Meningitis

    General Meningitis

    • Two types
      • Acute bacterial meningitis --> Life threatening
      • Viral (aka "aseptic") --> more common and less morbid.
    • Risk factors:
      • Parameningeal focus (otitis media, odentogenic infection, sinusitis)
      • Hematogenous spread from mucosal focus (resp, inf. endocarditis)
      • CNS exposure (penetrating trauma, neurosurgery, shunts)
      • Immunodeficiency (asplenia, odontogenic infection, sinusitis)
      • Contact with others w meningitis.
    • Causes:
      • Bacterial: (Bacterial meningitis)
        • Streptococcus pneumoniae
        • N. meningitidis
        • Listeria
        • Gram negatives.
      • Viral: (Asceptic meningitis)
        • 1. Enteroviruses
        • 2. HSV-1/2
        • 3. Varicella (non-immune)
        • 4. MUMPs, etc...
      • Cryptococcal meningtoencephalitis
        • Cryptococcus neoformans (pigeon droppings).   - IF HIV/Immunocompromised.
          • Can test for cryptococcus CSF antigen titre.
      • Tuberculous meningitis
    • Newborn

      (0-6mo)

      Children

      (6mo-6years)

      6-60y 60+ years

      - GBS

      - E.coli (GNRs)

      - Listeria

      - S. Pneumoniae

      - N. meningitidis

      - H. influenzae B

      - Enteroviruses

      - N. meningitidis

      - S. pneumoniae

      - Enteroviruses

      - HSV

      - S. pneumoniae

      - GNRs

      - Listeria

      - N. meningitidis


      Bacterial

      Immunocopromized/

      Elderly

      Neonates Viral Fungal Other

      S. pneumoniae

      N. meningitidis

      H. influenzae

      S. pneumoniae

      N. meningitidis

      L. monocytogenes

        (Listeria)

      GBS

      E.coli

      Legionella

      enteroviruses

      HIV

      HSV-2

      West  Nile

      Cryptococcus

      Coccidiodomycosis

      Lime Disease

      Neurosyphilis

      TB

    • HIV: Cryptococcus, CMV, HSV, VZV, TB, toxoplasmosis (brain abscess), and JC virus (PML)
    • History/Exam
      • Cardinal Features:
        • Generalized, Severe Headache
        • Neck Stiffness (meningeal inflammation - muscle spasms)
        • Vomiting
        • Depression of mental status
      • Other features: Fever, malaise, headache, neck stiffness, photophobia.
        • Altered mental status, nausea/vomiting, seizures
      • NOTE: absence of 1. fever, 2. neck stiffness 3. altered mental changes rules out dx
        • Fever: highest sensitivity
        • If jolt extentuation: do LP
      • Signs of meningeal irritation:
        • Nuchal rigidity  (30% sensitivity)
          • Inability to forward flex neck against rigid/tight neck muscles (ask chin to chest). 
        • Jolt Accentuation of H/A -  (97% sensitivity)
          • Headache worsens when head turned horizontally at 2-3 Hz.
          • Exacerbation of headache with sudden head movement.
        • Kernig's Sign:  (OBSOLETE! 5-9% sensitivity)
          • Lying supine, flex hip to 90°, but then pain when extend knees (leads to resistance)
            • Also positive in subarachnoid hemorrhage.
        • Brudzinski's Sign:  (OBSOLETE!!! 5-9% SENSITIVITY)
        •     Involuntary flexion of hip + knees when examiner flexes patient's neck in supine position.
        • kernigBrudz.png  (A - Kernig's, B - Brudzinski's)
        • Also look for sources of meningitis:
          • Ear --> AOM (S. Pneumo, H. influ)
          • Pharynx --> N. meningitidis
          • Nose --> CSF leak?
          • Cardiac --> diastolic aortic insufficiency murmur --> bact. endocarditis --> likely S.aureus
          • Lung (CSR) --> pneumonia --> S. pneumo
          • Skin --> purpuric lesions.  Petechiae and purpura:
            • Meningococcemia (most common)
            • Endocarditis - S. aureus
            • Echovirus 9
            • Rickettsia
            • If asplenic, can get petechial lesions from DIC caused by:
              • Pneumococcal and H. influ.
          • Neuro (GCS for prognosis)
            • Cranial nerves (Lateral gaze palsy due to VI nerve common in high ICP)
            • Focal lesions uncommon.  --> mass lesion?
            • fundoscopy --> high ICP.
        • Very young and old present atypically (old: mental status change, stiff neck from OA, etc..)
          • Fever, altered status are good predictors for suspicion.
    • Investigations:
      • CBC w diff, blood C&S, electrolytes (for SIADH)
      • LP  (in absence of papilledema or focal neuro findings)
        • CSF Cell count + differential (include RBC count)
        • CSF Glucose and protein
        • CSF Opening pressure  (in bacteria, almost always elevated)
        • CSF Microbiology
          • Gram stain
          • C&S
          • PCR (if suspected viral)
          • Mycobacterial +fungal culture.
      • CT, MRI, EEG if focality present

    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

    Bacterial Meningitis

    • One of the most feared and dangerous infectious diseases that a physician can encounter.
      • TRUE INFECTIOUS DISEASE EMERGENCY
      • Minutes make the difference between life and death!
      • NO TIME to look through text books for appropriate management: NEED TO KNOW MANAGEMENT!!!
    • Historic rates at all time low due to vaccines:
      • Haemophilus influenza B vaccine in kids.
      • Pneumococcal vaccine in >65 and chronic underlying diseases.

    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.

     

    ---------------------------------------------------------------------------

    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.

    ---------------------------------------------------------------------------

     

    • 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
        •  
      • MeningitisEmpiricTherapy.png
      • 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.

     

    Aseptic Meningitis

    • Defined as:
      • Diagnosis:

             Clinical and laboratory findings consistent with meningitis and normal CSF stains+culture.

    • Organisms:
      • 1. Enteroviruses (aka "non-polio enteroviruses", includes echoviruses, coxsackieviruses)   
               (85-95% of aseptic meningitis)
        • Symptoms: Fever, Headache, Nuchal Rigidity (50%), Photophobia.
        • Typically summer and fall and spread by fecal-oral route.
        • Most commonly children/infants, but also most common in adults.
        • Typically <7 days, recover rapidly!
      • 2. HSV-2   (0.5-0.3% of cases of AM)
        • Often accompanied by skin lesions in genital area.
        • Benign Recurrent Lymphocytic Meningitis (10 episodes lasting 2-5days and spontaneous recovery. (Aka Mollaret's aseptic meningitis)
        • Often recover without therapy spontaneously. (unclear if antivirals alter course of mild infection)
      • 3. West Nile Virus
        • Typically causes encephalitis, but <1% can get meningitis.
      • 4. MUMPs      (If non-immune, children 5-9y of age).
        • Fever, vomiting, headache.
        • 50% have salivary gland enlargement.
      • 5. Other:
        • Mononucleosis (CMV, EBV)
        • HIV virus
    • Symptoms:
      • Fever
      • Headache
      • Nuchal Rigidity (50%)
      • Photophobia
      • No LOC
      • Maculopapular Rash - echovirus (some strains)
      • Conjunctivitis (enterovirus)
    • LP:
      • Lower Opening Pressure
      • Leukocyte count 50-1000 /mcL, normal glucose, slightly elevated protein.
      • Sometimes early in presentation: can have high PMNs (instead of leuks), and mild glucose drop.
        • Can repeat LP in 12-24 hours --> if shows lymphocytic predominance, can send home.  Otherwise keep in abx.
        • Negative bacterial culture at 48hrs. --> bacterial meningitis highly unlikely.
        • CSF tests:
          • PCR for enteroviruses (PCR 86-100% sensitive, 90-100% specific).
          • HSV2 PCR. (especially if Benign recurrent lymphocytic meningitis).
          • West Nile - West Nile IgM in CSF.
        • Viral cultures in CSF: unsensitive for dx, not recommended.
    • Self limiting - resolves in 7-10 days.
      • Enteroviruses: Supportive.
      • Can use antiviral therapy in HSV-2 meningitis (unclear if benefit)

    Tuberulous Meningitis

    • Usually during miliary TB
    • No pulmonary disease in 25%
    • Meningitis:
      • Basilar process involving pons and optic chiasm
      • Deficits of 3rd, 4th, and 6th cranial nerves common.
      • Non-communicating hydrocephalus.
    • CSF:
      • (see table)
      • WBC <500, lymphocytes, protein <500mg/dL, glucose < 2.5 mmol/L (units messed)
    • Treat:
      • Isoniazid
      • Rifampin
      • Pyrazinamide
      • and corticosteroids for hydrocephalus.

    Cryptococcal Meningoencephalitis

    • Cryptococcus neoformans
      • Pigeon droppings.
      • Inhaled --> blood stream --> brain&meninges.
    • Organism:
      • Cryptococcus contains a capsule with negatively charged polysaccharides that are immunosuppressive.  They block cell mediated immune responses and leukocyte migration.
      • Highly virulent strains produce melanin (use dopamine in CNS as substrate)
      • Some produce mannitol to induce cerebral edema and inhibit phagocyte function.
    • Hosts:
      • Rarely healthy pts.
      • AIDS/HIV
    • Often waxy/wany course.  Symptoms:
      • Headache --> mild confusion --> personality changes --> stupor -->coma  crypto.jpg
      • "Basilar meningitis" (like TB)
        • Involves pons, optic chiasm --> dysfunction III, IV, and VI cranial nerves.
      • Initial presentation non-specific.
    • DX:Need CSF:
        • Microscopy - india ink (double refractile capsule), budding yeast forms.
        • Cryptococcal Polysaccharide Antigen (sensitivity?poor?)
        • Culture - need to culture large volumes of CSF to increase sensitivity. (5-7d)
    • Treatment:
      • If no AIDS:
        • Amphotericin B (0.5-0.7 mg/kg daily) (lipid preparations: 5mg/kg daily)
        • AND Flucytosine (100-150 mg/kg daily divided QID).
        • 3-6mo consolidation therapy.
        • Continue until CSF cultures are sterile (need to repeat culture)
      • Mortality: 25-30% (no HIV)
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