Pediatric Critical Care MedicineEmory University

Children’s Healthcare of Atlanta

CNS Bacterial Infections

Introduction• 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 mortality

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 connectivity• 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 development– 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

Pathogenesis• 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 SyndromesSyndrome Signs and Symptoms Pathogen

Acute Meningitis Acute onset of fever, HA, vomiting, meningismus, AMS

Progression over hours to days

Bacteria, viruses

Subacute or Chronic

Meningitis

Gradual onset, lower fever, progression over weeks

Tuberculous, fungal

Acute Encephalitis

Diffuse: AMS and seizures Focal: tropism of virus for

specific CNS location (HSV)

Viruses

Encephalopathy w/ Systemic

Infection

Symptoms vary, often AMS.Chorea?

Shigella, typhoid, malaria,

Rickettsia, endocarditis

Postinfectious Various, depending on lesionADEM, transverse myelitis,

optic neuritis, MS

Viruses, vaccines

DiagnosisThorough history and physical exam are very

important!Note chronicity of symptoms, comorbid conditions,

preceding illnesses, VP shuntTravel, surgery, trauma, sick contacts, insect bites,

animal contact, sexual activityLab evaluation: CBC, CMP, CPR, UA, blood culture

CSF: opening pressure, cultures, cytologyFungal, AFB, mycobacterial cx if appropriateCSF gram stain, PCR, antigen testing, serology

Other studies: Imaging, EEG, biopsy, I&D

CSF FindingsCharacteristics

Viral Bacterial Tubercular

WBC/mm3 Normal (<5) or raised (10-100)

Raised 100 – >1000

Raised 100 – 1000

Cell type Lymphocytes Neutrophils LymphocytesGlucose(CSF: serum)

Normal (<0.6) or decreased (<0.4)

Decreased <0.4 (or much lower)

Decreased <0.4

Protein Normal (<50) or up to 100

Raised 100 – >500

Raised 100-500

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 elevation– Level of consciousness correlates well with decreased

cerebral perfusion– 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

BACTERIAL MENINGITISEtiology, Pathophysiology, Diagnosis, Treatment,

Outcome

Bacterial Meningitis: Etiology*There are 3 main bacterial meningeal pathogens:

1. Haemophilus influenzae2. Neisseria meningitidis3. Streptococcus pneumoniae

*Incidence varies by region and age.

Haemophilus influenzae• Small GN, pleomorphic,

coccobacilli• 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 disease.

- Virulence depends on:1. Capsular

polysaccharide2. LPS(endotoxin)3. Pili4. IgA protease5. 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 E.coli – 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 deficiency– 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 meningitis• 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 deficiencies• Associated with maternal consumption of

unpasteurized cheese or contaminated meats

Other Pathogens: Anaerobes* Anaerobic meningitis occurs in only in certain

conditionsRupture of brain abscessChronic otitis, mastoiditis, sinusitisHead trauma, NS proceduresCongenital dural defectsGI infections, suppurative pharyngitisCSF shuntsImmune suppression

* Includes Bacteroides fragilis, Fusobacterium spp., Clostridum spp

Pathogenesis

Pathophysiology* With acute CNS infection there is loss of

autoregulation: Early increase in CBF, followed later by a decreaseAt risk for global cerebral hypoperfusion

* Focal hypoperfusion can result from vasculitis leading to ischemiaCan occlude large vessels: carotid, MCA, ACA

* Cerebral edema can be vasogenic, cytotoxic, or interstitialInterstitial edema is the main cause of obstructive

hydrocephalous in meningitis

Cerebral Edema

Clinical Presentation• Depends on the age of the patient and the

offending organism– Generally more abrupt onset than viral

• Infants have a variable presentation– Fever, poor feeding, lethargy, irritability, high-pitched

cry, full fontanelle• 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 childrenHave a low index of

suspicion with seizures + fever

*Papilledema is uncommon at presentation

*Focal signs can be found in 14% of casesSudural epyema, cortical

infarction, cerebritis*Rashes are not

uncommonPetechial or purpuric rash

highly suggests meningococcemia

Diagnosis* Definitive diagnosis is by analysis and culture of

the CSFLP should be done at earliest opportunityDo 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

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 RBC)– Observed CSF WBC/ predicted <0.01 and WBC/RBC ratio

of <0.01 are 100% reliable in ruling out bacterial meningitis

Diagnosis• 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 cases• 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 meningitisSpecific but not that sensitiveStrep pneumo – 96% specific, 70 -100 % sensitive

* PCRs are available for neisseria and pneumococcusBoth are sensitive and specificDNA load correlates with mortality for neisseriaVery 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

Complications• Raised ICP• Seizures• Subdural empyema• Infarcts• Cerebritis• Brain abscess• Hydrocephalous, ventriculitis• Cranial nerve involvement• Sensorineural hearing loss

Treatment: By AgeAge Common pathogens Antimicrobial

Therapy< 1 month GBS, E. coli, Listeria,

KlebsiellaAmp + cefotaxime or an aminoglycoside

1-23 months

S.pneumoniae, N. meningitidis, GBS, H.flu, E.coli

Vanc + 3rd gen cephalosporin

2-50 years N. meningitidis, S. pneumoniae

Vanc + 3rd gen cephalosporin

> 50 years S. pneumoniae, N. meningitidis, Listeria, GN bacilli

Vanc + amp + 3rd gen ceph

Treatment: Head TraumaType of Trauma Pathogens Antimicrobial

TherapyBasilar skull fracture

S.pneumo, H.flu, group A strep

Vanc + 3rd gen ceph

Penetrating trauma

S.aureus, coag-neg staph, GN bacilli (Pseudomonas)

Vanc + cefepime, ceftaz, or meropenem

Post-neurosurgery

GN bacilli, S. aureus, coag-neg staph

Vanc + cefepime, ceftaz, or meropenem

CSF shunt Coag-neg staph, GN bacilli, propionibacterium acnes

Vanc + cefepime, ceftaz, or meropenem

Duration of TherapyOrganism 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 production– 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 sequelaeAntibiotics 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 meningitis0.4 mg/kg q12h x 2 days

* Adult guys give it when strep pneumo is suspectedConsider adding rifampin?

* The benefits of steroids have NOT been established in neonatal meningitis

Prognosis• 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

Prevention• 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

Prevention• 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 students/military

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