years
N. meningitidis, S. pneumoniae Vanc + 3rd gen
> 50 years
S. pneumoniae, N.
meningitidis, Listeria, GN
Vanc + amp + 3rd gen
Treatment: Head Trauma
Type of Trauma
Antimicrobial Therapy
Basilar skull fracture S.pneumo, H.flu, group A
Vanc + 3rd gen ceph
Penetrating trauma
S.aureus, coag-neg staph,
GN bacilli (Pseudomonas)
Vanc + cefepime,
ceftaz, or meropenem
GN bacilli, S. aureus,
coag-neg staph
Vanc + cefepime,
ceftaz, or meropenem
CSF shunt
Coag-neg staph, GN
bacilli, propionibacterium
Vanc + cefepime,
ceftaz, or meropenem
Duration of Therapy
Length of Treatment
Neisseria meningitidis
7 days
Strep pneumoniae
10-14 days
GBS, Listeria, GN’s
3 weeks minimum
Other Considerations
• In developing countries, ampicillin and chloramphenicol are
sometimes used due to the high cost of cephalosporins
– Increasing resistance of H.flu to ampicillin, but it is via B-lactamase
– Remember that strep and meningococcus resistance is by alteration
of penicillin binding proteins
• Meropenem and newer fluoroquinolones are as effective as
cephalosporins, but still are not 1st line
– Meropenem is good for ESBLs
Other Considerations
• With treatment CSF culture and Gram stain will become
negative in 24-48 hours
– Glucose will normalize in 72 hours
– Cells and protein take days
• Fever may persist for 7-10 days (H.flu), but beyond this
consider other factors
– Thrombophlebitis, spread of infection, empyema, drug fever
– A recurrence of fever may also indicate a complication or a
secondary nosocomial infection
Do we need a repeat LP?
• Repeat LP’s are not routinely necessary if the patient gets
better and is afebrile
– EXCEPT for neonatal GN meningitis
• Consider repeat LP in these situations:
– No clinical improvement after 3-4 days of abx
– NEW focal neuro signs, AMS, or increased ICP
– Initial culture had resistant/weird bugs and no improvement after
24-48 hrs of appropriate therapy
Should we give steroids?
 * Inflammatory cascade in bacterial meningitis leads to tissue
damage and can worsen neurologic sequelae
 Antibiotics make this worse
 * Steroids can decrease inflammation, ICP, cerebral edema, and
CSF outflow obstruction
 * Dexamethasone given to patients with H.flu or pneumococcal
meningitis has shown benefit
 * The AAP recommends its use in H.flu meningitis
 0.4 mg/kg q12h x 2 days
 * Adult guys give it when strep pneumo is suspected
 Consider adding rifampin?
 * The benefits of steroids have NOT been established in neonatal
• Mortality continues to be as high as 15-20%
• Coma, raised ICP, seizures, and shock are significant
predictors of morbidity and mortality
• Neurologic sequelae are common
– Hydrocephalous, spasticity, vision/hearing loss, cognitive defects,
developmental delay
• Isolation is necessary for H.flu and Neisseria for the first 24
hours of treament
• Rifampin prophylaxis is indicated for household contacts of
H.flu if any of them is unvaccinated and <4yrs old
• Rifampin is also recommended for household and daycare
contacts of Neisseria
– Single oral dose of cipro or azithro is ok for adults
• H.flu vaccine is awesome and has virtually eliminated H.flu
meningitis in developed countries
• Heptavalent pneumococcus vaccine is good too
– Don’t forget kids with asplenia, nephrotic syndome, sickle cell, and
cochlear implants need 23-valent
• Quadrivalent meningococcal vaccine (A, C, Y, W135) is
recommended for high risk kids > 2 yrs and college