Meningitis

CSF Interpretation

• Send CSF for:
  • Tube #1 - Cell Count and Differential (Includes RBC, WBC, and Diff)
    • Xanthochromia (yellow bilirubin pigment of CSF) implies recent bleed
  • Type #2 - Chemistry (Glucose, Protein)
  • Tube #3 - Microbiology (Gram Stain + C&S)
  • Tube #4 - Cytology (Malignant cells)
  • Tube #5 - RBCs (Compare to tube 1)
    • If RBC in Tube 1 >> RBC in Tube 2 => traumatic tap.  (IF equal then SAH).

• 	Normal	Bacterial Untreated	Tuberculous, fungal or Bact. Treated	Viral
  Appearance	Clear	Normal/Cloudy	Opaque yellow	Normal/cloudy
  Glucose (mmol/L)	~2/3 of serum (ratio 0.4-0.5)	ratio <0.4 of serum.   Often less than 25% of serum glucose or <2.2 (bad outcome =<1.4)	Low	Normal  >0.4 ratio (>2.5mmol/L  >45 mg/dL)
  Protein (g/L) [Most Sensitive]	Newborns: <1.5g/L Adults: <0.45 g/L	Markedly Increased (150-1000 g/L)	Moderately elevated (80-500 g/L)	Mod. elevated (0.45-150 g/L)
  WBC (count x106/L) or (count /uL)	Newborns: <20 Adults: <5	1000-5000 87% will have >1000 99% will have >100		50-1000 <100 common
  Predominant WBC	70% Lymphocytes 30% Monocytes	Neutrophils (PMN)	Lymphocytes	Lymphocytes (PMNs can be in first 6-48hrs)
  RBC	0
  Opening Pressure (mmH2O)	VARIES! Kids: 10-100 >8yo: 50-200 - Obese: up to 250 mmH2O >600= cerebral edema	200-500 mmH2O		≤250 mmH2O
  Gram Stain Culture		Gram Stain: Positive 60-90% Culture: Positive 70-85% (cltre neg if abx given prior)		Negative

• Protein
  • Most sensitive for pathology.
  • Elevated: Infection, ICH, Guillian Barre, malignancies, some endocrine abnormalities, meds, inflammatory conditions.
  • Decreased in: Repeated LP, or chronic CSF leak.
• WBC Count
  • Normal <20 /mm^3 (newborns) and <5 /mm^3 (adults)
  • 87% bacterial meningitis will have WBC >1000/mm^3
  • Elevated after seizure, ICH, malignancy
• WBC Differential
  • Normal: 70% Lymphocytes, and 30% Monocytes.
  • Cannot distinguish bacterial from non-bacterial!  (i.e. 10% of bacterial meningitis has lymphocytic predominance)
  • Eosinophils >10%: consider fungal, rickettsial, etc..
• Other Tests for Encephalitis
  • HSV1, HSV2, VZV, CMV, EBV, enterovirus

Symptoms

• Fever
• Headache
• Stiff Neck
• Cerebral Dysfunction (confusion, delirium, decreased LOC).

Diagnosis

• Gold standard is LP (see table above).
• PCR: sensitivity 92-100%, specificity 100% for pneumococcal meningitis (not used, false positives, used if culture negative)

Mechanism

• Most commonly blood-borne.
• Primary infections of ears, sinuses, throat, lungs, heart and GI tract
  • --> bactermia --> large venous sinuses in brain --> meninges.
• Sometimes bacteria can enter through the cribriform plate
• Sometimes with trauma/ basal skull fracture primary S. pneumoniae can track up the CSF leak into subarachnoid space and cause abscess.. --> meningitis.
• BBB blocks entry of Ig and complement.  Bacteria spread FAST.
• PMN leukocytes enter the site, kill organisms, sometimes lyse, releasing toxic O2 products, proteolytic enzymes, and inflammatory cytokines  --> necrosis, edema.
  • Infammation damages microvasculature, increases permeability of BBB.
  • Serum leakage from damaged vessels into CSF --> High CSF Protein.
  • Inflammation at surface of cerebral cortex --> vasculitis --> small vessel occlusion --> Cerebral Infarction
  • Arachnoid and pia matter inflammation, decr glucose transport --> Low CSF glucose
  • Ultimate! --> intense inflam --> damage neural cells --> cerebral edema --> increased ICP --> decreased cerebral blood flow --> cerebral cortex hypoxia --> irreverrsible ischemic damage.

• FOUR major organisms.

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1. Streptococcus pneumoniae
   • Most common community-acquired meningitis,
   • 70% have otitis media/sinusitis/pneumonia/skull fracture, or immunocompromised
     (splenectomy/asplenia/hypogammaglobulinemia/MM/alcoholistm/CKD/malignancy/HIV)
   • Causes infections of ear, sinuses, lungs --> hematogenously seeds meninges.
   • Commonly CSF leak following head trauma.
   • Vaccine (esp 7-valent pneumococcal vaccine) decreased rates.
2. Neisseria meningitidis
   • Most often children and young adults.  (terminant complement def. C5-9)
   • Infects nasopharynx --> sore throat.
   • If lacks antibodies --> hematogenous seeing of meninges.
   • Crowded environments (college dormitories or military training facilities increase risk of N. meningitidis)
     • Epidemics in winter months, person-to-person tranmission via secretions.
3. Listeria monocytogenes
   • Infects primarily pts with depressed cell-mediated immunity:
     • neonates, immunosuppressed pts, HIV, and elderly >50 (pregnant).
     • Other RF's: DMII, EtOH, CKD, liver disease, transplant, anti-TNFi.
   • Sources:
     • Ingesting contaminated food. (esp if prolongued storage at 4° b/c organism can grow in cool environment)
     • Can contaminate unpasteurized soft cheeses, coleslaw, meats, and dairy. (hot dogs and fish)
   • Silently invades GI tract --> enters blood stream --> infects meninges.
   • Intra-cellular organisms - can cause negative gram stain, and lower percentage of PMNs. 
4. Haemophilus influenzae
   • Was common in kids
   • No uncommon due to HiB vaccine (late 80's)
   • Suggests: Sinusitis, otitis media, epiglottitis, pneumonia, DMII, EtOH, spleen disorders, CSV, hypogammaglob.

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• Note on Neonatal Meningitis
  • Most commonly contacts organisms in birth canal:
    • E. coli
    • Group B Strep (Strep agalactiae), screen at 35-37w, antimicrobials for carriers.
• Note on Nosocomial Meningitis
  • Following neurosurgery / head trauma:  (Gram negative meningitis)
    • Gram negative rods (commonly E.coli, Klebsiella, Serratia, Pseudomonas)
    • rarer: Staph aureus, streptococci
  • Ventricular shunt:  (Skin stuff)
    • S. aureus
    • S. epidermitis (CNSt)
    • Gram Negative Rods: Pseudomonas
    • Propionibacterium acnes (AnG+rod) - if internal ventricular drains.
    • B. subtilis
    • Corynebacteria (diphtheroids)
• Note on Recurrent Bacterial Meningitis
  • 1-6% of community acquired meningitis. (common head trauma, CSF leak, immunodefficiency). 

• Organism	Community (%)	Nosocomial (%)
  Streptococcus pneumoniae	38	8
  Gram-negative bacilli	4	38
  Neisseria meningitidis	14	1
  Listeria spp.	11	3
  Streptococci	7	12
  Staphylococcus aureus	5	9
  Haemophilus influenzae	4	4

Treatment

• Algorithmic Approach:

  • If Suspect Meningitis:   Step 1: Does the patient have a contraindication to LP? (high ICP risk factors) or INR > 1.5. Risk Factors for high ICP: Seizure Focal Neurological Deficit Immunocompromised (steroids, HIV, transplant) Papilledema Mod-to-severe impaired LOC Other: (hx of CNS disease, etc..)  If Risk factors present (high risk of uncal herniation): Get blood cultures + CT Scan FIRST! Often start antibiotics right away (do not delay, waiting for CT). IF CT head negative --> do LP (then determine if acute bacterial meningitis). Step 2: if no contraindications, draw stat Blood cultures and LP. Step 3: IMMEDIATELY after LP Adjunctive dexamethasone. (empiric for pneumococcal meningitis) Empiric antibiotics (based on age, underlying condition).

    
     
  • NOTE: Try to get LP before starting antibiotics, but if you have to wait for CT.. start antibiotics.
    If antibiotics are delivered first, should still be able to interpret LP for the most part.
     

• Signs o f Impending Herniation

  • Decreased LOC (especially GCS < 11).

  • Brain stem signs (pupillary changes, posturing, respiratory changes, seizure)

     

• Empiric abx

        (Often max doses for good penetration)

  • GENERAL PRINCIPLES:
  • Neonates (<1mo old): ampicillin +/- cefotaxime if >7days old
  • Infants/Children/Adults: (Strep pneumo + Neisseria meningitidis common)
    • ceftriaxone 2g IV q12h (all other organisms)   (or cefotaxime)
      • + vancomycin 1g IV q12h if person is extremely ill (for pen resistant strep pneumo)
      • • +/- max ampicillin 2g IV q4h for Listeria if >50years, alcohol, homeless, immunecopromised.  (Listeria not sensitive to 3rd gen cephalosporins, only sensitive to penicillin and ampicillin)
    • If any sort of immunocompromise:  (also worry about gram negatives and pseudomonas)
      • Use vancomycin, ampicillin, carbapenem (i.e. meropenem, or can use cefepime)
  • Neurosurg:  (Cover S. aureus, or CNSt, Gram negatives, pseudomonas, dipthroids)
    • Vancomycin, ceftazidime/cefepime/meropenem.
  • Rifampin + vanco for high pen-resistant S. pneumo.
    • Vancomycin isn't best at CSF penetration.  
    • Esp if on steroids decr. inflammation, and decr BBB permeability
    •  
  • 
  • NOTE: 3rd Generation cephalosporin = ceftriaxone or cefotaxime.
     
• DO NOT USE - do not cross BBB
  • Aminoglycosides, erythromycin, clindamycin, tetracyclines, and 1st gen cephalosporins
     

• Dex amethasone

  • 10mg (0.15mg/kg) IV q6h x4days started before or with first dose of abx in bacterial meningitis

  • Mostly for acute pneumococcal meningitis
  • Kids esp. H.influenzae: 0.15 mg/kg q6h x4 days.  Reduces CSF pressure, helps reduce neuro damage.
  • Adjunctive steroids shown to decrease morbidity/mortality (less inflammation, less ICP, more glucose, less neuro damage)
    • Can also protect against hearing loss.
  • Give just before or with abx (abx bacterial lysis = more inflammation)
  • NOTE: with vancomycin, b/c delivering dexamethasone (decreases inflammation) reduces vancomycin penetration (better CNS penetration in inflammation), so ensure that vanco troph levels are 15-20.
     

• Targeted Th erapy

  • Once gram stain comes back...

  • Organism	Therapy
    Streptococcus pneumoniae (Gram + diplococci)	Vancomycin + 3rd gen cephalosporin (ceftriaxone or ceftazidime)
    Neisseria meningitidis	3rd gen cephalosporin
    Listeria	Ampicillin or Penicillin G  (gentamycin can be used for synergy)
    H. influenza type b	3rd gen cephalosporin

  • In-vitro susceptibility testing.. modify regimen, check the MIC levels (cutoffs come from mice testing).

• Repeat Cul tures

  • Repeat lumbar puncture in 36-48hrs recommended to document CSF sterility for those receiving adjunctive dexamethasone + vanco+ceftriaxone for pts with pneumococcal meningitis who:

• Do not improve as expected
  OR

• Have cefotaxime or ceftriaxone MIC > 2.0 mcg/mL

• Discharge Criteria

1. Completion of inpatient therapy for >6 days.
2. Absence of fever for >24-48hrs.
3. No significant neurologic dysfunction, focal findings, or seizure activity
4. Clinical stability of improving infection
5. Ability to take fluids by mouth.
6. Access to home health nursing for antibiotics.
7. Reliable IV line and infusion device.
8. Daily physician availability
9. Plan for physician visits, nurse visits, laboratory monitoring, emergencies.
10. Patient and/or family compliance.
11. Safe environment for access to telephone, utilities food and fridge.

• Other Points

• Additional prevention of cerebral edema and seizures
  • No hypotonic solutions
  • Protect airway, do not hypoventilate (low PaCO2 --> vessel dilatation --> increased ICP)
    • Do not hyperventilate (high PaCO2 --> cerebral vessel constriction --> less cerebral blood flow).
  • If high ICP (opening pressure) on LP
    • Can give 20% mannitol to remove water.
  • Seizures common (20-30%), do not give prophylaxis unless had seizure.
     
• Prevention:
  • children: immunization against
    • H. influenzae (Pentacel)
    • S. pneumoniae (Prevnar)
    • N. meningitidis (Menjugate or Menactra)
  • Prophylaxis: rifampin or cipro for household or close contacts of H.influ and N.meningitidis.

Complications

• Headache, seizures, cerebral edema, hydrocephalus, SIADH, residual neuro deficit (esp CN VIII), deafness, death.
• Mortality:
  • 26% Listeria
  • 19% with Strep Pneumo
  • 13% N. meningititus
  • 3% H. influenza.
• Young: mental retardation, CP, seizure disorders, neuro changes, hearing loss.

Prevention

• HIB Vaccine (H. influenzae Type B)
• Meningococcal vaccine (Serogroups A, C, Y, and W135).  In Canada only C.
  • Recommended for high risk:
    • Military recruits
    • College students
    • Asplenic patients
    • Terminal complement deficiencies
  • Problems:
    • Only to Group C
    • Titres drop after 3 years of a single dose.
    • Hence, B/C incidence is low, not recommended as routine.
• Pneumococcal 23-valent?  in canada only C?
  • >65yo
  • Chronic Disease:
    • Cardiovascular
    • Pulmonary
    • Liver
    • DM
    • Sickle cell
    • Asplenic: Functional Asplenia or Splenectomy.
  • IM Injection... protect for 5-10 years.

Prophylaxis

• H.influenzae -
  • household contacts with at least one unvaccinated child <2years old
    • rifampin 20mg/kg daily for 4 days.
• N.meningitidis  (Controversial)
  • - Close contacts, household members, anyone in contact with secretions (ET tubes, kissing etc.)
    • Cipro 500mg x1 dose.
• Have lot threshold to prophylax.  Easy, and huge impact.