Pediatric Meningitis: Pearls and Pitfalls
by Brit Long (@long_brit)
EM Chief Resident Physician at SAUSHEC, USAF
Edited by Alex Koyfman MD (@EMHighAK) and Stephen Alerhand MD (@SAlerhand)
It’s about thirty minutes to the end of a calm, slow shift when an ambulance crew brings in a mother with her 10 day-old daughter who presents with fever of 101.1oF, vomiting, and decreased feeds. As you begin your exam and go through your pediatric assessment triangle, you see a poorly responsive, mottled female neonate. She is tachypneic and febrile. After IV access is obtained and 20cc/kg fluid bolus given, her appearance improves. Labs including CBC, LFTs, renal function panel, ammonia, VBG, blood cultures, lactate, and urine culture are obtained. You prep for your lumbar puncture (LP) and obtain purulent-appearing CSF (cerebrospinal fluid) on the first attempt. With concern for meningitis, you begin cefotaxime and ampicillin and call the NICU.
Meningitis results from inflammation of the tissues surrounding the meninges (pia, arachnoid, and dura mater) and spinal cord. Mortality in meningitis reaches close to 100% if left untreated!1 -4 Neurologic complications are common such as weakness, paresthesias, hearing changes, and cognitive changes.
Vaccines for pneumococcus and H. influenza type B have drastically changed the landscape of bacterial meningitis, dropping the H. influenza type B meningitis rates by 99% and pneumococcal meningitis rates by 60%. S. pneumoniae remains the most frequent cause of childhood meningitis in patients greater than two months. In patients less than two months, group B streptococcus (GBS) is most common. Patients less than two months still account for the predominant population affected, around 81 per 100,000 patients.1-5
Meningitis can be broken into two groups for pediatric patients: neonatal (first month), and childhood (beyond neonatal). This post will cover pediatric bacterial meningitis (neonatal and childhood), CSF controversies, complications, and the evidence behind dexamethasone.
- Neonatal meningitis
The incidence of bacterial meningitis has dropped to 0.3 per 1000 live births. It accounts for 15% of patients with bacteremia. Fortunately, the mortality rate has decreased to 10% of cases, down from 50% in the 1970s. This is due to vaccinations and intrapartum treatment of GBS.1-5 However, morbidity rates have remained the same.
Risk factors include low birth weight, preterm birth, premature rupture of membranes, traumatic delivery, fetal hypoxia, maternal peripartum infection, and urinary tract abnormalities.1-3
The time course reflects the organisms causing infection and risk factors. Early onset infection is meningitis within the first 6 days of life and reflects vertical transmission from the mother’s genital tract most commonly. Late onset, or after the first week of life, reflects community or nosocomial acquisition.6,7 The most common organisms are GBS, Listeria monocytogenes, E. coli, and other gram negative bacilli. N. meningitides, S. pneumoniae, and H. influenzae are rarer causes, accounting for 4% of presentations!1-6
The clinical features for neonatal meningitis are indistinguishable from neonatal sepsis without meningitis. Patients with neonatal meningitis most commonly present with temperature instability (too high or too low), irritability, and decreased feeding/vomiting. Temperature instability ranges from temperatures < 36oC to > 38oC and is found in 60% of presentations. Preterm infants are more likely to have hypothermia. Neurologic findings include lethargy, irritability, poor tone, twitching, and seizures. Increased irritability with cuddling or holding the infant suggests meningitis. Seizures are seen in 20-50% of infants with neonatal meningitis and are more common in gram-negative infections and often focal. Full fontanelle is the norm, rather than a bulging fontanelle (roughly 25% of cases, with likelihood ratio of 8). Poor feeding/vomiting is seen in 50% of patients, respiratory distress in 30-50%, apnea in 30%, and diarrhea in 20%. As you can see, a broad range of presentations is possible!7-10
The evaluation of these patients must include review of prenatal history, delivery issues, feeding and diaper history, hospital course, sick contact history, and a complete exam. The presentation of meningitis in the neonate is nonspecific, thus an evaluation for sepsis in a patient with the above complaints is a must! You must do an exam from head to toe. Look at the pediatric assessment triangle (appearance/activity, work of breathing, circulation), tone, fontanelle, capillary refill, back, and you must take off the diaper and look at the genitals!
A full laboratory evaluation must be completed including CBC, blood culture, urine culture, and lumbar puncture to include CSF studies. This should be obtained before the antibiotics are provided, but if there is any delay in obtaining CSF, provide antibiotics and resuscitate. Several studies have shown that you have two hours to clear the CSF of organisms in the setting of meningococcal meningitis once antibiotics are given (with pneumococcal meningitis having slower sterilization of CSF per one study).11 If the patient is sick or unstable, resuscitate and provide antibiotics. Once stable, then obtain the CSF sample.
Empiric antibiotic treatment is based on infant’s age, estimated microbes, and susceptibility patterns. In patients in the first 6 days of life, ampicillin (50 mg/kg IV every 8 hrs) and an aminoglycoside like gentamicin (2.5 mg/kg every 8 hrs) are provided. If Listeria is unlikely and there is high suspicion of gram-negative bacteria, cefotaxime (50mg/kg every 8 hours) can be provided. Late onset after 6 days calls for a change in frequency of dosing: ampicillin 50mg/kg every 6 hours, cefotaxime 50mg/kg every 6 hours, and gentamicin at 2.5mg/kg every 8 hours. Vancomycin at 10mg/kg every 6 hours should be given if concerned for MRSA.4,7,8,12,13
- Childhood meningitis
The most common pathogen involved in patients 3 months to 10 years is S. pneumoniae (45% of cases), with N. meningitides (34%), GBS (11%), and gram-negative bacilli (9%) accounting for the remainder of cases. For those over 10 years old, N. meningitides accounts for 55%.1,4
Risk factors for patients over 2-3 months of age include recent exposure to a patient with meningitis, recent upper respiratory tract infection, travel to a location with endemic meningococcal disease (sub-Saharan Africa), penetrating head injury, anatomic defect or recent neurosurgical procedure, and cochlear implant device presence.4,8
In this age group, meningitis can present progressively over several days or with an acute, fulminant course (thought to be due to severe cerebral edema). The classic triad of fever, neck stiffness, and mental status changes is seen in less than 40% of adults and even fewer children. Fever, headache, photophobia, vomiting, confusion, and irritability are all common complaints. “Classic” meningeal signs are only present in the latter course of disease after 4-5 days, and approximately 60% of patients will have meningeal signs such as neck stiffness (LR 7.7) at the time of presentation. Meningeal signs refer to inability to place chin on chest, difficulty with neck flexion, and presence of Kernig/Brudzinski signs. In older patients, you will most likely be able to ask the patient to do these maneuvers. However, in younger patients (toddlers), utilizing a toy that holds their attention can be used to assess neck active range of motion. Up to 80% of patients will be irritable or lethargic at initial evaluation, and the level of consciousness is correlated with prognosis. Focal findings such as limb weakness or cranial nerve abnormality are present in 16% of patients overall (34% of those with pneumococcal meningitis). Seizures in the first two days of illness are usually generalized and occur in 20-30% of patients with meningitis. Later seizures are often focal. Cutaneous findings such as petechiae and purpura are more common in N. meningitides (10% of cases), but can occur with any agent! The lesions are more common on the extremities and below the nipple line. N. meningitides can also cause arthritis and pericardial effusions.1,4,14,15
The evaluation of these patients is similar to neonates in that the focus should be on obtaining a quick history and exam and patient stabilization. In fulminant presentations, rapid intervention is vital. Obtain blood cultures and provide IV fluid and antibiotics. Once the patient is stabilized, then consider obtaining your CSF studies. If the patient presents in the more progressive course, you will most likely have time to gather a full history and exam, obtain your labs and LP, and then start your antibiotics based on LP results.
For history, focus on risk factors, immunization status, and recent antibiotic use. The exam is similar to the neonate in that a complete exam is vital. Look at the vital signs carefully, general appearance (again, the pediatric assessment triangle is key), meningeal signs, neurologic examination, and skin exam.
In terms of labs, CBC, blood cultures, renal function, lactate, and coag panel are important. Pretreatment antibiotics for another infection, such as URI or OM, affect blood cultures. With no antibiotic pretreatment, blood cultures will be positive in over 80% of patients.14-16
Empiric antibiotic treatment for children greater than one month includes ceftriaxone 50mg/kg two times per day (up to 2g) plus vancomycin at 15-20mg/kg two times per day. 1,4
- CSF and LP Controversies
LP should be completed in patients with fever, ill appearance, below nipple line petechiae / purpura, and meningeal signs. Any neonate with fever should be considered for lumbar puncture. Do not delay antibiotic administration for the LP. If the patient is altered, has focal deficit, or seizure, increased ICP may be present, which is a contraindication to LP before brain imaging (controversial). In this setting, obtain blood cultures, provide antibiotics and resuscitate, complete head CT, and then complete the LP.4,13,14
In terms of positioning, studies with ultrasound have shown the greatest interspinous space in patients in a position with the hips flexed, either in the lateral decubitus or truly seated position. Flexing the legs up to the abdomen or chest does not improve the size of the spaces and is uncomfortable for the patient. Neck flexion did not improve the space size. Opening pressure is helpful and should be obtained if possible.17
CSF results are often dependent on the disease time course. Early on, bacterial invasion may result in positive CSF culture but otherwise normal CSF results. Later, Gram stain may be negative, but inflammatory signs will be present in the CSF. Bacterial meningitis often results with elevated CSF WBC (> 1000 cells/microL), with neutrophil predominance.4,18,19
CSF studies can be difficult to interpret in neonates, as there is large overlap of CSF parameters in neonates with and without meningitis. Labs consistent with bacterial cause include positive Gram stain, increased WBC count above 1000 cells/microL, neutrophil predominance, protein > 150mg/dL in preterm and > 100mg/dL in term neonates, and decreased glucose < 20mg/dL in preterm and < 30 mg/dL in term infants. These “Classic” findings are not always present. The CSF WBC count can vary, with a count of > 20 cells/microL consistent with meningeal inflammation (sensitivity of 80%).4,8,18 GBS meningitis has a median count of 271 WBC/microL. Studies have shown that gram-negative causes will produce a greater CSF WBC count when compared to gram-positive organisms. CSF protein is extremely variable, with a median of 68mg/dL. Glucose values are also variable, and the CSF to serum glucose ratio is not very useful in the sick neonates (serum glucose may increase in the setting of stress, throwing off the ratio). Finally, two lab pearls: 1) approximately 20% of neonates with CSF culture-positive meningitis have negative Gram stains; 2) blood cultures are negative in close to 38% of patients with confirmed CSF meningitis!
For infants greater than 1 month, CSF WBC > 9 cells/microL is abnormal, and in kids older than 3 months, >6 cells/microL is abnormal. CSF glucose is more useful in infants/children older than one month. The normal CSF to serum glucose is 0.6. Values below 0.4 raise suspicion of meningitis. CSF protein in children older than one month with bacterial meningitis is usually above 40mg/dL, with WBC > 1000 cells/microL most common. In the first 48 hours, the CSF may not be classic and be normal. Gram stain may or may not be positive for the organism. Fortunately in this age group above one month, 90% will present with positive Gram stain if the agent is pneumococcus or Neisseria. The patient may have already received antibiotics for an ear infection or URI. In this case, the CSF will have elevated WBC count, elevated CSF protein, and decreased CSF glucose, but it may not have organisms present on CSF results. The CSF will clear of organisms classically within two hours of antibiotics, but inflammatory markers will be present for up to 24-48 hours. If suspicious of meningitis, admit the patient and speak with the pediatrician about a repeat LP! A traumatic LP can cause issues with CSF result interpretation. No formula to “correct” the CSF WBC can be used with complete confidence to exclude meningitis. If the LP is traumatic and the child appears sick, treat for meningitis!4,14,18-21
Other testing including CSF antigen tests for specific bacteria, cytokines, and PCR testing can be helpful to rule in meningitis, but not rule it out. The Bacterial Meningitis Score (BMS) has been studied and validated to predict patients at very low risk of bacterial meningitis (versus aseptic meningitis), as long as none of the following are present: CSF protein >80mg/dL, positive CSF Gram stain, peripheral absolute neutrophil count ≥10,000 cells/microL, CSF absolute neutrophil count ≥1000 cells/microL or a seizure before or after presentation. This score has demonstrated a sensitivity of 98.3% and negative predictive value of 99.9%. Two patients under the age of two months had bacterial meningitis despite a negative score. This has only been studied in developed nations.22
CSF lactate has also been evaluated for distinguishing bacterial versus viral meningitis. Studies have demonstrated that CSF lactate is significantly higher in patients with bacterial meningitis. Cutoff values of 3.8 mmol/L were used in an adult population. A meta analysis evaluated using lactate versus other conventional CSF markers in adult patients found AUC of 0.98 for lactate, with much greater accuracy than CSF glucose, CSF protein, CSF WBC, and CSF:plasma glucose. This meta analysis included studies using lactate cutoffs varying from 2 to 6 mmol/L.23 Unfortunately, the use of CSF lactate is not common in many labs, but if available, this lab test can be helpful.23,24 A Brazilian study evaluated the addition of CSF lactate to the BMS, and it found the addition of the CSF lactate did not improve on the performance of the score alone. A CSF lactate of 3mmol/L or higher demonstrated a 100% sensitivity and negative predictive value when used alone for predicting bacterial meningitis, as did the BMS (with one criteria positive) in this study.25
These are divided into neurologic and systemic. Factors related to increased risk of complications include S. pneumoniae meningitis, longer duration of illness, poor response to treatment, efficacy of antibiotic therapy, lower CSF glucose, seizure, ataxia, focal deficit on presentation, and younger age.4,8,26,27
Neurologic complications include impaired mental status, sensorineural hearing loss, seizures, ataxia, hydrocephalus, and cerebral edema. Studies have shown that close to 50% of survivors will experience a neurologic complication, with intellectual/behavioral deficit accounting for 78% of the complications and hearing loss for 7%. Up to 30% of these deficits last the remainder of the patient’s life.4,8,26-28
Systemic complications include septic shock, disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and septic arthritis.4,26
A number of studies have evaluated the use of dexamethasone in the treatment of bacterial meningitis. Several meta-analyses have found no mortality difference, but instead a reduction in hearing loss complications in those with H. flu meningitis. Most of these studies were completed when H. flu was the predominant cause, but now S. pneumoniae is the predominant cause in childhood meningitis. Studies have not supported the decrease in hearing loss in those infected with S. pneumoniae. The AAP does recommend providing dexamethasone to patients with H. flu and pneumococcal meningitis before or at the same time of the first dose of antibiotics.29 The IDSA recommends providing dexamethasone after six weeks of age for those patients with H. flu meningitis.30 It is likely not beneficial if given even more than 1 hour after antibiotics! Do not give dexamethasone to patients less than 6 weeks of age or in patients with congenital or acquired CNS abnormalities. The dose is 0.15 mg/kg per dose every 6 hours for 2 days. Adverse effects include recurrent fever after ending 48 hours of treatment and gastrointestinal bleeding (1% of patients).1,4,8,29-31
- Meningitis results from inflammation of the meninges. Mortality approaches 100% when left untreated. Thus, early diagnosis and treatment are key.
- Vaccines, specifically Hib and pneumococcal, have drastically reduced the incidence of meningitis.
- Two types exist: neonatal and childhood.
- Classic exam findings are not all that classic. The classic triad of fever, neck stiffness, and mental status changes is seen in less than 40% of adults and even fewer children. Meningeal findings will be present in 60% of patients.
- Treat empirically with antibiotics based on age, patient risk factors, and CSF results.
- The Bacterial Meningitis Score and CSF lactate can be helpful in differentiating aseptic vs. bacterial meningitis.
- Neurologic complications such as behavior / cognitive deficit and/or sensorineural hearing loss are common morbidities of the disease.
- Dexamethasone should be given for patients older than 6 weeks within 1 hour of providing antibiotics. It is most efficacious in flu meningitis.
- Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364:2016.
- Harvey D, Holt DE, Bedford H. Bacterial meningitis in the newborn: a prospective study of mortality and morbidity. Semin Perinatol 1999; 23:218.
- de Louvois J, Halket S, Harvey D. Neonatal meningitis in England and Wales: sequelae at 5 years of age. Eur J Pediatr 2005; 164:730.
- Nigrovic LE, Kuppermann N, Malley R, Bacterial Meningitis Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era. Acad Emerg Med 2008.
- Kaplan SL, Mason EO Jr, Wald ER, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004; 113:443.
- May M, Daley AJ, Donath S, et al. Early onset neonatal meningitis in Australia and New Zealand, 1992-2002. Arch Dis Child Fetal Neonatal Ed 2005; 90:F324.
- Heath PT, Nik Yusoff NK, Baker CJ. Neonatal meningitis. Arch Dis Child Fetal Neonatal Ed 2003; 88:F173.
- Chávez-Bueno S, McCracken GH Jr. Bacterial meningitis in children. Pediatr Clin North Am 2005; 52:795.
- Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 1999; 13:711.
- Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious Diseases of the Fetus and Newborn Infant, 7th ed, Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, Philadelphia 2011. p.222.
- Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001; 108:1169.
- American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia and meningitis in neonates). In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.340.
- Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267.
- Feigin RD, McCracken GH Jr, Klein JO. Diagnosis and management of meningitis. Pediatr Infect Dis J 1992; 11:785.8.Chávez-Bueno S, McCracken GH Jr. Bacterial meningitis in children. Pediatr Clin North Am 2005; 52:795.
- Curtis S, Stobart K, Vandermeer B, et al. Clinical features suggestive of meningitis in children: a systematic review of prospective data. Pediatrics 2010; 126:952.
- Feigin RD, Dodge PR. Personal experience: Unpublished data for prospective studies of bacterial meningitis, 1974-1979.
- Abo A, Chen L, et al. Positioning for lumbar puncture in children evaluated by bedside ultrasound. Pediatrics. 2010 May;125(5):e1149-53.
- Garges HP, Moody MA, Cotten CM, et al. Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics 2006; 117:1094.
- Bonadio WA, Stanco L, Bruce R, et al. Reference values of normal cerebrospinal fluid composition in infants ages 0 to 8 weeks. Pediatr Infect Dis J 1992; 11:589.
- Kestenbaum LA, Ebberson J, Zorc JJ, et al. Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants. Pediatrics 2010; 125:257.
- Ansong AK, Smith PB, Benjamin DK, et al. Group B streptococcal meningitis: cerebrospinal fluid parameters in the era of intrapartum antibiotic prophylaxis. Early Hum Dev 2009; 85:S5.
- Nigrovic LE, Malley R, et al. Meta-analysis of bacterial meningitis score validation studies. Arch Dis Child. 2012 Sep;97(9):799-805.
- Abro AH, Abdou AS, et al. CSF lactate level: a useful diagnostic tool to differentiate acute bacterial and viral meningitis. J Pak Med Assoc. 2009 Aug;59(8):508-11.
- Huy NT, Thao NT, et al. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care. 2010;14(6):R240.
- Mekitarian Filho, EM, et al. The bacterial meningitis score to distinguish bacterial from aseptic meningitis in children from Sao Paulo, Brazil. Ped Infect Dis J 32(9):1026, September 2013.
- Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J 1993; 12:389.
- Chandran A, Herbert H, Misurski D, Santosham M. Long-term sequelae of childhood bacterial meningitis: an underappreciated problem. Pediatr Infect Dis J 2011; 30:3.
- Koomen I, Grobbee DE, Roord JJ, et al. Hearing loss at school age in survivors of bacterial meningitis: assessment, incidence, and prediction. Pediatrics 2003; 112:1049.
- American Academy of Pediatrics. Pneumococcal infections. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.626.
- Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267.
- Schaad UB, Kaplan SL, McCracken GH Jr. Steroid therapy for bacterial meningitis. Clin Infect Dis 1995; 20:685.