Lise E. Nigrovic
• In the era of widespread conjugate vaccines, most children have aseptic, not bacterial meningitis. Enteroviruses are the major viral pathogen with yearly peaks in the summer. In endemic regions, Lyme meningitis has been increasingly common.
• Empiric antibiotic coverage while awaiting results of bacterial cultures should cover the most likely pathogens for patients with suspected bacterial meningitis.
• Validated clinical decision rules can be used to identify children at low risk for bacterial meningitis and, in endemic regions, Lyme meningitis.
Meningitis refers to an infection of the cerebrospinal fluid (CSF) that bathes the brain whereas encephalitis is an infection of the brain itself. Most meningitis pathogens enter the CSF space by hematogenous spread. More unusually, pathogens may enter through a mechanical disruption (e.g., a fracture of the base of the skull) or by direct extension from a local infection (e.g., ear, mastoid air cells, sinuses, or orbit). Once the blood–brain barrier has been breached, natural defense mechanisms are less able to stop the multiplication of organisms. In the United States, over the past decade, the incidence of bacterial meningitis in children under 18 years of age has declined by approximately one-third due to the widespread uptake of the highly effective vaccines against Haemophilus influenzae type B (1990), Streptococcus pneumoniae (7-valent 2000; 12-valent 2010), and Neisseria meningitidis (2005). The predominant bacterial pathogens for children older than 2 months of age remain S. pneumoniae and N. meningitidis and for the youngest infants Group B streptococcus and Escherichia coli.1
The younger a child with meningitis, the less specific the presenting signs and symptoms will be. Neonates and young infants are likely to present with fever, poor feeding, irritability, inconsolability, or listlessness. Older children with meningitis may present with “classic” signs and symptoms of meningitis which include headache, photophobia, stiff neck, change in mental status, bulging fontanel, nausea, and vomiting. The Brudzinski sign (neck flexion causes the hips and knees to flex involuntarily) and the Kernig sign (hip flexed prevents full extension of the leg) are both late signs of meningeal irritation. Recent works suggests that these signs have poor diagnostic accuracy in identifying cases of bacterial meningitis.2
In the early phases, meningitis may be confused with gastroenteritis or intussusception, respiratory infections (e.g., pneumonia), or deep neck space infections (e.g., retropharyngeal abscess or cervical adenitis). For children with altered mental status, encephalitis, cerebral hemorrhage or abscess, or toxic ingestions must also be considered.
The initial management of an unstable patient with suspected meningitis must focus on assuring airway, breathing, and cardiovascular stability. Supplemental oxygen is always administered. (See Chapter 19for management of shock). If signs of increased intracranial pressure develop, clinicians should elevate the head slightly and initiate controlled hyper-ventilation (target PaCO2 between 30 and 35 mm Hg). Children unresponsive to initial therapy may benefit from the use of mannitol (0.25–1 g/kg). Associated seizures are controlled with rapid-acting benzodiazepines followed by an appropriate second-line agent (see Chapter 52). If hypoglycemic (defined as a blood glucose of <40 mg/dL), children require an intravenous glucose infusion and monitoring.
If the child with suspected meningitis is unstable, lumbar puncture should be delayed.3 Although the early administration of antibiotics may prevent recovery of the organism from CSF culture,4 appropriate antibiotics should be administered early. Of note, bacterial pathogens are isolated from blood culture in approximately half of children with bacterial meningitis and may help guide decisions about duration and type of parenteral antibiotics.
Stable patients with suspected meningitis should have prompt blood testing and diagnostic lumbar puncture, especially in children at higher risk of bacterial infections (e.g., neonates, immunocompromised children, and close contacts of a confirmed bacterial meningitis case). The initial laboratory evaluation should include a complete blood count (CBC) with differential,5 peripheral glucose, as well as CSF white blood cell (WBC) with differential, red blood cell count (RBC), glucose, protein, and Gram stain. In children without bacterial meningitis, CSF glucose should be approximately 60% of peripheral glucose.6 Cultures of blood and CSF should also be obtained.
Normal CSF parameters are age-related (Table 58-1).6–9 Traumatic lumbar punctures occur commonly, especially in the youngest children, which may complicate the interpretation of CSF cell counts. Correction formulas are designed to correct CSF WBC for the presence of CSF RBCs. Either the standard 500:1 or the actual peripheral RBC: WBC ratio has a can be applied. The introduction of peripheral blood also elevates the CSF protein by approximately 1.1 mg/dL per 1000 RBCs per mm.10
Normal Range for Cerebrospinal Fluid (CSF) Parameters by Patient Age
For children with a CSF pleocytosis, additional testing should be dictated by the clinical scenario. Enteroviral polymerase chain reaction (PCR) testing can confirm a viral infection and shorten duration of hospitalization and of parenteral antibiotics11 as bacterial meningitis would be very unlikely.12 Newer enteroviral tests can return results within a few hours and may guide ED decision-making for children with CSF pleocytosis.13 For the youngest infants, HSV PCR testing should be considered. In Lyme disease endemic areas such as the Northeast, Mid-Atlantic and upper Midwest, Lyme serology should be ordered. Due to low sensitivity, clinicians should not order CSF Lyme PCR.14
DISTINGUISHING BACTERIAL FROM ASEPTIC MENINGITIS
Bacterial cultures take several days to either identify a bacterial pathogen or to reliably exclude bacterial growth. Meningitis prediction models, such as the Bacterial Meningitis Score (Table 58-2), combine presenting signs and symptoms to calculate the risk of bacterial meningitis.15,16 Children with none of the six included high-risk predictors are at very low risk of bacterial meningitis. The Bacterial Meningitis Score has now been validated in several published studies with a high degree of diagnostic accuracy: sensitivity of 99.3% (95% confidence interval [CI] 98.7%–99.7%), specificity 62.1% (95% CI 60.5%–63.7%), and negative predictive value (NPV) 99.5% (95% CI 99.3%–99.9%).3
The Bacterial Meningitis Score: a validated clinical prediction rule to identify children at very low of bacterial meningitis
Antibiotic pretreatment prior to diagnostic lumbar puncture may render bacterial cultures falsely negative. The time to culture sterilization depends on bacterial pathogen with almost immediate sterilization for N. meningitidis, but several hours of culture positivity for S. pneumoniae or Group B streptococcus.5 In children with proven bacterial meningitis, antibiotic pretreatment lowered CSF protein and raised CSF glucose.3 Therefore, meningitis prediction rules should not be applied to children pretreated with antibiotics.
DISTINGUISHING LYME FROM ASEPTIC MENINGITIS
In Lyme endemic areas such as Northeast, Mid-Atlantic and upper Midwest, children with CSF pleocytosis who are at low risk of bacterial meningitis may still have Lyme meningitis. The treatment for Lyme meningitis is 3 to 4 weeks of parenteral antibiotics.5,17 The “Rule of 7’s” is a previously validated clinical decision rule to distinguish Lyme from septic arthritis (Table 58-3 ).18 Children with none of the three high-risk clinical predictors are at low risk of Lyme arthritis: sensitivity 96% (95% CI 90%–99%), specificity 41% (95% CI 36%–47%), and NPV 91% (95% 86%–94%).19 Application of a validated prediction rule for Lyme meningitis has the potential to decrease unnecessary hospital admissions and parenteral antibiotic treatment for low-risk patients while awaiting Lyme serology results.
The Rule of “7’s:” a validated clinical prediction rule to identifychildren at very low risk of lyme meningitis
Encephalitis refers to an infection that extends into the brain tissue which can be associated with infection of the CSF (meningoencephalitis). Most commonly, encephalitis is caused by a viral infection (e.g., enteroviruses, HSV, rabies, eastern and western equine encephalitis viruses, or west Nile virus). Signs and symptoms include altered mental status, focal neurologic deficits, ataxia, aphasia, or focal seizures and those associated with meningitis.
Initial laboratory evaluation should include peripheral WBC, CSF cell count, and chemistries. Typically, children will have a mild CSF pleocytosis with lymphocyte predominance. CSF can be sent for the appropriate viral studies. If herpes meningitis is suspected (e.g., young infants with a history of maternal infection), CSF HSV PCR testing should be obtained.20 If obtained, an EEG may demonstrate seizure activity or diffuse slowing.
For children with suspected bacterial meningitis, initial antibiotic treatment is directed by the predominant organisms, depending on patient age. Newborns are generally treated with an initial dose of ampicillin, 100 mg/kg, and an aminoglycoside, such as gentamicin, 2.5 mg/kg. Infants and children are generally treated with a third-generation cephalosporin (ceftriaxone 100 mg/kg/dose once daily or cefotaxime 50 mg/kg/dose three times daily). If the organism is known to be S. pneumoniae or if gram-positive cocci are seen on Gram stain of the CSF, vancomycin (15 mg/kg/dose divided twice daily) should be added empirically to cover resistant pneumococcus. After isolation of and sensitivity testing of the bacterial pathogen, antibiotic coverage and duration can be determined.
Treatment for viral meningitis is largely supportive and may include hydration, and fever and pain control. Empiric acyclovir should be started when HSV infection is considered. Although HSV infections are quite rare, HSV causes significant morbidity and mortality.21 Acyclovir can be discontinued in those children with a negative CSF HSV PCR test.
When given prior to the antibiotic, the anti-inflammatory effect of dexamethasone (0.15 mg/kg intravenously) significantly decreases hearing loss and other neurologic sequelae in meningitis caused by H. influenzae type B.22Clinical trials and meta-analyses suggest that dexamethasone therapy improves the outcome for patients with bacterial meningitis caused by other agents, but the evidence is not yet conclusive. For S. pneumoniae meningitis, dexamethasone should be considered, but there is no clear consensus on the empiric use of steroids for bacterial meningitis when the bacterial agent is unknown.3Corticosteroids may also be considered for children with encephalitis to reduce associated brain inflammation.
The vast majority of children with aseptic meningitis have a self-limited illness without subsequent problems. The mortality of children with bacterial meningitis has remained markedly constant at approximately 7%.1 In addition, approximately 20% to 30% of survivors of bacterial meningitis will have some long-term sequelae23,24 which include mild learning defects, sensorineural hearing loss, afebrile seizures, and more serious neurologic deficits (e.g., mental retardation and blindness).
1. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011;364(17):2016-2025.
2. Bilavsky E, Leibovitz E, Elkon-Tamir E, Fruchtman Y, Ifergan G, Greenberg D. The diagnostic accuracy of the ‘classic meningeal signs’ in children with suspected bacterial meningitis. Eur J Emerg Med.2012;20(5):361–363.
3. Nigrovic LE, Malley R, Kuppermann N. Meta-analysis of bacterial meningitis score validation studies. Arch Dis Child. 2012;97(9):799–805.
4. 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(5):1169–1174.
5. Centers for Disease Control and Prevention (CDC). Lyme disease–United States, 2001-2002. MMWR Morb Mortal Wkly Rep. 2004; 53(17):365–369.
6. Nigrovic LE, Kimia AA, Shah SS, Neuman MI. Relationship between cerebrospinal fluid glucose and serum glucose. N Engl J Med. 2012; 366(6):576–578.
7. Shah SS, Ebberson J, Kestenbaum LA, Hodinka RL, Zorc JJ. Age-specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med. 2011; 6(1):22–27.
8. Chadwick SL, Wilson JW, Levin JE, Martin JM. Cerebrospinal fluid characteristics of infants who present to the emergency department with fever: establishing normal values by week of age. Pediatr Infect Dis J.2011;30(4):e63–e67.
9. Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr. 2011; 158(1):130–134.
10. Nigrovic LE, Shah SS, Neuman MI. Correction of cerebrospinal fluid protein for the presence of red blood cells in children with a traumatic lumbar puncture. J Pediatr. 2011; 159(1):158–159.
11. King RL, Lorch SA, Cohen DM, Hodinka RL, Cohn KA, Shah SS. Routine cerebrospinal fluid enterovirus polymerase chain reaction testing reduces hospitalization and antibiotic use for infants 90 days of age or younger. Pediatrics. 2007;120(3):489–496.
12. Nigrovic LE, Malley R, Agrawal D, Kuppermann N. Low risk of bacterial meningitis in children with a positive enteroviral polymerase chain reaction test result. Clin Infect Dis. 2010;51(10):1221–1222.
13. Lyons TW, McAdam AJ, Cohn KA, Monuteaux MC, Nigrovic LE. Impact of in-hospital enteroviral polymerase chain reaction testing on the clinical management of children with meningitis. J Hosp Med.2012;7(7):517–520.
14. Avery RA, Frank G, Eppes SC. Diagnostic utility of Borrelia burgdorferi cerebrospinal fluid polymerase chain reaction in children with Lyme meningitis. Pediatr Infect Dis J. 2005;24(8):705–708.
15. Nigrovic LE, Kuppermann N, Malley R. Development and validation of a multivariable predictive model to distinguish bacterial from aseptic meningitis in children in the post-Haemophilus influenzae era. Pediatrics.2002;110(4):712–719.
16. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA. 2007;297(1):52–60.
17. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089–1134.
18. Garro AC, Rutman M, Simonsen K, Jaeger JL, Chapin K, Lockhart G. Prospective validation of a clinical prediction model for Lyme meningitis in children. Pediatrics. 2009;123(5):e829–e834.
19. Cohn KA, Thompson AD, Shah SS, et al. Validation of a clinical prediction rule to distinguish Lyne meningitis from aseptic meningitis. Pediatrics. 2012;129(1):e46–e53.
20. Caviness AC, Demmler GJ, Selwyn BJ. Clinical and laboratory features of neonatal herpes simplex virus infection: a case-control study. Pediatr Infect Dis J. 2008;27(5):425-430.
21. Long SS, Pool TE, Vodzak J, Daskalaki I, Gould JM. Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. Pediatr Infect Dis J. 2011; 30(7):556–561.
22. Odio CM, Faingezicht I, Paris M, et al. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med. 1991;324(22):1525–1531.
23. Nigrovic LE, Kuppermann N, Malley R. Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era. Acad Emerg Med. 2008;15(6):522–528.
24. Chandran A, Herbert H, Misurski D, Santosham M. Long-term sequelae of childhood bacterial meningitis: an underappreciated problem. Pediatr Infect Dis J. 2011; 30(1):3–6.