Meningitis

After completing this article, the reader should be able to:Bacterial meningitis is a severe, life-threatening infection of the central nervous system that requires immediate medical attention. Even with appropriate treatment, morbidity and mortality can be substantial. It is essential for clinicians to recognize the clinical signs and symptoms of meningitis and understand its management and prevention. The focus of this review is acute bacterial meningitis in children, including its causes in different age groups, epidemiology, clinical features, diagnosis, treatment, and sequelae.Acute bacterial meningitis has a relatively rapid onset of symptoms, and routine laboratory techniques can usually identify the pathogen. The most common causes have been Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b (Hib), group B Streptococcus (GBS), and Listeria monocytogenes (Table 1). (1)(2)(3) These organisms caused more than 80% of acute bacterial meningitis in children during the 1970s and 1980s. In 1990, conjugate Hib vaccine was introduced. It has almost eliminated Hib meningitis in countries where it has been implemented and decreased the overall incidence of acute bacterial meningitis by 55%. Implementation of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 resulted in a 59% reduction in rates of pneumococcal meningitis in children younger than 2 years of age. (4) Through herd immunity, the vaccine also protected nonimmunized children and adults. From 1998 to 2007, the overall incidence of bacterial meningitis decreased by 31% from 2.00 cases per 100,000 population to 1.38 cases per 100,000 population. (5) However, mortality from bacterial meningitis remained substantial, and the case fatality rate did not change. In addition, rates of pneumococcal meningitis from non-PCV7–serotype strains began to increase, including cases of meningitis due to drug-resistant strains, such as serotype 19A. (6) In 2010, PCV13 was introduced to respond to the emerging invasive strains of pneumococcus. Currently, S pneumoniae remains the most common cause of acute bacterial meningitis for children older than 1 month.In developed countries, conjugated vaccines have decreased the incidence of bacterial meningitis in all age groups except children younger than 2 months. The success of the vaccines has shifted the median age of meningitis disease from younger than 5 years of age to 42 years. (5) Nonetheless, the highest incidence of bacterial meningitis remains among children younger than 2 months of age, primarily because the pathogens responsible for meningitis in young infants differ from those causing infection in older children (Table 1). GBS causes 50% to 60% of bacterial meningitis cases among neonates, Escherichia coli about 20% of cases, and other Gram-negative bacilli another 10%. (1)(2) These organisms are usually acquired from the maternal genitourinary tract. Since 1996, the practice of maternal GBS screening and use of intrapartum antimicrobials has become routine in developed countries, resulting in an 86% reduction in early-onset GBS disease in the United States. (7) However, the incidence of late-onset disease has not fallen. Risk factors for acute bacterial meningitis in neonates and older children are highlighted in Table 2. (8)(9)(10)Aseptic meningitis is characterized by clinical signs and symptoms of meningitis without evidence of a bacterial cause by usual laboratory testing methods. Some bacteria that do not grow in routine culture, such as Mycobacterium tuberculosis and Borrelia burgdorferi, can cause aseptic meningitis. Aseptic meningitis has many infectious and noninfectious causes. The most common are listed in Table 3.The incidence is uncertain because aseptic meningitis is not a reportable disease. A birth cohort study from Finland found the annual incidence to be 28 per 100,000 persons, with the highest rates in children younger than 4 years of age. (11) Enteroviruses and parechoviruses account for most of all known cases. In temperate climates, infections with these viruses typically occur in the summer and fall seasons. Arboviruses encompass a vast number of viruses from different biologic families that are transmitted by arthropods, especially mosquitoes. The most commonly reported arboviruses causing aseptic meningitis infections in the United States are West Nile virus and La Crosse virus.Noninfectious causes include medications, autoimmune and auto-inflammatory diseases, and neoplasms. Herpes simplex virus (HSV) is a cause of life-threatening meningoencephalitis in neonates. It is beyond the scope of this review to discuss the clinical features and management of HSV meningoencephalitis.Chronic meningitis involves ongoing signs and symptoms of meningitis for 4 or more weeks without clinical improvement. It has many infectious and noninfectious causes (Table 4), each with its own epidemiology. The overall incidence of chronic meningitis is unknown due to limitations in data collection. The epidemiology differs according to the causative agent.The clinical manifestations of neonatal bacterial meningitis are generally nonspecific and usually comprise a constellation of signs and symptoms. Although temperature instability is a common feature, with either fever or hypothermia occurring in about 60% of newborns who have bacterial meningitis, normothermia is not unusual. (12) There is often a report of vomiting and poor feeding. Parents frequently state that their infant is fussy, inconsolable, sleepy, weak, or jittery. Seizures occur in 20% to 50% of infants with the presentation of illness. Neck stiffness is uncommon in neonates. Parents may report that the baby has a “knot on its head” to describe the presence of a bulging fontanelle. Important information to ascertain includes risk factors for meningitis (Table 2), the birth history, trauma, congenital anomalies, and maternal history of sexually transmitted infections (recognizing that there is often no history suggestive of maternal genital HSV in infants with HSV disease).The clinical presentation of meningitis in older children often occurs over a few days and may include a progressive history of fever, headache, lethargy, irritability, confusion, photophobia, nausea, vomiting, back pain, and stiff neck. (13) Sometimes the presenting signs and symptoms are severe and sudden, occurring within a period of hours. About 20% of affected children have a seizure before diagnosis, and about 25% have a seizure during the first few days of hospitalization. The seizures are frequently complex and more common with meningitis due to Hib or S pneumoniae than N meningitidis. Important historical information to obtain includes risk factors for meningitis (Table 2) and recent medications, including use of antibiotics that might interfere with the ability to isolate a pathogen from blood or cerebrospinal fluid (CSF) culture.Vital signs and general appearance should be assessed. Affected infants usually do not like to be moved or examined. Neurologic features of meningitis in infants include inconsolable irritability, lethargy, poor tone, and seizures. (12) Nuchal rigidity is uncommon. The anterior fontanelle is usually full but not often bulging. Poor capillary refill and respiratory difficulty with grunting, tachypnea, and nasal flaring are frequent findings. The infant is less active and often seems apathetic and disinterested in its surroundings. Head circumference should be measured daily to monitor for increased intracranial pressure.The child with meningitis is usually irritable or lethargic on physical examination. Vital signs, including pulse oximetry, should be obtained promptly to help evaluate for hypovolemia, shock, and increased intracranial pressure (ICP). Cushing triad (hypertension, bradycardia, and respiratory depression) is a late finding of increased ICP. Although the following signs of ICP are uncommon, patients should screened for papilledema, diplopia, and cranial nerve paralysis. (13) The pediatric Glasgow Coma Scale can be a useful tool to monitor the patient’s level of consciousness. Children who are obtunded or comatose upon admission have worse outcomes than those who are not.Nuchal rigidity, a sign of meningeal inflammation, is demonstrated when the child is unable to flex the neck so that it touches the chest, and by the presence of a Kernig or Brudzinski sign. With the child in the supine position, the Kernig sign is present when the hip and knee are flexed at 90 degrees and the leg cannot be passively extended more than 135 degrees or the patient flexes the opposite knee. The Brudzinski sign occurs when the child is in the supine position and passive flexion of the neck causes the legs to bend at the hip and knee.Two separate blood cultures and a complete blood cell (CBC) count with differential count should be obtained. If not pretreated with antibiotics, 80% to 90% of children with bacterial meningitis have positive blood cultures. The peripheral white blood cell (WBC) count might be high in bacterial meningitis, but it is frequently within normal limits and may be low in neonates. If the CBC count reveals thrombocytopenia or if petechiae or purpura are present on examination, tests for disseminated intravascular coagulation should be obtained. Serum electrolytes, blood urea nitrogen, creatinine, and glucose should be monitored to assess for syndrome of inappropriate antidiuretic hormone (SIADH), manage fluid administration, adjust antimicrobial doses, and compare the CSF-to-blood glucose ratio. Elevated serum procalcitonin and C-reactive protein values are suggestive of bacterial meningitis but cannot reliably discriminate between bacterial and viral meningitis. (14) However, serial C-reactive protein measurements can be an adjunctive tool to monitor the patient’s clinical response and screen for potential complications.Unless otherwise contraindicated, a lumbar puncture (LP) should be performed on any child suspected of having bacterial meningitis (Figure). (9)(15) Contraindications to LP include increased ICP, coagulopathy, hemodynamic or respiratory instability, or skin infection over the LP site. If contraindications to LP exist, antimicrobial therapy should not be delayed; blood cultures should be obtained and empiric antibiotics started promptly. When obtained, CSF should be evaluated for CBC count with differential count, glucose and protein concentrations, Gram stain, and bacterial culture. If the patient has not been pretreated with antibiotics, the typical CSF findings in bacterial meningitis include a neutrophilic pleocytosis (often >1,000 WBCs/μL), elevated protein, low glucose, and a positive culture for a pathogenic bacterium. However, in rare instances, no or few CSF WBCs may be seen very early in the course of infection. Because of possible misinterpretation of CSF Gram stains, antimicrobial therapy should not be narrowed based on the Gram stain result; empiric broad-spectrum antibiotics should be continued until culture results are known. Table 5 provides the normal CSF parameters based on age and usual CSF findings based on selected microbial cause of meningitis.Bleeding into the CSF from a traumatic LP can make it difficult to interpret the CSF cell count. One formula estimates the expected number of CSF WBCs from a traumatic LP by comparing the ratio of (expected CSF WBCs)/(actual CSF red blood cells [RBCs]) to (blood WBCs)/(blood RBCs). The calculated number of expected CSF WBCs is then subtracted from the actual number of CSF WBCs to determine if there is a CSF pleocytosis. A simpler correction method is to subtract 1 to 2 CSF WBCs for every 1,000 CSF RBCs/mm3. However, these formulas are inexact, and clinicians must be cautious when interpreting the results. Empiric antibiotics should be administered while awaiting culture results for children with a traumatic LP. Furthermore, if the CSF is grossly bloody, attempting a repeat LP is a prudent course.Children with suspected meningitis sometimes receive oral or parenteral antibiotics before a lumbar puncture is performed. CSF cultures remain the reference standard for diagnosing bacterial meningitis, but antibiotic pretreatment decreases the likelihood of obtaining a positive CSF culture. In one study of 128 cases of pediatric meningitis, CSF cultures were negative in 29% of children who were pretreated with oral antibiotics and 44% of children who were pretreated with parenteral antibiotics. (16) Within 1 hour of receiving a third-generation parenteral cephalosporin, three of nine children with meningitis CSF and all were within 2 hours. With pneumococcal meningitis, CSF cultures usually become by 4 or more parenteral antibiotic pretreatment the organisms have decreased to antibiotics. pretreatment not the CSF cell count and is with CSF glucose and protein values than be expected for bacterial meningitis. However, these are to the of bacterial meningitis. tests have been for patients with suspected bacterial meningitis and negative CSF Gram stain and culture. However, these tests have the and are no for patients pretreated with antibiotics. (14) The overall for tests such as from to for to for S pneumoniae, and to for N meningitidis. (14) The results are usually from patients who antimicrobial study is to determine if CSF useful in the management of patients with suspected bacterial meningitis who have been the other CSF can be a useful tool to identify an to bacterial of the obtained to increased ICP often LP. However, findings are rare in children without clinical findings of a papilledema, or In addition, a normal not that an LP is children with suspected bacterial meningitis and no clinical signs of should LP. If a is blood cultures should be obtained first and antibiotics LP should be performed promptly if no is Although antibiotics are in routine can to in obtaining a and the patient’s should be in children with suspected bacterial signs and symptoms of fever, irritability, lethargy, headache, vomiting, and rigidity are suggestive of bacterial meningitis. However, other should be in the differential and can sometimes cause meningitis that bacterial meningitis in or and neck or are other infectious that may acute bacterial meningitis. such as central nervous system and are also in the differential A review of the medical history, of the laboratory and use of should help the if bacterial meningitis is is usually in an to and of bacterial meningitis increased often occur in the first 2 to days of and must be administered to appropriate blood pressure and The serum electrolytes, and should be monitored in the first to of hospitalization. If the patient not have or upon there may be a for fluid until can be especially if the serum is less than can cause and to confusion, lethargy, and increased ICP. If is serum and should also be can be when the 135 often within to should receive a daily and a during the first few days of Children younger than months of age should have daily circumference early signs of increased ICP can be by the of the However, severe signs of increased ICP bradycardia, or more therapy with and seizures occur early in the disease course in 20% to 25% of meningitis cases and can usually be with standard seizure medications, such as or or seizures occurring more than admission should a to one of children with bacterial meningitis a In most cases, cause symptoms or are and do not manifestations of are often or If a is usually can present as fever, headache, and rigidity or onset of features, such as in the of appropriate antibiotic should be started promptly LP to the risk of if a is before the blood cultures should be obtained first and antibiotics administered (Figure). It is to determine that the antibiotics administered can in the CSF and are the bacterial antimicrobial therapy of suspected bacterial meningitis in the has often of and However, with of coli and other Gram-negative organisms to clinicians with when bacterial meningitis is Although the use of has been to the of Gram-negative this risk must be the risk of Gram-negative meningitis in the of CSF by When the causative and its antibiotic are therapy can be (Table meningitis caused by or S pneumoniae, days of antibiotics is days of antibiotics is often the of therapy for neonatal meningitis caused by Gram-negative antimicrobial are for meningitis, such as and antimicrobial therapy of suspected bacterial meningitis for children 1 of age and older involves either or is because of the of It not to be continued if the is to or When the causative and its antibiotic are therapy can be (Table pneumococcal meningitis, clinicians should the has to of and 2) a repeat LP reveals the presence of the has a high or has been must be when pneumococcal meningitis to that antimicrobial is for meningitis and not for or are possible for children with to and should not be administered because it has CSF and clinical it as for meningitis is should not be administered because can during meningitis, the usual of antimicrobial therapy is to days for S pneumoniae, to days for 5 to days for N meningitidis, to days for and a of weeks for Gram-negative A pediatric infectious should be especially for cases, including CSF trauma, or recent are for patients with an CSF and negative blood and CSF cultures. If the child has a positive blood culture, CSF and negative CSF culture, is usually for meningitis as if the CSF culture been In this Gram-negative and suspected meningitis for days of patients with but suspected bacterial meningitis pretreated with is often days or more of and for neonates and days of for older infants and However, the management of patients with a CSF pleocytosis and negative blood and CSF cultures to be on an clinical with a pediatric infectious is CSF pleocytosis sometimes occurs in young infants with infections who have not been pretreated with antibiotics. These infants are often not for bacterial meningitis and are at very low risk for has been as adjunctive therapy to the response and of bacterial meningitis, especially However, its use in children with bacterial meningitis has been A recent of children from a found that use of with meningitis caused by but not meningitis caused by other Nonetheless, children in this study from countries who meningitis and reduction in severe the that these children might from because there was no evidence of from the However, the results are and the use of adjunctive for meningitis remains Because Hib meningitis has become rare in developed countries, empiric therapy is to In addition, was not of the for most of the adjunctive has CSF and there is that may its into the CSF by meningeal of on a potential of for patients with Hib meningitis and that empiric use might be for suspected bacterial meningitis in infants and children weeks of age and older the possible potential The that data are to routine adjunctive therapy for pediatric pneumococcal meningitis. If is it should be administered before or at the as the first of antibiotics. has no if more than 1 hour antibiotics. The usual is per every for 2 on a repeat LP to of therapy for all infants with Gram-negative bacilli meningitis to of the If the CSF culture remains the antimicrobial should be and another LP performed. Some a repeat LP to of therapy for all cases of neonatal meningitis to CSF In the United for and repeat LP in neonates if are receiving appropriate antibiotic for the causative and are a clinical a repeat LP in neonates or fever, 2) in clinical clinical findings or cases of pneumococcal meningitis, an LP of therapy the is and testing is not 2) the is not or is or the patient has because it can clinical features such as fever, headache, and If the is repeat LP at to should be to CSF of the an LP for bacterial meningitis is no common However, if one is obtained, the of antimicrobial therapy might to be extended if the CSF has more than the glucose is less than or the CSF-to-blood glucose ratio is less than usually 4 to days of appropriate of fever or continued fever for more than days should an for the The of adjunctive often results in a of fever for such as or should be and appropriate performed when The to repeat an LP for CSF and culture should be on a from a viral infection is not uncommon. A from a peripheral central is also a fever is uncommon and a of A cause for fever is often not is often performed early in the course of disease to identify possible fluid or other In addition, obtain a or with 1 to days before the expected of in cases. is to identify any potential such as or that antimicrobial In addition, it might information and the for early with or is for infections from and because of their to cause are in with LP in the of bacterial meningitis. with or is usually not during the management of bacterial meningitis in the older infant and However, or with is in including signs, seizures of antimicrobial positive CSF meningitis, and infection with Gram-negative especially or meningitis can be a disease. rates all pediatric from less than to on the pathogen and when the was The patient’s and are affected by many including age, bacterial and clinical when antibiotics are age, bacterial and CSF are all with worse A decreased level of at presentation is with increased risk for or The of seizures more than antibiotics has been with to Hib or N meningitidis, infection caused by S pneumoniae is with a occurs in 20% to of children with pneumococcal meningitis, with meningitis, and with Hib meningitis. is also with CSF glucose less than at the of can in and difficulty with include and cranial nerve and generally over and may months or years the can be for to when are and able to and have been for to hours. In selected of antimicrobial therapy may be at for therapy should the have 5 to days of and have with immediate to and of therapy include of to a normal and decreased should be performed before or testing is if the and should be as Children with should be appropriate for and other so have the to their Even infants and children who upon of therapy are at risk for and routine with their are to monitor their and Furthermore, infants and young children may be for early Children completing antimicrobial therapy at from the who was their S pneumoniae, and N is the for meningitis from these of the Hib conjugate vaccines in infants has resulted in a in the incidence of Hib meningitis. The conjugated vaccines for and have been relatively in disease from for and to cause life-threatening with invasive Hib or disease should be in until have of therapy with a third-generation or 4 days of In addition, of patients with Hib and disease should be antimicrobial is for all of a patient with invasive Hib infection if at one of is younger than age 4 years and is or is daily by for 4 If or more cases of invasive Hib disease occur within days at a child or and or children is for all of age or vaccine of patients with of vaccine should receive with or The of antimicrobial on the for the daily is for patients with and to invasive pneumococcal disease.