CNS Bacterial Infections

Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta

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 26-2 8 • 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 Syndromes

Syndrome

Acute Meningitis Subacute or Chronic Meningitis Acute Encephalitis Encephalopathy w/ Systemic Infection

Signs and Symptoms

Acute onset of fever, HA, vomiting, meningismus, AMS Progression over hours to days Gradual onset, lower fever, progression over weeks Diffuse: AMS and seizures Focal: tropism of virus for specific CNS location (HSV) Symptoms vary, often AMS.

Chorea?

Postinfectious Various, depending on lesion ADEM, transverse myelitis, optic neuritis, MS

Pathogen

Bacteria, viruses Tuberculous, fungal Viruses Shigella, typhoid, malaria, Rickettsia, endocarditis Viruses, vaccines

Diagnosis

   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

Characteristics WBC/mm 3 Cell type Glucose (CSF: serum) Protein Viral

CSF Findings

Bacterial

Normal (<5) or raised (10-100) Lymphocytes Raised 100 – >1000 Neutrophils

Tubercular

Raised 100 – 1000 Lymphocytes Normal (<0.6) or decreased (<0.4) Normal (<50) or up to 100 Decreased <0.4 (or much lower) Raised 100 – >500 Decreased <0.4

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 MENINGITIS

Etiology, Pathophysiology, Diagnosis, Treatment, Outcome

Bacterial Meningitis: Etiology

*There are 3 main bacterial meningeal pathogens:

1. Haemophilus influenzae 2. Neisseria meningitidis 3. 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 polysaccharide 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

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 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

Pathogenesis

Pathophysiology

   * 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 ischemia  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 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 children  Have a low index of suspicion with seizures + fever *Papilledema is uncommon at presentation *Focal signs can be found in 14% of cases  Sudural epyema, cortical infarction, cerebritis *Rashes are not uncommon  Petechial or purpuric rash highly suggests meningococcemia

Diagnosis

  * 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

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 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

Complications

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

Age

Treatment: By Age

Common pathogens Antimicrobial Therapy

< 1 month 1-23 months 2-50 years > 50 years GBS, E. coli, Listeria,

Klebsiella S.pneumoniae, N. meningitidis,

GBS, H.flu, E.coli Amp + cefotaxime or an aminoglycoside Vanc + 3 rd gen cephalosporin N. meningitidis, S. pneumoniae Vanc + 3 rd gen cephalosporin

S. pneumoniae, N.

meningitidis, Listeria, GN bacilli Vanc + amp + 3 ceph rd gen

Treatment: Head Trauma

Type of Trauma

Penetrating trauma

Pathogens Antimicrobial Therapy

Basilar skull fracture S.pneumo, H.flu, group A strep Vanc + 3 rd gen ceph Post-neurosurgery S.aureus, coag-neg staph, GN bacilli (Pseudomonas) GN bacilli, S. aureus, coag-neg staph Vanc + cefepime, ceftaz, or meropenem Vanc + cefepime, ceftaz, or meropenem CSF shunt Coag-neg staph, GN bacilli, propionibacterium

acnes

Vanc + cefepime, ceftaz, or meropenem

Organism

Duration of Therapy

Length of Treatment

Neisseria meningitidis Strep pneumoniae

GBS, Listeria, GN’s 7 days 10-14 days 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 1 st 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 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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