Meningitis

David A. Wilfret, MDPediatric 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

• Meningoencephalitis – Inflammation of the meninges and the cerebral cortex

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.

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

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

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

• 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 Meningitis

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

Signs and Symptoms Incidence (%)

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 neonateClassic symptoms of meningitis not until 18 – 24 months

• CBC with Differential

• Electrolytes and LFTs

• Urinalysis

• Cerebrospinal Fluid– WBC with Differential– RBC– Protein– Glucose– Gram-stain

What Laboratory Studies Would you Order?

• Blood Culture

• Urine Culture

• CSF Culture

• Viral Culture CSF and surfaces

• HSV and Enterovirus PCR

• 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

Laboratory Results

Is this consistent with meningitis?

Cerebrospinal Fluid - Neonates

Normal Cerebrospinal Fluid of Neonates and Children

CSF Study Premature Infants

Term to 7 days old

Term 8 – 30 days old

Term > 1 month old

WBC / ul 0 – 21 0 – 21 0 – 21 0 – 6

Neutrophils / ul < 40 – 60 % < 50 – 60 % < 20 % (0 - 2)

0

RBC / ul 0 - 2 0 – 2 0 – 2 0 – 2

Glucose (mg/dl)

30 - 100 35 – 80 40 – 80 40 – 80

Protein (mg/dl) 45 - 200 20 - 140 15 - 100 10 - 45

• 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

• Gram Stain Gram-positive cocci in pairs / chains

• CSF Culture Group B Streptococcus

• Blood Culture Negative

• Urine CultureNegative

• Virus Culture, Cancelled after Gram-stain Positive

and HSV and

Enterovirus PCR

Culture Results

• 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 are the most Common Organisms that cause Bacterial

Meningitis in Neonates?

Ampicillin

Plus an Aminoglycoside

Or Cefotaxime

What Antibiotics would you Empirically Start?

Infants (> 1 month)

Vancomycin plus Cefotaxime

Organism Antibiotic Duration 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

Specific Therapy

Neonatal Complications

• Development Delay 26%

• Hydrocephalus 24%

• Ventriculitis 20%

• Late Seizure 19%

• Cerebral Palsy 17%

• Brain Abscess 13%

• Hearing Loss 12%

• Subdural Effusion 11%

• Cortical Blindness <10%

Mortality 15 – 20 %

• 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.

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 present 5% of adults with meningitis

Nuchal rigidity present in 30% of adults with 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

What Laboratory Studies Would you Order?

• Blood Culture

• CSF Culture

• Viral Culture CSF, Nasopharyngeal, and Perirectal

• Enterovirus PCR

• 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

Would you Order a Head CT prior to the LP?

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.

• 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

Laboratory Results

• 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)

Bacterial vs. Aseptic Meningitis

Cerebrospinal Fluid

Typical Cerebrospinal Fluid Findings

Component Bacterial Meningitis

Viral Meningitis

Herpetic Meningitis

Tuberculous Meningitis

Leukocytes / mcL

> 1000 < 100 10 – 1000 10 – 1000

Cells Neutrophils Lymphs Lymphs Lymphs

CSF – Serum Glucose

Normal – Low

Normal Normal Low

Protein (mg/dL)

> 100 50 – 100 > 75 >100

Erythrocytes / mcL

0 – 10 0 - 2 10 – 500 0 - 2

• 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

Cerebrospinal Fluid

Negrini B. Pediatrics 2000;105:316.

• Gram Stain Gram-positive cocci in pairs / chains

• CSF Culture Streptococcus pneumoniae

• Blood Culture Streptococcus pneumoniae

• Viral CulturesNegative

and Enterovirus

PCR

Culture Results

• 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%

Cerebrospinal Fluid

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

Bonsu BK. PIDJ 2006;25:8.

Rules

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

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

Traumatic Tap

Partially Treated 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 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.

Streptococcus pneumoniae

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

Neisseria meningitidis

B, C, Y, W-135

Haemophilus influenzae type B

What are the most Common Organisms that cause Bacterial Meningitis in this Age Group?

Viral Meningitis

• Enteroviruses (Coxsackie and ECHO viruses)

• 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)

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

Aseptic Meningitis - Infectious

• Bacteria– 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

• Parasites– Toxoplasma gondii– Neurocysticercosis– Trinchinosis– Naeglaria– Bartonella henselae

• Rickettsia– RMSF– Typhus

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

Aseptic Meningitis - Noninfectious

• Postinfectious / Postvaccinial

• Drugs

• Systemic Diseases (Rheumatologic)

• Neoplastic Diseases

• Parameningeal Inflammation

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

Vancomycin

Third-generation cephalosporin

(Ceftriaxone or Cefotaxime)

What antibiotics would you empirically start?

PICU Admission and ID Consult• Definitive Meningitis:

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

Organism Antibiotic Duration

S. pneumoniae MIC PCN < 0.1 Penicillin G or Ampicillin 10 – 14 daysMIC PCN 0.1-1.0 3rd Gen Cephalosporin MIC PCN > 2 Vancomycin (MIC Ceph >1.0) plus 3rd Gen Cephalosporin

(Rifampin)

N. meningitidisMIC <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

Specific Therapy

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

Organism Antibiotic Duration

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

Specific Therapy

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

Condition Organism Antibiotic

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

Neurosurgical

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

• 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

Steroids

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

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

• 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 - Meningococus

Age Dose Duration Efficacy

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%

Chemoprophylaxis - Meningococcus

Red Book 27th Ed. 2006.

• 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

Chemoprophylaxis – Haemophilus

Red Book 27th Ed. 2006.

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

Meningococcal Vaccines

Red Book 2006

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 visitHigh-school entry or 15 years oldCollege students living in dorms

A, C, Y, W-135

Swartz MN. NEJM 2004;351:18.

• 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)

Prognosis

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

• 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

Neurologic Sequelae

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