Abstract:

This article provides a review of the evaluation and management of meningitis in young children. It highlights the most common causes of meningitis and the most current treatment recommendations. Since the development of the hemophilus and pneumococcal conjugate vaccines, pediatric bacterial meningitis has been diagnosed less frequently. Viral meningitis is far more common and tends to be a less severe disease. It is very important to maintain a high index of suspicion and a low threshold for evaluation of meningitis in febrile young infants younger than 3 months.

Keywords:
meningitis; encephalitis; children; herpes simplex

Meningitis in Children: Diagnosis and Treatment for the Emergency Clinician

Gabriella Cardone Richard, MD, Marcos Lepe, MD
59-day-old girl, former full-term healthy infant, presented to the emergency department with a 1-day history of fever to 102F, poor feeding, and increased fussiness. The mother remembers brief moments when the infant rolled her eyes for a few seconds and abnormal arm movements. The physical examination was unremarkable, including a flat fontanel and normal capillary refill. Blood, urine, and cerebrospinal fluid (CSF) were obtained. A complete blood count revealed a white blood cell (WBC) count of 13 480 with a left shift. The CSF revealed the following: WBC 1519/mm 3 (77% neutrophils and 4% lymphocytes); red blood cells (RBC) 3270/mm 3; glucose 98 mg/dL (vs a venous glucose of 111); and protein 205 mg/dL. She was admitted to the hospital and started on empiric vancomycin, ceftriaxone, and acyclovir. Cerebrospinal fluid culture was positive for Gram (+) organisms and grew group B streptococcus (GBS). Results of herpes simplex virus (HSV) and enterovirus polymerase chain reaction (PCR) assays were negative. When the diagnosis of GBS meningitis was confirmed, acyclovir was discontinued. After a 2week hospitalization, the baby was discharged home in excellent condition.

*Texas Children's Hospital, Houston, TX; Universidad Autnoma de Baja California. Reprint requests and correspondence: Gabriella Cardone, MD, Texas Children's Hospital, 6621 Fannin Suite A-210, Houston, TX 77030. gabriellamd@me.com
1522-8401/$ - see front matter 2013 Elsevier Inc. All rights reserved.

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INTRODUCTION AND DEFINITIONS

Meningitis is an inflammation of the membranes surrounding the central nervous system: dura mater, arachnoid mater, and pia mater manifested by CSF pleocytosis. 1-3 It reflects an inflammation of the arachnoid mater and the CSF in both the subarachnoid space and the cerebral ventricles. Meningitis is caused by a myriad of pathogens that can incite different symptoms, often making diagnosis difficult. In younger age groups before speech development, frequently few signs and symptoms can be detected. Meningitis, in particular bacterial meningitis, carries very high morbidity rates (21%-56%), which stresses the importance of prompt and correct treatment. 3 The mortality of bacterial meningitis when untreated can approach 100%. There is also a great emphasis on promptly diagnosing and empirically treating meningitis because of the risk of permanent neurologic sequelae, which ranges from 10% to 30%, according to some sources for bacterial meningitis. 4-7 Some authors argue that morbidity and mortality vary with geographical location and age and from one pathogen to another. 7 It is not surprising that failure to diagnose pediatric meningitis constitutes one of the most common causes of medical malpractice cases within pediatric emergency medicine. 4,8,9 There must always be a high degree of suspicion whenever certain symptoms arise. Table 1 lists some of the nonspecific presenting complaints of infants with meningitis. Encephalitis, which is defined as an inflammatory process of the brain parenchyma, shares some of the same etiology and symptoms. 10 Encephalitis represents further disease invasion or progression. 11 The presence or absence of normal brain function distinguishes meningitis from encephalitis. The presence of flaccid paralysis and reduced reflexes is a manifestation of inflammation of the spinal cord, referred to as myelitis. Aseptic meningitis is a clinical syndrome in which cultures for routine bacterial pathogens are negative and there were no antibiotics given before the lumbar puncture (LP). The causes can be infectious and noninfectious, but viruses remain the most common cause. For this reason, aseptic meningitis and viral meningitis are frequently interchangeable terms. 12-15 This article will provide a review of ageappropriate clinical presentations, current diagnostic methods, and treatment options available to the emergency clinician.

TABLE 1. Signs and symptoms of meningitis in infants.

General Signs Fever or hypothermia Respiratory distress or apnea Jaundice Drowsiness Reduced feeding Failure to thrive Unconsciousness Lethargy High-pitched cry Vomiting Irritability Specific Signs Convulsions Bulging fontanelle

Data from: the World Health Organization 37 and Curtis et al. 4

ETIOLOGY AND PREDISPOSING FACTORS

Bacteria, viruses, fungi, and parasites are considered infectious causes and are described in Table 2. 16,17 Noninfectious causes include drugs, neoplastic disease, and other systemic diseases. 3 Viral pathogens remain the number 1 cause of meningitis in the United States. 14,18,19 The most common viruses that cause meningitis are enteroviruses. Other frequent viral pathogens include arboviruses (eg, St Louis encephalitis virus, tickborne encephalitis virus, dengue virus, West Nile virus), and herpesviruses (eg, Epstein-Barr virus, herpesvirus types 1 and 2, varicella-zoster virus). 18 Fortunately, several diagnostic methods have been developed to diagnose viral or aseptic meningitis, the most important being reverse transcriptase PCR, which is increasingly being used as the incidence of aseptic meningitis rises. 20 PCR is often more readily available than the viral culture, which can still be sent as a confirmation. Certain viruses produce some clues to the etiology, some of which can be found in Table 2. Findings frequently associated with viral infections such as conjunctivitis, rash, herpangina, hand-footmouth disease, generalized lymphadenopathy, oral or genital ulcers, chicken pox, parotid swelling, and others, should be noted. Since the development and Food and Drug Administration acceptance and use of the Haemophilus influenzae B (Hib) vaccine for use in infants, there has been a tremendous decrease in its incidence as a causative agent of meningitis. 21-24 Because of this, in the 1990s, Streptococcus pneumoniae became the primary cause of bacterial

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TABLE 2. Clinical indicators of viral etiologies of central nervous system infections.

Clinical Indicators Enteroviruses Hand-foot-mouth disease, herpangina, pharyngitis, conjunctivitis, pleurodynia, myopericarditis, rash Rash Flaccid paralysis Arboviruses Rash, mosquito exposure Mosquito exposure Etiology Meningitis Encephalitis

Coxsackie A and B Echoviruses Polioviruses West Nile virus La Crosse (California) encephalitis virus, Western equine encephalitis virus, St Louis encephalitis virus Eastern equine encephalitis virus Powassan virus Cytomegalovirus and Epstein-Barr virus Herpes simplex type 1 Herpes simplex type 2 Varicella zoster virus Influenza virus Human immunodeficiency virus Rabies virus

Common Common Common Uncommon Common

Rare Rare Rare Common Common

Mosquito exposure Tick exposure Herpesviruses Lymphadenopathy, pharyngitis, immunocompromised host Oral lesions Genital ulcers, sacral radiculopathy Vesicular rash (chicken pox), shingles Other viruses Fever, cough, sore throat, vomiting, headache, diarrhea Intravenous drug use, risky sexual behavior Animal exposure; prodrome of nonspecific symptoms (fever, headache, malaise, myalgia, cough, sore throat, nausea, vomiting) Rodent pets or contact with rodent urine or droppings Parotitis unvaccinated or partially vaccinated individuals Conjunctivitis, cough, coryza in unvaccinated or partially vaccinated individuals

Rare Uncommon Uncommon Rare Common Common Rare Common Rare

Common Common Common Common Rare Rare Common Common Common

Lymphocytic choriomeningitis virus Mumps virus Measles virus

Common Common Common

Uncommon Uncommon Rare

meningitis in children, 21,22 thus marking 2 distinct eras: a pre-Hib vaccine era and a post-Hib vaccine era. 23 Another vaccine of great importance is the S pneumoniae vaccine (pneumococcal conjugate vaccine [PCV]). The vaccine is presently composed of 13 polysaccharides or serotypes and 2 cross-reactive serotypes. These and the newly identified serotypes were responsible for most cases (80%) of invasive pneumococcal disease in the United States between 2000 to 2010. 21,25,26 After the introduction of this vaccine, several sources have reported a decreased incidence of pneumococcus as the cause of meningitis in unimmunized patients. 27,28 With the introduction of both vaccines, the incidence of bacterial meningitis declined in all groups except children younger than 2 months. 28,29 Currently, S pneumoniae remains the most frequent cause of bacterial meningitis in children. 21,27,29-32 Table 3 summarizes some predisposing factors for bacterial meningitis. There are other factors that increase the risk for bacterial meningitis such as penetrating trauma,

recent exposure to an individual with meningococcal or Hib meningitis, and anatomical defects such as dermal sinus or a urinary tract anomaly. 33

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT

Patients 0 to 30 Days Old
The classic signs of meningismus such as neck stiffness, headaches, photophobia, and Kernig or Brudzinski signs are not present either because of the immature nervous system in the newborn and infant or because the patient's not-yet developed speech makes it increasingly difficult to rely on the usual adult signs and symptoms. 4,34,35 Instead, in the neonate and infant, one must rely on other nonspecific signs such as abrupt onset of fever, accompanied by decreased activity, decreased feeding, irritability, failure to thrive, and sleepiness, among others (Table 1). 4-37

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TABLE 3. Entry site, age, and predisposing factors for bacterial meningitis.
Pathogen N meningitidis S pneumoniae Entry Site Age Range Predisposing Factors None, rarely complement deficiency Conditions that predispose to pneumococcal bacteremia, choclear implants, defects of ear ossicle, cribiform plate fracture, and basilar skull fracture with otorrhea Surgery and foreign body such as ventricular drains, endocarditis, cellulitis, and skin ulcerations Cell mediated immunity defects (eg, transplants and use of steroids), pregnancy, liver disease, and malignancy) Foreign bodies such as ventricular drains, surgery Neurosurgery, ventricular drains, advanced medical illness Diminished humoral immunity

Nasopharynx All ages Nasopharynx, direct extension across skull All ages fracture, or from contiguous or distant foci of infection Skin, foreign body, bacteremia Gastrointestinal tract and placenta All ages Neonates

S aureus L monocytogenes

Coagulase-negative Foreign body staphylococci Gram-negative bacilli Various H influenzae Nasopharynx, contiguous spread from local infection

All ages Neonates Nonvaccinated children, adults

Neonates are at increased risk for severe systemic disease, particularly by HSV, with progression to encephalitis with seizures and/or focal neurologic findings. 36 They can manifest with systemic presentations that include pneumonia, hepatitis with hepatic necrosis, myocarditis, and necrotizing enterocolitis. 36 In the above presentations, disseminated intravascular coagulation and findings of sepsis can mimic overwhelming bacterial infections. To optimize evaluation and management, one should obtain a thorough history in neonates with fever greater than 100.4F or 38C. The history should include perinatal and birth history (maternal fever, maternal GBS status, and sexually transmitted infections, in particular HSV, gonorrhea, and chlamydia). It should also include history of prolonged rupture of membranes and nursery events, sick contacts and daycare presence, associated symptoms (vomiting, diarrhea, cough, congestion, etc), and changes in behavior, feeding, and activity.

Along with the aforementioned clinical characteristics, there are also other key points to have in mind. One would be the age of the patient. There are well-defined differences between cases of meningitis within the first month of life and cases described in infants older than 60 days. The former group is of special mention because the highest incidence of bacterial meningitis is seen within the first month of life. 30 The physical examination should readily identify the patient who requires resuscitation vs the well-appearing infant. Vital signs including pulse oximetry and capillary refill should be documented, and signs of toxicity such as inconsolability, poor perfusion and tone, and lethargy should be noted. A bulging fontanelle typically presents late in the illness. Nuchal rigidity can be present in one third of the patients aged 0 to 6 months and 95% of patients older than 19 months. 38 There are multiple studies that document the use of peripheral WBCs in the evaluation of all febrile young infants. These studies are not the focus of this review. Despite their common use, there is

TABLE 4. Cerebrospinal fluid analysisreference ranges.

Age Preterm Term Child WBC 9 (0-25 WBCs/mm 3); 57% PMNs 8 (0-22 WBCs/mm 3); 61% PMNs 0-7 WBCs/mm 3; 0% PMNs Glucose 50 (24-63 mg/dL) 52 (34-119 mg/dL) 40-80 mg/dL CSF Glucose/Blood Glucose 55%-105% 44%-128% 50% Protein 115 (65-150 mg/dL) 90 (20-170 mg/dL) 5-40 mg/dL

Data from: McMillan JA, Feigin RD. Oski's Pediatrics: Principles & Practice. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006.

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significant variability in the sensitivity and specificity of this test in determining the presence or absence of meningitis, and the decision to perform a blood culture and a lumbar puncture (LP) should not be based solely on the WBC count. Various observational studies indicate that the use of C-reactive protein and procalcitonin enhances the ability to detect serious bacterial infection and invasive bacterial illness. These tools in combination with a urine dipstick, WBC, and absolute neutrophil count (ANC) can direct the clinical management. Procalcitonin has variable performance by age and is not usually available at bedside, limiting its use. 39-41 An LP should be performed in all febrile children younger than 28 days and in all ill-appearing febrile infants and should be strongly considered in febrile young infants treated with empiric antibiotics before the evaluation. The presence of invasive infection including osteomyelitis, abscess, mastitis, omphalitis, or cellulitis obligates the consideration of LP, as does the presence of seizures. Reference CSF ranges are displayed in Table 4.

pox, or paratid swelling should be noted. Viral meningitis may be suspected based on epidemiologic data and clinical features, but these are unreliable in the earliest stages of bacterial meningitis; therefore, the approach should be similar to that of bacterial meningitis until the identification of the pathogen is accomplished or the etiology for the symptoms is clear to the practitioner. In meningococcemia, an erythematous maculopapular eruption may be present initially and be followed by the development of petechiae and purpura. 42

Evaluation
As discussed earlier, meningitis, in particular bacterial meningitis, is an emergency and the diagnostic interventions have to be done immediately. A careful history and physical examination, blood tests, and LP ideally should be performed before the administration of antibiotics. However, in fulminant cases (eg. decreased blood pressure), resuscitation and shock management take priority, and a blood culture should be obtained before antibiotics, if at all possible, with the LP performed as soon as it is feasible. The current criterion standard in establishing the diagnosis of meningitis in infants is obtaining CSF and then analyzing its contents: protein, glucose, cell count and differential, Gram stain, and culture. 4,34,35,44,45 Typical CSF findings in meningitis are displayed in Table 5. The presence of pleocytosis is strongly associated with meningitis. In addition, it is generally accepted that viral meningitis has fewer and more vague symptoms than bacterial meningitis. 43 The CSF findings can direct further diagnostic tests such as PCR to look for viral genomes. 46 The CSF results aid the physician in deciding whether to give antibiotics for bacterial causes, acyclovir for HSV, or supportive care for other viral causes. 20 If bacterial meningitis is suspected and the LP is contraindicated or unsuccessful or if neuroimaging is needed before performing the LP, antibiotics should not be delayed. Additional studies including serology for measles, mumps, arboviruses, varicella, Ebstein-Barr virus, lymphocytic chorionic meningitis virus (LCMV), HIV, syphilis, and Lyme disease may be sent if indicated.

Patients Older Than 1 Month

Clinical Presentation and Diagnosis
Most infants older than 1 month with bacterial meningitis present with fever and signs of inflammation of the meninges (nausea, vomiting, headache, back pain, nuchal rigidity, confusion, anorexia, irritability). Paradoxical irritability, when attempts to console the infant cause further distress or pain, is commonly reported by parents of children with serious illness, particularly meningitis. Frequently, upper respiratory infections precede the illness. There is no single sign that is pathognomonic for the disease. 42 The triad of fever, neck stiffness, and mental status changes is present only in 44% of adults with meningitis and less frequently in children, or may not occur until late in the course. 32 Papilledema is a rare finding in acute bacterial meningitis, and subdural empyema, brain abscess, and venous sinus occlusion should be ruled out if papilledema is seen on clinical examination. 42 Seizures occur in 20% to 30% of patients before hospitalization. 15 The manifestations of viral meningitis are generally similar to those of bacterial meningitis but are usually less severe. 43 Certain viruses provide some clues to the etiology (Table 2). Findings frequently associated with viral infections such as conjunctivitis, rash, herpangina, hand-foot-mouth disease, generalized lymphadenopathy, oral or genital ulcers, chicken

How to Interpret CSF Reference Ranges

The CSF WBC count in acute bacterial meningitis is usually more than 1000/high-power field, with predominance of neutrophils, but in early presentations, few or no WBC may be present. 13 The glucose is less than 40 mg/dL (2.2 mmol/L), and the ratio of the CSF to blood glucose concentration is usually depressed (b 0.6). The CSF protein ranges

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TABLE 5. Cerebrospinal fluid analysis in meningitis.

Total WBC Count (cells/L) N 1000 Less common 100-1000 5-100 Encephalitis Glucose (mg/dL) b 10 a 10-45 b Protein (mg/dL) N 250 c 50-250 d

Some cases Encephalitis of mumps and LCMV

More common

Bacterial meningitis

TB meningitis; Neurosyphilis; TB meningitis fungal meningitis some viral infections (such as mumps and LCMV) Bacterial or Early bacterial Bacterial Bacterial Bacterial viral meningitis; meningitis; viral meningitis meningitis meningitis TB meningitis meningitis; neurosyphilis; TB meningitis

Viral meningitis; Lyme disease; neurosyphilis

TB indicates tuberculosis, LCMV indicates lymphocytic chorionic meningitis virus.

Data from: Feigin RD, Cutrer WB. Bacterial meningitis beyond the neonatal period. In: Feigin and Cherry's Textbook of Pediatric Infectious Diseases, 6th ed, Feigin RD, Cherry J, Demmler-Harrison GJ, Kaplan SL (Eds), Saunders, Philadelphia 2009. p.439. a Less than 0.6 mmol/L. b Ranging from 0.6 to 2.5 mmol/L. c Greater than 2.5 g/L. d Ranging from 0.5 to 2.5 g/L.

between 100 and 500 mg/dL. In a traumatic LP, the protein concentration may be increased; it can be corrected by subtracting 1 mg/dL for every 1000 RBC/L. 42,47 The presence of polymorphonuclear (PMN) cells is not pathognomonic for bacterial meningitis because aseptic meningitis can have an early neutrophilic predominance. With a traumatic LP, it is common to use cell count correcting formulas, none of which have total confidence, but a commonly used formula is to subtract 1 WBC for every 1000 RBCs/L. 48 The presence of immature bands does not help distinguish between viral and bacterial etiologies (Table 5). In viral meningitis, the cell count typically ranges from 10 to 500 cells/L. Some exceptions have been described with particular viruses, as previously published. 14,19,49,50 Normal counts can be seen early in the course of the infection. The predominance of mononuclear cells is the norm in viral meningitis, but as described earlier, PMN cells can be seen in the first 24 to 48 hours of the illness. 19 Glucose is normal or slightly reduced, but usually 40% of the serum value or greater, and CSF protein is less than 100 mg/dL. Gram stain of the CSF should be negative for bacteria. Improvement of symptoms after an LP is also frequently observed, even in young infants. Samples of CSF should be sent for PCR analysis for enterovirus, and in appropriate patients, for herpes simplex and West Nile viruses. Rectal swabs and throat swabs may be sent for viral culture to confirm the PCR results in enteroviral illness. PCR

has largely replaced viral cultures in the diagnosis of viral meningitis. Diagnostic accuracy is improved, and time to diagnosis is shortened compared with cultures, therefore reducing unnecessary days of hospitalization, intravenous antibiotic therapy, and additional diagnostic testing. 51-56 The absence of a positive Gram stain does not exclude bacterial meningitis because it depends on the number of organisms present and the use of cytocentrifugation, yet it is positive in 90% of patients with pneumococcal meningitis 57 and 80% of those with meningococcal meningitis. 58 For Listeria and gram-negative bacilli, the Gram stain is positive in one third to one half of the samples. 59,60 The isolation of the bacterial pathogen confirms the diagnosis for bacterial meningitis. The PCR of CSF is most helpful in meningococcal disease in patients with negative cultures. 61 The use of prior antibiotics, in particular oral, has minimal effects on CSF cytology, but it may affect the chemistry results. Cerebrospinal fluid glucose and protein levels should be interpreted with caution in the setting of antibiotic pretreatment. The culture and Gram stain are more commonly affected by prior use of antibiotics. 62,63 Table 6 reflects a previously validated score by Nigrovic et al, 64 the Bacterial Meningitis Score. This score is a clinical prediction rule for use in otherwise healthy children older than 2 months with CSF pleocytosis (WBC count N 10 cells/L) and no prior use of antibiotics. It should be used in combination

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TABLE 6. Bacterial Meningitis Score (BMS).

Predictor CSF Gram stain CSF total protein CSF ANC Peripheral ANC Seizures Criteria (Points) Positive (2 points if present, 0 if absent) 80 mg/dL (1 point if present, 0 if absent) 1000 cells/mm 3 (1 point if present, 0 if absent) 10 000 cells/mm 3 (1 point if present, 0 if absent) During or before presentation (1 point if present, 0 if absent)

pathogens. One should err on the side of early antibiotic administration rather than later. Delays in administering antibiotics have been associated with worse patient outcomes. 68-71 Eventually, antibiotics should be adjusted, depending on the

TABLE 7. Suggested antibiotic dosing and administration.

Outpatient or emergency center empirical therapy (IM/IV) Ceftriaxone Infants aged N 28 d: 100 mg/kg sodium per dose once a day or divided every 12 h Empirical parenteral therapy (IV) Ampicillin Neonates Aged b 7 d: 150 mg/kg per dose every 12 h Aged N 7 d: 75 mg/kg per dose every 6 h Treatment for 48 h, neonates No meningitis: 75 mg/kg per dose every 12 h Meningitis or no LP performed: 75 mg/kg per dose every 6 h Infants aged N 28 d No meningitis: 50 mg/kg per dose every 6 h Meningitis or no LP performed: 100 mg/kg per dose every 6 h Cefotaxime Neonates sodium Aged b 7 d: 50 mg/kg per dose every 12 h Aged 7-28 d: 50 mg/kg per dose every 8 h Infants aged N 28 d: No meningitis: 75 mg/kg per dose every 8 h Meningitis or no LP performed: 75 mg/kg per dose every 6 h Gentamicin sulfate Neonates: 4 mg/kg per dose every 12 h Infants aged N 28 d: 2.5 mg/kg per dose every 8 h Treatment of choice of suspected staphylococcus Vancomycin Neonates Aged 7 d: 15 mg/kg per dose every 12 h Aged N 7 d: 15 mg/kg per dose every 8 h Infants aged N 28 d No meningitis: 15 mg/kg per dose every 8 h Meningitis or no LP performed: 15 mg/kg per dose every 6 h Treatment of choice for HSV Acyclovir Neonates and infants 20 mg/kg per dose every 8 h
IM indicates intramuscular, HSV indicated herpes simplex virus, LP indicates lumbar puncture.

A BMS of 2 or higher indicates bacterial meningitis with 100% sensitivity and 97% specificity. A BMS of 0 predicted aseptic meningitis with 73% sensitivity and 100% sensitivity. BMS indicates Bacterial Meningitis Score, ANC indicates absolute neutrophil count, CSF indicates cerebrospinal fluid.
Data from: Nigrovic et al.64

with clinical judgment to detect children at very low risk for bacterial meningitis.

Treatment
Once the question of whether the clinical picture favors bacterial vs viral/aseptic meningitis is answered, the course of treatment can be determined. A clinical picture of less specific signs/symptoms plus negative CSF criteria is sufficient evidence to allow the physician to cease antibiotic treatment and consider CSF PCR to verify a viral etiology. Reverse transcriptase PCR is now regarded as the criterion standard to diagnose viral meningitis; this is probably explained by the near-dominance of viral etiologies for most cases of meningitis in children. 20 It is perhaps most valuable for serving as an indicator as to when to stop antibiotic treatment and when to adjust for either a course of acyclovir or just supportive therapy until viral meningitis runs its course. 65 If CSF pleocytosis is minimal but the patient exhibits specific clinical features of HSV meningitis, acyclovir should be initiated immediately and PCR should be done for HSV as soon as possible. 20 Herpes simplex virus is presently the only viral meningitis for which acyclovir is recommended; other forms of viral meningitis usually run a mild course and require no specific treatment. 66 If the diagnosis of bacterial meningitis is established or suspected, empirical antibiotic treatment should be initiated immediately following the guidelines outlined in Tables 7 and 8. 7,67 Empiric antibiotics should be directed toward the patient's age because there is a correlation between age and most probable bacterial

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TABLE 8. Etiology and treatment of bacterial meningitis.

Patient Group 0-28 d 1 and b 3 mo 3 mo and b 3 y 3 and b19 y Neurosurgical problems and head trauma Common Organisms GBS, Escherichia coli, Listeria monocytogenes, and other gram-negative bacteria GBS, gram-negative bacilli, S pneumoniae, N meningitidis S pneumoniae, N meningitidis, GBS, gram-negative bacilli S pneumoniae, N meningitidis S aureus, S pneumoniae Antimicrobial Therapy Third-generation cephalosporin plus an aminoglycoside Third-generation cephalosporin Third-generation cephalosporin Third-generation cephalosporin Vancomycin + third-generation cephalosporin

For resistant S pneumoniae, the American Academy of Pediatrics recommends vancomycin plus cefotaxime or ceftriaxone as empiric therapy. It should also be used in any sick patients or patients with clear bacterial meningitis until sensitivities and specificities of culture are completed. Some data were from Sez-Llorens X, McCracken GH Jr. Antimicrobial and anti-inflammatory treatment of bacterial meningitis. Infect. Dis. Clin. North Am. 1999 Sep;13(3):619636, vii 57; and 2013 Up to Date, Evaluation and management of fever in the neonate and young infant (less than three months of age) and TCH Evidence-Based Outcomes Center Clinical Algorithm for Neonates & Infants with Fever Without Localizing Signs (FWLS) (0-60 days). Evidence-Based Outcomes Center, Quality and Outcomes Center. Texas Childrens Hospital; 2009. Plus additional data from other sources. 5863

specific CSF culture and sensitivity analysis, 20 but the initial management should be aggressive to include coverage for resistant pneumococcal meningitis (grade 1A recommendation) with cefotaxime (300 mg/kg/d, to a maximum of 12 g divided into 3 doses) or ceftriaxone (100 mg/kg/d, to a maximum of 4 g divided into 2 doses) plus vancomycin (50 mg/kg/d intravenously [IV]; to a maximum of 4 g divided in to 4 doses). Acyclovir should be given when a neonate is ill appearing, if there is history of maternal genital herpes and/or the presence of mucocutaneous vesicles, if the child presents with seizures or focal neurologic abnormalities, or if hepatic enzyme levels are elevated. If a traumatic tap is suspected, one must be conservative in making the decision to start acyclovir, especially if the infant is seriously ill. The dose of acyclovir is 60 mg/kg/d in 3 divided doses and continued until the result of CSF culture or CSF HSV DNA PCR is negative. An algorithm for patients older than 1 month has been modified for this review (Figure 1). Resuscitation should be a priority when indicated. Laboratory evaluation should include a complete blood count with platelets and differential, blood cultures, and serum electrolytes with glucose, blood urea nitrogen, and creatinine. In patients with clinical sepsis, petechiae or purpura, prothrombin time and partial thromboplastin time, and other markers of sepsis or disseminated intravascular coagulation should be obtained. If imaging is required on clinical grounds, treatment including antibiotic therapy should not be delayed; imaging should be obtained as soon as reasonably possible. The use of dexamethasone reduces the risk of hearing loss in children with Hib meningitis, but there

is no clear evidence that it alters other neurologic outcomes in children with bacterial meningitis. 72,73 The debate among experts continues in relation to the efficiency of dexamethasone for children with meningitis caused by other organisms. The American Academy of Pediatrics Committee of Infectious Diseases suggests that this therapy is beneficial in children with Hib meningitis, if given before or at the same time as the first dose of antimicrobial therapy. The use of this agent after 1 hour of the administration of the first dose of antibiotic does not improve the outcome. Dexamethasone should not be used in infants younger than 6 weeks or those with congenital abnormalities of the central nervous system. 72,73 Treatment for special circumstances such as immunodeficiency, recent neurosurgery, anatomical defects, penetrating head trauma, CSF leak, and epidemics requires consultation with an expert in infectious disease and is beyond the scope of this review. N meningitidis is best treated with penicillin, but a third-generation cephalosporin or chloramphenicol can be considered in patients allergic to -lactams. 74,75 In the referenced Red Book from the American Academy of Pediatrics, alternative antibiotics per etiology can be found, including the use of naficilin or oxacillin for methicillin-sensitive Staphylococcus aureus. Treatment should be adjusted upon availability of cultures.

SUMMARY
Meningitis is an acute illness with signs and symptoms of meningeal irritation. The manifestations of viral and bacterial meningitis can be similar,

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Figure 1. Management algorithm for infants ( 1 month) and children with suspected bacterial meningitis. Data from: Tunkel et al 73 and Fleisher. 43

but the severity of viral etiologies is usually less. As detailed previously, no signs or symptoms are pathognomonic, and the clinician should be very careful to avoid missing the diagnosis. Neonates often present with vague and nonspecific complaints. Children who present with suspicion of meningitis should be treated as bacterial meningitis until the diagnosis can be excluded. Bacterial meningitis is an emergency that should be evaluated and treated promptly, and the man-

agement algorithm should be followed closely. The evaluation of clotting factors is particularly indicated when purpuric lesions or petechiae are noticed or clinical sepsis is present. Antibiotics should never be withheld when bacterial meningitis is suspected, and the LP cannot be performed or must be delayed. The isolation of bacterial pathogen or a positive PCR finding in the CSF confirms the diagnosis of either viral or bacterial meningitis. In enterovirus season (late summer/early fall), clinical findings and

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epidemiology can aid in the diagnosis, as with other viral syndromes. Beyond the neonatal period, S pneumoniae and N meningitidis are the most common causes of bacterial meningitis; certain host factors may predispose to a particular organism. Very sick patients with selected features such as immunosuppression and prior use of antibiotics or history of exposures (ticks, tuberculosis, etc) should be approached accordingly.

18. 19. 20.

21.

REFERENCES
1. Van de Beek D, De Gans J, Tunkel AR, et al. Communityacquired bacterial meningitis in adults. NEJM 2006;354: 44-53. 2. Grandgirard D, Leib SL. Meningitis in neonates: bench to bedside. Clin Perinatol 2010;37:655-76. 3. Mace SE. Acute bacterial meningitis. Emerg Med Clin North Am 2008;26:281-317. 4. Curtis S, Stobart K, Vandermeer B, et al. Clinical features suggestive of meningitis in children: a systematic review of prospective data. Pediatrics 2010;126:952-60. 5. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J 1993;12:389. 6. Berg S, Trollfors B, Hugosson S, et al. Long-term follow-up of children with bacterial meningitis with emphasis on behavioural characteristics. Eur J Pediatr 2002;161:330-6. 7. Kim KS. Acute bacterial meningitis in infants and children. Lancet Infect Dis 2010;10:32-42. 8. Carroll AE, Buddenbaum JL. Malpractice claims involving pediatricians: epidemiology and etiology. Pediatrics 2007; 120:10-7. 9. Selbst SM, Friedman MJ, Singh SB. Epidemiology and etiology of malpractice lawsuits involving children in US emergency departments and urgent care centers. Pediatr Emerg Care 2005;21:165-9. 10. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47: 303-27. 11. Romero JR. Aseptic and viral meningitis. Principles and practice of pediatric infectious diseases: expert consult online and print. 4th ed. Philadelphia (Pa): WB Saunders; 2012292. 12. Case definitions for infectious conditions under public health surveillance. US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention (CDC); 1997. 13. Feigin RD, Cherry J. Feigin and Cherry's textbook of pediatric infectious diseases: expert consult. 6th ed. Philadelphia (Pa): WB Saunders; 2009. 14. Rotbart HA. Viral meningitis. Semin Neurol 2000;20:277-92. 15. Tapiainen T, Prevots R, Izurieta HS, et al. Aseptic meningitis: case definition and guidelines for collection, analysis and presentation of immunization safety data. Vaccine 2007;25: 5793-802. 16. Batra P, Gupta S, Gomber S, et al. Predictors of meningitis in children presenting with first febrile seizures. Pediatr Neurol 2011;44:35-9. 17. Kamat D, Adam HM, Cain KK, et al, editors. American Academy of Pediatrics: quick reference guide to pediatric 22. 23. 24.

25.

26. 27. 28. 29. 30.

31.

32. 33. 34. 35. 36. 37.

care. 1st ed. Elk Grove Village (Ill): American Academy of Pediatrics; 2010. Bartt R. Acute bacterial and viral meningitis. Continuum 2012;18:1255-70. Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 2000;105: 316-9. Archimbaud C, Chambon M, Bailly JL, et al. Impact of rapid enterovirus molecular diagnosis on the management of infants, children, and adults with aseptic meningitis. J Med Virol 2009;81:42-8. Nigrovic LE, Kuppermann N, Malley R, et al, for the PEMCRC 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;15:522-8. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. NEJM 1997;337:970-6. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA 1993;269:221-6. American Academy of Pediatrics Committee on Infectious Diseases. Haemophilus influenzae type b conjugate vaccines: recommendations for immunization with recently and previously licensed vaccines. Pediatrics 1993;92:480-8. Hausdorff WP, Bryant J, Paradiso PR, et al. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000;30:100-21. Sucher AJ, Chahine EB, Nelson M, et al. Prevnar 13, the new 13-valent pneumococcal conjugate vaccine. Ann Pharmacother 2011;45:1516-24. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of proteinpolysaccharide conjugate vaccine. NEJM 2003;348:1737-46. Poehling KA, Talbot TR, Griffin MR, et al. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. JAMA 2006;295:1668-74. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. NEJM 2011;364: 2016-25. Wenger JD, Hightower AW, Facklam RR, et al. Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis 1990;162:1316-23. Kaplan SL, Mason EO, 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;113:443-9. Van de Beek D, De Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. NEJM 2004;351:1849-59. Chvez-Bueno S, McCracken Jr GH. Bacterial meningitis in children. Pediatr Clin North Am 2005;52:795-810. Kacica MA, Lepow ML. Meningitis: clinical presentation and workup. Pediatr Ann 1994;23:6970,735. Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child 2004;89:751-6. Sawyer M, Rotbart H. Aseptic and viral meningitis. Principles and practice of pediatric infectious diseases. 2nd ed. New York, NY: Churchill Livingstone; 2008. p. 305. World Health Organization. Pocket book of hospital care for children: guidelines for the management of common illnesses with limited resources. 1st ed. Geneva: World Health Organization; 2006.

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VOL. 14, NO. 2 MENINGITIS IN CHILDREN / RICHARD AND LEPE

38. Walsh-Kelly C, Nelson DB, Smith DS, et al. Clinical predictors of bacterial versus aseptic meningitis in childhood. Ann Emerg Med 1992;21:910-4. 39. Gomez B, Bressan S, Mintegi S, et al. Diagnostic value of procalcitonin in well-appearing young febrile infants. Pediatrics 2012;130:815-22. 40. Bressan S, Gomez B, Mintegi S, et al. Diagnostic performance of the lab-score in predicting severe and invasive bacterial infections in well-appearing young febrile infants. Pediatr Infect Dis J 2012;31:1239-44. 41. Maniaci V, Dauber A, Weiss S, et al. Procalcitonin in young febrile infants for the detection of serious bacterial infections. Pediatrics 2008;122:701-10. 42. Feigin RD, McCracken GH, Klein JO. Diagnosis and management of meningitis. Pediatr Infect Dis J 1992;11:785-814. 43. Fleisher GR. Infectious disease emergencies. In: Fleisher GR, Ludwig S, Bachur RG, et al, editors. Textbook of pediatric emergency medicine. 5th ed. Philadelphia (Pa): Lippincott Williams & Wilkins; 2006. p. 783. 44. Nigrovic L, Kuppermann N, Macias C, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 2007;297:52-60. 45. Dubos F, Martinot A, Gendrel D, et al. Clinical decision rules for evaluating meningitis in children. Curr Opin Neurol 2009; 22:288-93. 46. Gendrel D, Raymond J, Assicot M, et al. Measurement of procalcitonin l levels in children with bacterial or viral meningitis. Clin Infect Dis 1997;24:1240-2. 47. 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;159:158-9. 48. Naqvi SH, Dunkle LM, Naseer S, et al. Significance of neutrophils in cerebrospinal fluid samples processed by cytocentrifugation. Clin Pediatr 1983;22:608-11. 49. Sawyer MH. Enterovirus infections: diagnosis and treatment. Pediatr Infect Dis J 1999;18:1033-9 [quiz 1040]. 50. Simko JP, Caliendo AM, Hogle K, et al. Differences in laboratory findings for cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex virus (HSV) documented by detection of HSV DNA. Clin Infect Dis 2002;35:414-9. 51. Verboon-Maciolek MA, Nijhuis M, Van Loon AM, et al. Diagnosis of enterovirus infection in the first 2 months of life by real-time polymerase chain reaction. Clin Infect Dis 2003;7: 1-6. 52. Noordhoek GT, Weel JFL, Poelstra E, et al. Clinical validation of a new real-time PCR assay for detection of enteroviruses and parechoviruses, and implications for diagnostic procedures. J Clin Virol 2008;41:75-80. 53. Kupila L, Vuorinen T, Vainionp R, et al. Diagnosis of enteroviral meningitis by use of polymerase chain reaction of cerebrospinal fluid, stool, and serum specimens. Clin Infect Dis 2005;40:982-7. 54. Wolthers KC, Benschop KSM, Schinkel J, et al. Human parechoviruses as an important viral cause of sepsislike illness and meningitis in young children. Clin Infect Dis 2008;47: 358-63. 55. King RL, Lorch SA, Cohen DM, et al. Routine cerebrospinal fluid enterovirus polymerase chain reaction testing reduces hospitalization and antibiotic use for infants 90 days of age or younger. Pediatrics 2007;120:489-96. 56. Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 2000;283:2680-5.

57. Arditi M, Mason EO, Bradley JS, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics 1998;102:1087-97. 58. Andersen J, Backer V, Voldsgaard P, et al. Acute meningococcal meningitis: analysis of features of the disease according to the age of 255 patients. J Infect 1997;34:227-35. 59. Gray LD, Fedorko DP. Laboratory diagnosis of bacterial meningitis. Clin Microbiol Rev 1992;5:130-45. 60. Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system infection with Listeria monocytogenes. Medicine 1998; 77:313-36. 61. Kotilainen P, Jalava J, Meurman O, et al. Diagnosis of meningococcal meningitis by broad-range bacterial PCR with cerebrospinal fluid. J Clin Microbiol 1998;36:2205-9. 62. Talan DA, Hoffman JR, Yoshikawa T, et al. Role of empiric parenteral antibiotics prior to lumbar puncture in suspected bacterial meningitis: state of the art. Rev Infect Dis 1988;10: 365-76. 63. 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: 1169-74. 64. 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;110:712-9. 65. Peters ML. Suspected meningitis in the emergency department: diagnosis and management. Clin Pediatr Emerg Med 2003;4:186-94. 66. Kumar R. Aseptic meningitis: diagnosis and management. Indian J Pediatr 2005;72:57-63. 67. Sez-Llorens X, O'Ryan M. Cefepime in the empiric treatment of meningitis in children. Pediatr Infect Dis J 2001;20:356-61. 68. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998;129:862-9. 69. Miner JR, Heegaard W, Mapes A, et al. Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center. J Emerg Med 2001;21:387-92. 70. Proulx N, Frechette D, Toye B, et al. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005;98:291-8. 71. Auburtin M, Wolff M, Charpentier J, et al. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: The PNEUMOREA prospective multicenter study. Crit Care Med 2006;34:2758-65. 72. Brouwer MC, McIntyre P, De Gans J, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2010;9 CD004405. 73. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267-84. 74. Marhoum El Filail K, Noun M, Chakib A, et al. Ceftriaxone versus penicillin G in the short-term treatment of meningococcal meningitis in adults. Eur J Clin Microbiol Infect Dis 1993;12:766-8. 75. Pickering LK, Kimberlin DW, Long SS, editors. Red book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village (Ill): American Academy of Pediatrics; 2012.