The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Raúl Rudoy. This current third edition chapter is a revision and update of the original author’s work.
A 3-month old male presents to the emergency department with lethargy. He was seen 3 days before with fever and symptoms of an upper respiratory infection, diagnosed with otitis media and treated with oral amoxicillin. This morning he became irritable and was less active than usual. He has vomited three times and his urine output is noticeably decreased. He has no diarrhea.
Exam: VS T 40.0, HR 90, RR 30, BP 120/90, weight 8 kg. He is lethargic and arousable only to painful stimuli. His anterior fontanel is full and tense, and he has questionable neck rigidity. His tympanic membranes are red and bulging. His pupils are reactive, but his eyes do not focus well on his parents. His heart, lungs and abdomen are normal. His color and perfusion are good. He has no petechiae. He moves all his extremities weakly and his deep tendon reflexes are hyperactive.
A complete blood count (CBC), blood culture and chemistry panel are drawn. Intravenous (IV) access is started. Since increased intracranial pressure (ICP) is suspected, a lumbar puncture (LP) is initially deferred, but he is immediately given 500 mg of ceftriaxone IV. A stat computed tomography (CT) scan of the brain is normal, so a LP is done and the cerebrospinal fluid (CSF) is visibly hazy. The CSF results return 1 hour later showing 450 white blood cells (WBCs) per cubic mm, 95% neutrophils, 5% monocytes, total protein 75 mg/dl, and glucose 25 mg/dl. Gram-stain of the CSF shows many WBCs with few gram-positive cocci. He is admitted to the pediatric intensive care unit.
This patient presented with a rapidly evolving febrile illness, changes in sensorium and evidence of increased ICP, clinical features highly suggestive of a central nervous system (CNS) infection. In addition, his laboratory results are suggestive of bacterial meningitis. The most common causes of bacterial meningitis in the pediatric population include Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (also known as pneumococcus), Neisseria meningitides (also known as meningococcus), Group B streptococcus (GBS), and Listeria monocytogenes. The specific etiology is dependent on various factors including age, immunization status, immune function, as well as geographical location (1).
Among the pediatric population, the highest risk groups for bacterial meningitis include premature infants, neonates, and infants less than 2 months of age. Following the introduction of the pneumococcal and Hib conjugate vaccines to the infant immunization schedule in the United States, there has been a large reduction in incidence of bacterial meningitis in all age groups, except in infants less than 2 months old. Children in this age group are predisposed to developing bacterial meningitis due to immaturity of their immune system, impaired leukocyte phagocytic ability, and lack of maternal immunoglobulins, which start to cross the placenta at 32-week gestation. Risk factors for bacterial meningitis in the neonate include prematurity, maternal rectovaginal colonization of GBS, premature or prolonged (greater than 18 hours) rupture of membranes, very low birth weight (less than 1,500 grams), prolonged hospitalizations, and presence of shunts, catheters or other internal devices (2).
The two most common pathogens causing early-onset bacterial meningitis in neonates (i.e., presenting within the first 72 hours of life) include GBS and Escherichia coli. In the context of late-onset meningitis (i.e., presenting after 72 hours of life), the most common pathogens include coagulase-negative staphylococci, Staphylococcus aureus, E. coli and Klebsiella species. Late-onset meningitis is predominantly seen in premature neonates and is directly related to decreased gestational age and weight. A significant drop in cases of L. monocytogenes meningitis has been seen due to a decreasing incidence of food-borne listeriosis in pregnancy (2). In older infants and children, S. pneumoniae and N. meningitidis are the most frequent pathogens. In the adolescent age group, N. meningitidis is the most common pathogen. Overall, S. pneumoniae remains the most common cause of bacterial meningitis in the pediatric population. Prior to the introduction of Hib vaccine in the late 1980s, this pathogen was the most common cause of bacterial meningitis, but Hib vaccination has almost eradicated this as a cause of bacterial meningitis (1,3).
Manifestations of bacterial meningitis are variable and depend upon the child's age and the duration of illness. There is no single reliable sign or symptom that is pathognomonic for meningitis. Experienced clinicians have a gestalt that the child is very ill appearing; often the word "toxic" in appearance is used. In young infants, clinical manifestations may include fever, lethargy, irritability, poor feeding, vomiting, or diarrhea. Other more severe manifestations include bulging fontanel, seizures, or respiratory distress, signs that may be indicative of increased ICP. Body movements of infants with meningitis result in pain; accordingly a strong suspicion of CNS infection is aroused when the child resists handling but prefers to remain motionless. Such paradoxical irritability (which worsens when the child is carried, rocked or gently bounced), is highly suggestive of meningitis. In contrast, children older than 2 years and adolescents will often present with more characteristic systemic symptoms including fever, lethargy, confusion, headache, nuchal rigidity, photophobia, nausea and/or vomiting. Signs of meningeal irritation (nuchal rigidity, headache, photophobia), is present in 60% to 80% of affected children during hospital presentation. The classical Kernig and Brudzinski signs may be difficult to elicit in young children (1).
Given the nonspecific clinical presentation of bacterial meningitis in neonates, work-up should include a full laboratory evaluation with CBC with differential, blood culture, urine culture (especially if child older than 6 days of age) and LP. Examination of CSF obtained during a LP is necessary to confirm the diagnosis of bacterial meningitis. Inflammatory markers (such as CRP, or procalcitonin), serum electrolytes, BUN/creatinine, coagulation studies (PT, INR, aPTT) and lactate level can be helpful but are not as diagnostic as an LP (1,3).
Strong consideration should be given to delaying the LP in patients who are clinical unstable and at risk of deteriorating. If deciding to delay an LP for CSF evaluation, immediate blood cultures should be obtained and antibiotics administered immediately once bacterial meningitis is suspected based on initial evaluation (1). The patient in our case had evidence of increased ICP given his decreased sensorium, bulging tense fontanel, and hyperactive reflexes, in addition to systemic bradycardia, hypertension and irregular respirations consistent with Cushing’s triad. Accordingly, caution should be taken before performing the LP given the possibility of precipitating herniation. In such a case, performing the LP is delayed due to the need for neuroimaging, but this should never delay the administration of antibiotics. A CT scan of the head is a rapid and accurate means to confirm increased ICP and, if present, measures such as the administration of mannitol should be initiated. Note that neuroimaging is not performed to diagnose meningitis but rather to diagnose potential complications that may dictate management.
A LP and CSF culture are the gold standard of diagnosis of meningitis. Acute bacterial meningitis is characterized by an elevated CSF white count (pleocytosis) with a predominance of polymorphonuclear cells (neutrophils), a decreased CSF glucose level, an increased protein value, and a positive Gram-stain and culture. Other suggestive laboratory results that are less reliable include abnormal peripheral blood cell counts (high or low WBC count, increase in immature neutrophils, low platelet count). Definitive diagnosis of bacterial meningitis is made by any of the following: 1) isolation of a bacterial pathogen from the CSF culture, 2) isolation of bacteria from blood cultures with CSF pleocytosis, and 3) detection of a bacterial pathogen in CSF by polymerase chain reaction (PCR) and other molecular methods (1).
Immediate initiation of specific broad-spectrum antibiotics is the standard of care for possible bacterial meningitis. Antibiotics used to treat meningitis must reliably penetrate the blood brain barrier in addition to reliably cover 100% of the organisms involved. Current recommended empiric treatment for neonates up to 1 month of age include IV ampicillin and cefotaxime (or ceftazidime, or cefepime). Gentamicin is not a preferred choice given its lower CNS penetration. For patients older than 1 month to 18 years old, ampicillin IV, ceftriaxone IV, and IV vancomycin are recommended. The use of a third-generation cephalosporin such as cefotaxime or ceftriaxone provides coverage for most of the agents responsible for bacterial meningitis. Ceftriaxone, not only provides gram-negative coverage but is very effective against S. pneumoniae and N. meningitidis, and has improved CNS penetration. Cefotaxime is a third-generation cephalosporin that is equivalent to ceftriaxone and is safe for neonates. Additionally, ampicillin offers coverage for Listeria organisms. Vancomycin is added empirically because some pneumococcal meningitis cases are resistant to high dose ampicillin and cephalosporins. The duration of treatment is dictated mostly by the clinical course, but it is usually 5 to 7 days for meningococcal infections and 10 days for infections due to S. pneumoniae (4).
The use of corticosteroids in bacterial meningitis is currently controversial due to lack of sufficient supportive evidence. In cases of H. influenzae meningitis, corticosteroids were found to reduce hearing impairment in children.
In the setting of increased ICP, as seen in the patient presented, some interventions must be initiated to maintain cerebral perfusion. This includes placing the patient in reverse Trendelenburg (head higher than the rest of the body), and administering 25% mannitol or hypertonic 3% saline to reduce cerebral edema.
The survival of patients with bacterial meningitis has improved but it still remains a disease with high morbidity. In developed settings, mortality is only 4% to 5%. Yet, approximately half of those with S. pneumoniae and 15% of those with H. influenzae meningitis will develop neurological sequela, the most common being seizures, hearing loss, and intellectual disability. Seizures occur in 20% to 30% of children with acute bacterial meningitis. Though often attributed to febrile illness, the cause of most seizures is often cerebrovascular inflammation, microinfarcts, or neurochemical changes. Seizures that are prolonged and difficult to control, or late-onset beginning 72 hours following hospitalization, are more frequently associated with permanent neurological sequelae. Permanent sensorineural hearing loss occurs in 5% to 10% of patients overall. In those with pneumococcal meningitis, hearing loss is three times more frequent than with other causes, occurring in up to 30% of patients. The hearing loss is usually severe, bilateral and permanent, and it occurs during the first few days of the infection (1). In the late 1980s, studies showed a reduction in the incidence of hearing loss with the use of corticosteroids (dexamethasone) for cases of H. influenzae meningitis (5). Unfortunately, the benefits of dexamethasone are less clear for children with meningitis caused by S. pneumoniae, the most common current cause of bacterial meningitis. Consequently, since data is not definitive, some providers may (and some may not) elect to use corticosteroids for cases of suspect bacterial meningitis in children (6). If used, the first dose of dexamethasone must be given before or concomitant with the first dose of antibiotics; if given later, any potential benefit is reduced or lost (7).
Children with acute bacterial meningitis are at an increased risk for developmental delays, behavioral problems, and learning difficulties in the future. A more serious neurological complication of meningitis is cerebral edema and increased ICP, a result of vasogenic, cytotoxic or interstitial mechanisms. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs in bacterial meningitis and thus, the patients electrolytes and fluid status must be monitored (1).
Primary prevention of meningitis is accomplished by the administration of Hib and S. pneumoniae vaccines to infants. Meningococcal vaccines are also available and are recommended for children age 11 and above. Recommended antibiotic chemoprophylaxis for close contacts of patients with invasive Hib include rifampin, and for those with N. meningitidis meningitis include rifampin, ciprofloxacin, or ceftriaxone. In the setting of ciprofloxacin-resistant N. meningitidis exposure, azithromycin is recommended. In case of meningitis caused by S. pneumoniae, no prophylaxis is recommended for exposed contacts (1).
Aseptic meningitis is defined as a febrile illness with clinical manifestations of meningeal irritation without evidence of bacterial pathogens in the CSF and no associated neurological dysfunction.
Aseptic meningitis is almost always due to viral etiologies. The most common cause of viral meningitis are the enteroviruses. Other less common causes include herpesviruses, arboviruses and human parechoviruses. Rare cases of tuberculous and fungal meningitis will present as an aseptic meningitis as well (8).
The incidence of viral meningitis is highest among infants less than one year of age and in children greater than five years. Patients with viral meningitis can have all of the signs and symptoms of patients with bacterial meningitis; however, their findings are less severe. Similar to bacterial meningitis, infants may present with non-specific symptoms such as poor feeding, vomiting and irritability. Older children may also present with headache, fever, nuchal rigidity, photophobia, nausea and vomiting. In the context of enterovirus infection, which is the most common cause of viral meningitis, patients can often present in the late summer or early fall, with concurrent symptoms of conjunctivitis, pharyngitis, rash or hand-foot-mouth disease (8).
Generally, children presenting with symptoms concerning for meningitis should be presumed to have bacterial meningitis until the diagnosis can be excluded. An LP should also be performed for CSF evaluation. A LP has two objectives in cases of viral meningitis in that it will ascertain a firm diagnosis and it will usually provide some degree of headache relief. Other lab studies such as a CBC, chemistry, and inflammatory markers can be helpful, but they are not diagnostic and are not a substitute for an LP. There are times when the diagnosis of viral meningitis is almost certain and bacterial meningitis is very unlikely based on history and examination alone. For example, the child is older and is describing mild symptoms, the child is fully immunized, and the patient’s exam finds an alert and active child and other findings indicative of viral meningitis. In such cases, parents might decline an LP but they should be advised about the risks of missing an early bacterial meningitis that has not had the time to reveal itself clinically.
The definitive diagnosis of viral meningitis is established by negative bacterial cultures and presence of a viral pathogen in CSF. A CSF PCR for enterovirus is highly accurate in making an etiological diagnosis and will be positive in the great majority of cases. In contrast to bacterial meningitis, aseptic meningitis is characterized by lower CSF protein, higher CSF glucose, and a lower neutrophil percentages (1). CSF neutrophil predominance can be initially seen in up to two thirds of cases of meningitis due to enterovirus; however, a repeated LP done 12 to 24 hours after the first one will show a rapid shift in the CSF differential count from neutrophils to mononuclear predominance. In other words, the early high percentage of neutrophils rapidly shifts to lymphocyte/monocyte predominance.
Supportive care is the recommended treatment for children with viral meningitis who are deemed to have a very low risk of bacterial meningitis. Stable vital signs, improved symptoms following LP, rehydration and antipyretic and analgesic therapy, and good access to follow-up care describe a patient who can be discharged for outpatient follow-up with supportive care (8). If the diagnosis of viral meningitis is highly suspected but confirmation is pending culture or PCR result, the decision on further treatment and disposition will need to be made with the clinical information and the existing laboratory information. In other words, the clinician must be clinically certain that bacterial meningitis is not present. Empiric acyclovir can be considered if the patient presents with signs of encephalitis or if there is concern for herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection in neonates and immunocompromised patients. Empiric antibiotic therapy and possible hospitalization should be considered if there is any concern for bacterial meningitis on initial examination given the serious neurological consequences of a delayed treatment.
The prognosis of viral meningitis is excellent. Most children experience symptoms for less than one week and recover completely without any neurological sequelae. It is likely that many patients who have viral meningitis do not present for medical care since their symptoms are mild. Methods of prevention include simple hand washing measures, particularly important to spreading of enteroviruses (8).
Questions
1. A 6 YO male presents with a bad headache, nausea, photophobia and fever (38 degrees C). His immunizations are up to date. He is not toxic in appearance. He is alert and cooperative. He has mild photophobia and mild nuchal discomfort without rigidity. He can speak and ambulate normally. The remainder of his exam is unremarkable. If this patient has meningitis, does he/she have bacterial or viral meningitis? What factors suggest one or the other? Does he need an LP? Does he require hospitalization?
2. A LP is done on the patient in question #1. The results show the following: 3 RBCs, 200 WBCs, 70% neutrophils, 10% lymphocytes, 20 % monocytes, total protein 45 mg/dl, glucose 50 mg/dl. Gram stain of the CSF shows many WBCs and no organisms are seen. Is this CSF analysis consistent with bacterial or viral meningitis? Which factors suggest one or the other?
3. What are the three most common bacteria that cause meningitis and what antibiotic covers them with close to 100% certainty?
4. Match the CSF results with the diagnosis (normal CSF, viral meningitis, bacterial meningitis). Validate your answer. Assume that the patient is 6 months old.
References
1. Panuganti SK, Nadel S. Acute Bacterial Meningitis Beyond the Neonatal Period. Long SS, Pickering LK, Prober CG (eds). Principles and Practice of Pediatric Infectious Diseases, 6th Edition, Churchill Livingstone, Philadelphia, PA. 2023; Chapter 40: 286-297
2. Bundy LM, Noor A. Neonatal Meningitis. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://ncbi.nlm.nih.gov/books/NBK532264
3. Ouchenir L, Renaud C, Khan S, et al. The Epidemiology, Management, and Outcomes of Bacterial Meningitis in Infants. Pediatrics 2017;140(1):e20170476
4. American Academy of Pediatrics. Table 4.12. Systems-based Treatment Table. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 Report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics: 2021:1001-1002
5. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al. Dexamethasone therapy for bacterial meningitis: results of two double-blind, placebo-controlled trials. N Eng J Med 1988;319(Oct 13):964-971
6. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacte3rial meningitis. Cochrane Database of Systematic Reviews 2015 Sep 12: CD004405
7. 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
8. Al-Quahtani SM, Shati AA, Alqahtani YA, Ali AS. Etiology, Clinical Phenotypes, Epidemiological Correlates, Laboratory Biomarkers and Diagnostic Challenges of Pediatric Viral meningitis: Descriptive Review. Frontiers in Pediatrics 2022(10: 923125
Answers to questions
1. This is most likely a viral meningitis. He is older, so his risk of bacterial meningitis is lower. He has been fully immunized, which presumably means that he has had H. influenzae type B vaccine and pneumococcal vaccine also. On initial evaluation, he is alert, ambulatory, and not toxic in appearance. Given that his symptoms appear less severe, this is more suggestive of viral meningitis. An LP would make the diagnosis more definitive and it would most likely rule out bacterial meningitis; however, his parents declined an LP. He does not need to be hospitalized if his clinical appearance is good and if bacterial meningitis has been determined to be of extremely low likelihood. Other factors that might be helpful is that his symptoms have lasted for two days. If he had bacterial meningitis during these two days, his clinical appearance would be very seriously ill by this time. His parents are reliable and you have informed them of the pros and cons of doing an LP. They have declined it.
2. This is most consistent with viral meningitis. Although he has a high percentage of neutrophils, this is still consistent with early viral meningitis. Cases of bacterial meningitis which have not been pre-treated with antibiotics almost always have more than 90% neutrophils. The gram stain does not show any organisms, which makes bacterial meningitis less likely. This laboratory analysis of his CSF suggesting viral meningitis, is consistent with his clinical appearance which also suggests viral meningitis (see the answer to #1 above).
3. Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae type b. Third generation cephalosporins such as cefotaxime or ceftriaxone provide coverage for most of the agents responsible. Ceftriaxone is very effective against S. pneumoniae and N. meningitidis, and also provides gram-negative coverage. Specifically in the setting of meningitis, ceftriaxone and cefotaxime have improved CNS penetration. Cefotaxime is also a third-generation cephalosporin, equivalent to ceftriaxone, that is safe for neonates. The addition of ampicillin offers Listeria coverage. H. influenzae type B is sensitive to ceftriaxone and cefotaxime as well, but this organism is no longer a common cause of bacterial meningitis due to widespread Hib immunization. Vancomycin will need to be added since some highly resistant pneumococci are resistant to cephalosporins.
4.A. CSF A shows bacterial meningitis. The increased number of cells in the CSF with a predominant number of neutrophils makes this a strong likelihood possibility. In addition, he also has a very low glucose CSF level (CSF to blood glucose ratio of 25%) and an increased protein value. Cases of early viral meningitis can present with an increased number of cells and neutrophils but usually the CSF glucose is normal or not lower than 40% of the blood CSF value.
4.B. CSF B is normal. The normal number of WBCs in the CSF depends upon the age of the patient. The younger and more immature the infant is, the higher the value is. CSF glucose value depends upon the value of glucose in the blood and upon the integrity of the blood brain barrier. In patients with normal meninges the CSF value is usually about 75% of the blood level. When the meninges become inflamed, the active transport of glucose across the blood brain barrier becomes altered and the ratio drops proportionately to the degree of inflammation. Bacterial meningitis results in more inflammation and affects the blood brain barrier more significantly than viral meningitis, resulting in lower CSF glucose values.
4.C. CSF C shows viral meningitis. Most cases of viral meningitis will present with a moderate increase in the number of white cells and if the percentage of neutrophils not less than 70%, it is very likely to be viral meningitis, since bacterial meningitis almost always has >90% neutrophils.
4.D. CSF D is inconclusive. The high percentage of neutrophils indicates that bacterial meningitis is possible. It would be wise to administer antibiotics until more information can be obtained. The gram stain result will be helpful. If it is positive for organisms, then this indicates bacterial meningitis. If the gram stain is negative, bacterial meningitis still cannot be totally excluded. The child's clinical condition is not part of this table, but in reality, a child who is alert, active and playful is more likely to have viral meningitis, as opposed to a lethargic, toxic child who is more likely to have bacterial meningitis. This will probably turn out to be a case of viral meningitis despite the high percentage of neutrophils, since an early viral meningitis will often have high neutrophil percentages. A repeat LP 12 to 24 hours from the first LP will be helpful; a clear shift toward mononuclear cell dominance would be consistent with viral meningitis, while no shift, or only a slight shift would suggest bacterial meningitis. Culture of the CSF will be most definitive if it is positive, but this result will not be available for at least 24 hours.