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Meningitis. David A. Wilfret, MD Pediatric Infectious Diseases Duke University Medical Center. Meningitis. Meningitis – Inflammation of the membranes that surround the brain and spinal cord (the dura mater, archnoid mater, and pia mater) Encephalitis – Inflammation of the cerebral cortex

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Meningitis

Meningitis

David A. Wilfret, MD

Pediatric Infectious Diseases

Duke University Medical Center


Meningitis1
Meningitis

  • Meningitis – Inflammation of the membranes that surround the brain and spinal cord (the dura mater, archnoid mater, and pia mater)

  • Encephalitis – Inflammation of the cerebral cortex

  • Meningoencephalitis – Inflammation of the meninges and the cerebral cortex


Pathogenesis
Pathogenesis

  • Bacteria

    • Maternal genital secretions or nasopharyngeal colonization

    • Mucosal invasion and penetration into the blood stream

    • Hematogenous spread through the BBB (choroid plexus) or direct inoculation

  • Virus

    • Upper respiratory tract or gastrointestinal tract

    • Primary viremia

    • Proliferation in other organs (lymph nodes, liver, spleen)

    • Secondary viremia through the BBB

Chavez-Bueno S, Pediatr Clin N Am 52;795-810.


Pathogenesis1
Pathogenesis

  • Inflammation within the subarachnoid space

  • Cell wall or membrane components

    • Gram positive - Peptidoglycan

    • Gram negative - Lipopoly-saccharides

  • Inflammatory mediators

    • TNF-alpha, IL-1, IL-6, IL-8, IL-10, PAF, NO, prostaglandins, and macrophage induced proteins

  • Cerebral edema, increased ICP, and toxic oxygen radicals causing apoptosis

Chavez-Bueno S. Pediatr Clin N Am 52;795-810.


Neonatal meningitis
Neonatal Meningitis

  • Patient is a 3 wk old formerly full-term, vaginal delivery who presents to the ED

  • He has been irritable throughout the day with poor feeding throughout the day

  • One hour prior to arrival, he developed a rectal temperature of 100.6 F

  • In the ED he appears fussy and difficult to console, but otherwise stable

  • On physical examination he has a temperature of 101 F, a flat fontanelle, no nuchal rigidity, and no Kernig’s nor Brudzinski’s sign


Neonatal meningitis1
Neonatal Meningitis

  • Incidence 0.25 – 1 per 1000 live births

  • Risk factors

    • Perinatal and intrauterine infection (T > 100.4oC), prolonged rupture of membranes (> 18 hours), prematurity (< 37 wks), low birth weight, previous infant with GBS disease, maternal urinary tract infection

  • Early and late onset meningitis

  • Neonatal sepsis arises < 1 %,

  • Meningitis 25 % of septic neonates

    • One percent of lumbar punctures


Clinical manifestations neonate
Clinical Manifestations - Neonate

Signs and SymptomsIncidence (%)

Temperature Instability 60

Fussy / Lethargy 60

Poor Feeding and Vomiting 48

Seizures 42

Respiratory Distress 33

Apnea 31

Bulging Fontanelle 25

Diarrhea 20

Nuchal Rigidity 13

Signs of meningitis are often subtle in the neonate

Classic symptoms of meningitis not until 18 – 24 months


What laboratory studies would you order
What Laboratory Studies Would you Order?

  • CBC with Differential

  • Electrolytes and LFTs

  • Urinalysis

  • Cerebrospinal Fluid

    • WBC with Differential

    • RBC

    • Protein

    • Glucose

    • Gram-stain

  • Blood Culture

  • Urine Culture

  • CSF Culture

  • Viral Culture CSF and surfaces

  • HSV and Enterovirus PCR


Laboratory results
Laboratory Results

  • CBC: WBC 8000 cells/mm3, N 60% B 10% L 23%, H/H 11.2 / 30 and Platelets 150,000

  • Electrolytes: CO2 18 and Glucose 80, LFTs normal

  • Urinalysis: Protein 1+, Ketones 1+, Nitrites neg, LE neg, WBC 1, RBC 0, Bacteria 0-5

  • CSF: WBC 120, P 80% L 10% M 10%, RBC 5, Protein 240, Glucose 30

Is this consistent with meningitis?



  • Evaluated 9111 neonates > 34 weeks gestation to establish concordance of CSF culture, CSF parameters, and blood culture in culture-proven neonatal meningitis

  • Thirty-eight percent of neonates with culture-proven meningitis had a negative blood culture

  • Peripheral WBCs were neither sensitive nor specific for bacterial meningitis


Due to the variability in CSF parameters, unable to develop an algorithm to accurately and precisely predict meningitis based on CSF parameters alone


Ten percent of neonates with bacterial meningitis had < 3 CSF WBCs/mm3

A threshold value of 21 cells as the upper limit of normal would have missed 12.6% of meningitis cases

Meningitis can occur in the presence of normal CSF WBC, protein, and glucose levels


Culture results
Culture Results

  • Gram Stain Gram-positive cocci in pairs / chains

  • CSF Culture Group B Streptococcus

  • Blood Culture Negative

  • Urine Culture Negative

  • Virus Culture, Cancelled after Gram-stain Positive

    and HSV and

    Enterovirus PCR


What are the most common organisms that cause bacterial meningitis in neonates
What are the most Common Organisms that cause Bacterial Meningitis in Neonates?

  • Group B Streptococcus (30 – 40 %)

  • Gram-negative enteric bacilli (30 – 40 %)

    • Escherichia coli, Klebsiella, Enterobacter, Salmonella, Serratia marcesans, Citrobacter, and Proteus mirabilis

  • Listeria monocytogenes (10 %)

  • Others include Staphylococcus aureus, viridans streptococci, and coagulase-negative staphylococci


What antibiotics would you empirically start
What Antibiotics would you Empirically Start? Meningitis in Neonates?

Ampicillin

Plus an Aminoglycoside

Or Cefotaxime

Infants (> 1 month)

Vancomycin plus Cefotaxime


Specific therapy
Specific Therapy Meningitis in Neonates?

OrganismAntibioticDuration

GBS

Sensitive Penicillin or Ampicillin 14 – 21 days

L. Monocytogenes Ampicillin plus Aminoglycoside 14 - 21 days

Gram-Negative 3rd Cephalosporin 21 days

Enteric Organisms plus Aminoglycoside 14 days after Negative

Staphylococcus

Sensitive Nafcillin or Oxacillin 21 days

Resistant Vancomycin plus Rifampin


Neonatal complications

Development Delay 26% Meningitis in Neonates?

Hydrocephalus 24%

Ventriculitis 20%

Late Seizure 19%

Cerebral Palsy 17%

Brain Abscess 13%

Hearing Loss 12%

Subdural Effusion 11%

Cortical Blindness <10%

Neonatal Complications

Mortality 15 – 20 %


Meningitis2
Meningitis Meningitis in Neonates?

  • Patient is a 4 year old Hispanic male without past medical history who presents to the ED

  • He complains of fevers (T 103.8 F), headaches, photophobia, neck stiffness, vomiting, myalgias, and drowsiness over the past 24 hours

  • On physical examination, he is febrile (T 102.4 F), but vitals are otherwise stable. He is alert and irritable, but able to cooperate with the examination. He is without focal neurologic signs and there is no rash.


What would you look for on physical examination that is specific for meningitis
What would you look for on Physical Examination that is Specific for Meningitis?

Nuchal Rigidity

Kernig’s Sign

Brudzinski’s Sign


Kernig and brudzinski s sign
Kernig and Brudzinski’s Sign Specific for Meningitis?

Kernig and Brudzinski’s sign present 5% of adults with meningitis

Nuchal rigidity present in 30% of adults with meningitis


What laboratory studies would you order1
What Laboratory Studies Would you Order? Specific for Meningitis?

  • CBC with Differential

  • Electrolytes and LFTs

  • Cerebrospinal Fluid

    • Opening Pressure

    • WBC with Differential

    • RBC

    • Protein

    • Glucose

    • Gram-stain

    • India Ink / Cryptococcal Antigen if Immuno-compromised

  • Blood Culture

  • CSF Culture

  • Viral Culture CSF, Nasopharyngeal, and Perirectal

  • Enterovirus PCR


Would you order a head ct prior to the lp
Would you Order a Head CT prior to the LP? Specific for Meningitis?

  • Head CT should be performed if signs of increased intracranial pressure on physical examination and should not result in delay of blood tests nor start of antibiotics

  • Abnormalities detected on CT scan were already suspected by neurological examination and did not effect clinical management

Signs of Increased Intracranial Pressure

focal neurologic signs, altered level of consciousness, bradycardia, hypertension or hypotension, and altered respiratory pattern (papilledema late sign)

Cabral DA. J Pediatr 1987;111:201.


Laboratory results1
Laboratory Results Specific for Meningitis?

  • CBC: WBC 21,000 cells/mm3, N 70% B 5% L 15%, H/H 14 / 36 and Platelets 470,000

  • Electrolytes (Glucose 70) and LFTs Normal

  • CSF: Cloudy, WBC 1400, P 80% L 10% M 10%, RBC 120, Protein 180, Glucose 20


Bacterial vs aseptic meningitis
Bacterial vs. Aseptic Meningitis Specific for Meningitis?

  • Bacterial Meningitis

    • Meningitis caused by identified bacteria

    • Peak in the Fall and Winter

  • Aseptic Meningitis

    • Meningitis not caused by identified bacteria

    • Most common type of meningitis

    • Peak in the late Spring to Fall

    • Biphasic fever (especially with enteroviruses)


Cerebrospinal fluid
Cerebrospinal Fluid Specific for Meningitis?


Cerebrospinal fluid1
Cerebrospinal Fluid Specific for Meningitis?

  • Bacterial meningitis

    • WBCs >1000 cells/mm3 with neutrophil predominance > 80%

    • Early infection can have a lymphocyte predominance in 10% of patients with WBCs < 100 cells/mm3 then neutrophil predominance at 48 h

    • Neutrophil predominance related to bacterial meningitis but no threshold of clinical significance (N 90 % = PPV 25%)

  • Viral meningitis

    • WBC < 100 cells/mm3 with lymphocyte predominance

    • Early infection neutrophil predominance (59%) with WBCs >1000 cells/mm3 then lymphocyte predominance after 24 h

    • During the peak season for aseptic meningitis, a patient with neutrophil predominance is more likely to have aseptic meningitis than bacterial meningitis

Negrini B. Pediatrics 2000;105:316.


Culture results1
Culture Results Specific for Meningitis?

  • Gram Stain Gram-positive cocci in pairs / chains

  • CSF Culture Streptococcus pneumoniae

  • Blood Culture Streptococcus pneumoniae

  • Viral Cultures Negative

    and Enterovirus

    PCR


Cerebrospinal fluid2
Cerebrospinal Fluid Specific for Meningitis?

  • Gram-stain Sensitivity

    • S. pneumoniae 90%

    • H. influenzae 86%

    • N. meningitidis 75%

    • Gram-negative bacilli 50%

    • L. monocytogenes 33%

    • Specificity > 97%

  • Bacterial Culture

    • Sensitivity 70-85%


Traumatic tap
Traumatic Tap Specific for Meningitis?

CSF is Uninterpretable

  • CSF contaminated with blood in up to 20% of taps

  • Both underdiagnose and overdiagnose bacterial meningitis

  • Repeat lumbar puncture after 48 hours

Rules

1 WBC/mm3 for every 500 – 1000 RBC/mm3

WBC (CSF) = WBC (CSF) – [WBC (Bld) x RBC (CSF)]/RBC (Bld)

Bonsu BK. PIDJ 2006;25:8.


Partially treated meningitis
Partially Treated Meningitis Specific for Meningitis?

  • Up to 50% of cases may initially

    receive oral antibiotics

  • CSF WBCs, protein, and glucose

    generally remain abnormal for

    at least 44 – 68 hours after antibiotics

  • CSF Sterilization

    • N. meningitidis within 1 – 2 hours

    • S. pneumoniae within 4 hours

    • Gram-stain sensitivity ~20% lower

Feigen RD. Textbook of Pediatric Infectious Diseases 4th Ed. 1998.

Kanegave JT, et al. Pediatrics 2001;108:1169.


Partially treated meningitis1
Partially Treated Meningitis Specific for Meningitis?

  • Latex agglutination

    • Detects bacterial capsular antigens, thus results are not affected by prior antibiotics

    • Low PPV and NPV - A positive or negative latex agglutination does not change clinical therapy or hospital course

  • Polymerase Chain Reaction

    • Enterovirus and Herpes Simplex Virus

    • Sensitivity and specificity > 90%

  • Presumed bacterial meningitis treat at least 10 days

Hayden RT. PIDJ 2000;19:290-2

Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.


  • Of pretreated children, Gram-stain was positive in 60% and latex agglutination was positive in 42%

  • Latex agglutination test did not identify any pathogen that was not identified by blood or CSF culture

  • Of culture-negative, pretreated children, none were positive by latex agglutination

  • Negative latex agglutination test did not decrease the risk of bacterial meningitis

Nigrovic LE, et al. PIDJ 2004;23:786.


What are the most common organisms that cause bacterial meningitis in this age group
What are the most Common Organisms that cause Bacterial Meningitis in this Age Group?

Streptococcus pneumoniae

4, 6B, 9, 14, 18F, 19F, 23F

Neisseria meningitidis

B, C, Y, W-135

Haemophilus influenzae type B


Viral meningitis

Enteroviruses (Coxsackie and ECHO viruses) Meningitis in this Age Group?

Arboviruses (St. Louis, Western and Eastern Equine, West Nile, California (Lacrosse) Viruses

Herpes viruses

Mumps Virus

Human Immunodeficiency Virus

LCMV

Respiratory Viruses (Adenovirus, Rhinovirus, Influenza Virus, Parainfluenza Virus)

Viral Meningitis

Kumar R. Indian J Pediatr 2005;72:57.


Aseptic meningitis infectious

Bacteria Meningitis in this Age Group?

Partially Treated

M. tuberculosis

M. pneumoniae

C. pneumoniae

Ehrlichiosis

B. burgdorfi

T. pallidum

Brucella

Leptospirosis

Fungi

C. neoformans

H. capsulatum

Coccidioides immitis

Blatomyces dermatitides

Candida

Aseptic Meningitis - Infectious

  • Parasites

    • Toxoplasma gondii

    • Neurocysticercosis

    • Trinchinosis

    • Naeglaria

    • Bartonella henselae

  • Rickettsia

    • RMSF

    • Typhus

Kumar R. Indian J Pediatr 2005;72:57.


Aseptic meningitis noninfectious

Postinfectious / Postvaccinial Meningitis in this Age Group?

Drugs

Systemic Diseases (Rheumatologic)

Neoplastic Diseases

Parameningeal Inflammation

Aseptic Meningitis - Noninfectious

Kumar R. Indian J Pediatr 2005;72:57.


What antibiotics would you empirically start1
What antibiotics would you empirically start? Meningitis in this Age Group?

Vancomycin

Third-generation cephalosporin

(Ceftriaxone or Cefotaxime)


Picu admission and id consult

Definitive Meningitis: Meningitis in this Age Group?

Positive CSF Gram-stain for bacteria

Probable Meningitis:

Age < 6 months and CSF WBC ≥100 and low glucose in

CSF; or CSF WBC ≥ 500 or;

CSF WBC elevated for age and >70% neutrophils or;

CSF WBC elevated for age and localizing neurologic exam

regardless of age or;

CSF WBC elevated for age and one risk factor:

Seizures

Altered mental status

Hypotension or hemodynamic instability

Age < 12 months and not vaccinated

Immunocompromised; e.g. sickle cell, IgG deficiency, HIV

PICU Admission and ID Consult


Specific therapy1
Specific Therapy Meningitis in this Age Group?

OrganismAntibioticDuration

S. pneumoniae

MIC PCN <0.1 Penicillin G or Ampicillin 10 – 14 days

MIC PCN 0.1-1.0 3rd Gen Cephalosporin

MIC PCN > 2 Vancomycin

(MIC Ceph >1.0) plus 3rd Gen Cephalosporin

(Rifampin)

N. meningitidis

MIC <0.1 Penicillin G, Ampicillin 7 days

MIC 0.1-1.0 3rd Gen Cephalosporin

H. Influenzae

Sensitive Ampicillin 7 - 10 days

Resistant 3rd Gen Cephalosporin

Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.


Specific therapy2
Specific Meningitis in this Age Group? Therapy

OrganismAntibioticDuration

Gram-Negative 3rd Gen Cephalosporin 21 days or

Enteric Organisms plus Aminoglycoside 14 days after Negative

Pseudomonas Ceftazidime, Carbapenem,

Ticarcillin, Piperacillin

plus Aminoglycoside

S. aureus

Meth Sensitive Nafcillin or Oxacillin 21 days

Meth Resistant Vancomycin and Rifampin

Enterococcus

Sensitive Ampicillin plus Aminoglycoside 14 – 21 days

Amp Resistant Vancomycin plus Aminoglycoside

Vanc Resistant Linezolid plus Aminoglycoside

Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.


Neurosurgical
Neurosurgical Meningitis in this Age Group?

ConditionOrganismAntibiotic

Basilar Skull S. pneumoniae Vancomycin plus

Fracture H. influenzae 3rd Gen Cephalosporin

S. pyogenes

Penetrating S. aureus, CoNS Vancomycin plus Cefepime,

Trauma Gram-Neg Bacilli Ceftazidime, or Meropenem

Postneurosurgery Gram-neg Bacilli Vancomycin plus Cefepime,

S. aureus, CoNS Ceftazidime, or Meropenem

CSF Shunt CoNS, S. aureus Vancomycin plus Cefepime,

Gram-Neg Bacilli Ceftazidime, or Meropenem

P. acnes

Tunkel AR. IDSA Guidelines Meningitis. CID 2004;39:1267.


Steroids
Steroids Meningitis in this Age Group?

  • Dexamethasone

    • Decrease inflammatory mediators associated with worsening of morbidity and mortality (deafness and nerve damage)

    • Decrease penetration of antibiotics into the CSF (Vancomycin)

    • Mask fever and rebound fever after discontinuation

  • Recommendations (prior or with first dose of antibiotics)

    • Haemophilus influenzae beneficial effect (hearing loss)

    • S. pneumoniae possible effect - “For infants and children 6 weeks of age and older, adjunctive therapy with dexamethasone may be considered after weighing the potential benefits and possible risks.”

    • N. meningitidis no supporting data

McIntyre PB, et al. JAMA 1997;278:925.

AAP Committee on Infectious Diseases 2003.

Tunkel AR, et al. CID 2004;39:1267.


All S. pneumoniae were susceptible to penicillin Meningitis in this Age Group?

Reduction in risk of an unfavorable outcome (RR, 0.59; 95% CI, 0.37 to 0.94; P=0.03) and mortality (RR of death, 0.48; 95% CI, 0.24 to 0.96; P=0.04)

No beneficial effect on neurologic sequelae including focal neurologic abnormalities and hearing loss


Chemoprophylaxis meningococus
Chemoprophylaxis - Meningococus Meningitis in this Age Group?

  • High risk: Chemoprophylaxis recommended

    • Household contact, Child care or nursery school contact, Direct exposure to index patient’s secretions (kissing, toothbrushes, eating utensils), Mouth-to-mouth resuscitation, Unprotected contact during endotracheal intubation, Frequently slept or ate in same dwelling, Passengers seated directly next to the index case during airline flights lasting more than 8 hours

  • Low risk: Chemoprophylaxis not recommended

    • Casual contact: No history of direct exposure to index patient’s oral secretions (eg, school or work), Indirect contact - only contact is with a high-risk contact, Health care professionals without direct exposure to patient’s oral secretions

  • In Outbreak or cluster

    • Chemoprophylaxis for people other than people at high risk should be administered only after consultation with local public health authorities

Red Book 27th Ed. 2006.


Chemoprophylaxis meningococcus
Chemoprophylaxis - Meningococcus Meningitis in this Age Group?

Age DoseDurationEfficacy

Rifampin

< 1 mo 5 mg/kg q12 2 days

>1 mo 10 mg/kg q12 2 days 90-95%

(max 600 mg)

Ceftriaxone

< 15 yo 125 mg Single dose 90-95%

> 15 yo 250 mg Single dose 90-95%

Ciprofloxacin

>18 yo 500 mg Single dose 90-95%

Red Book 27th Ed. 2006.


Chemoprophylaxis haemophilus
Chemoprophylaxis – Haemophilus Meningitis in this Age Group?

  • High risk: Chemoprophylaxis recommended

    • For all household contact in the following circumstances: Household with at least 1 contact < 4 years of age who is unimmunized or incompletely immunized, Household with a child < 12 months of age who has not received the primary series, Household with a contact who is an immunocompromised child, regardless of that child’s Hib immunization status

    • For nursery school and child care center contacts when 2 or more cases of Hib invasive disease have occurred within 60 days

  • Chemoprophylaxis not recommended

    • For occupants of households with no children < 4 years of age

    • For occupants of households when all household contacts 12 to 48 months of age have completed their Hib immunization series and when household contacts < 12 months have completed their primary series of Hib immunizations

    • For nursery school and child care contacts of 1 index case

    • For pregnant women

Red Book 27th Ed. 2006.


Meningococcal vaccines
Meningococcal Vaccines Meningitis in this Age Group?

Menactra (MCV4)

Licensed in 2005

11 – 55 years old

Protection at least 10 years

Recommendations:

High-risk groups (>10 years old)

11- to 12-year visit

High-school entry or 15 years old

College students living in dorms

Menomune (MPSV4)

Licensed in 1981

> 2 years old

Protection 3 – 5 years

Recommendations:

High-risk groups (2 – 10 yrs old)

- Functional or anatomic

asplenia

- Terminal C’ or properdin

deficient

- Travel to areas where

Meningococcus is epidemic

A, C, Y, W-135

Red Book 2006


Swartz MN. NEJM 2004;351:18. Meningitis in this Age Group?


Prognosis
Prognosis Meningitis in this Age Group?

  • Mortality rate (4 – 10%)

    • Infants and Children < 5 %

    • Streptococcus pneumoniae 10 %

    • Neisseria meningitis 3 – 5 %

    • Haemophilus influenzae 3 – 5 %

  • Factors associated with a poor outcome

    • Extremes of age

    • Hypotension

    • Altered mental status

    • Seizures

    • S. pneumoniae, GBBS, Gram-negative bacilli

    • High bacterial burden

    • Delayed sterilization of CSF

    • Low CSF glucose (<20 mg/dL)

Chavez-Bueno S. Pediatr Clin N Amer 2005;52:795.


Neurologic sequelae
Neurologic Sequelae Meningitis in this Age Group?

  • Sensorineural Hearing Loss

    • S. pneumoniae 20 - 35 %

    • N. meningitidis 5 - 10 %

    • H. influenzae 5 - 10 %

  • Cranial Nerve Palsies

  • Vascular Insults (Hemiparesis)

  • Seizures

  • Hydrocephalus

  • Ataxia

  • Diabetes insipidus

  • Behavior Disorders

  • Learning Disabilities

Chavez-Bueno S. Pediatr Clin N Amer 2005;52:795.


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