823 • The classic triad of fever, neck stiffness, and a change in men tal status is present in less than 50% of pediatric meningitis cases • Streptococcus species (particularly viridans, pneumoniae, a[.]
67 Central Nervous System Infections and Related Conditions KEVIN M HAVLIN, CHARLES R WOODS JR, AND MARK E ROWIN PEARLS • The classic triad of fever, neck stiffness, and a change in mental status is present in less than 50% of pediatric meningitis cases • Streptococcus species (particularly viridans, pneumoniae, and milleri) and Staphylococcus aureus are the most common pathogens identified in pediatric subdural empyemas, although up to 30% demonstrate no bacterial growth • Viral causes of encephalitis are very common in children, with enteroviruses, herpesviruses, and arboviruses causing the greatest burden of disease in the northern hemisphere Central nervous system (CNS) infections and the need for neurologic intensive care represent an important patient population in the pediatric intensive care unit (PICU) These infections can progress rapidly and lead to devastating and permanent neurologic sequelae The diversity of infectious agents causing CNS disease includes bacteria, viruses, fungi, parasites, and amoebas In addition, inflammatory postinfectious diseases such as acute disseminated encephalomyelitis and autoimmune processes such as acute hemorrhagic leukoencephalitis and anti-N-methyl-d-aspartate (NMDA) receptor-mediated encephalitis feature diverse presentations and require a high index of suspicion Care of these patients requires a knowledge of epidemiology, signs and symptoms, predisposing factors, and appropriate laboratory and radiologic diagnostic tools Understanding the importance of timely diagnosis and treatment of these conditions could help reduce both morbidity and mortality capsular polysaccharide-protein conjugate vaccines against the most common bacterial etiologies.1–3 Incidence of bacterial meningitis remains highest in the first year of life, with greatest risk among infants younger than months In 2009, the overall incidence of bacterial meningitis by age group in the United States was about 65 per 100,000 in the first year of life and between 2.0 and 2.5 per 100,000 in children to 17 years old.1 Epidemiology of common organisms causing pediatric meningitis is summarized on ExpertConsult.com Bacterial Meningitis Acute bacterial meningitis is less common than in the past but remains a potentially severe infection in childhood The majority of children with bacterial meningitis are admitted to a PICU for the initial phases of their care Bacterial meningitis occurs when bacteria invade the cerebrospinal fluid (CSF) within the pia-arachnoid spaces surrounding the brain and spinal cord This is most often the result of hematogenous dissemination of microorganisms arising from colonization or infection of the upper respiratory tract or other distant sites Bacterial meningitis also may be associated with trauma, surgery, and placement of neurosurgical intracranial devices Epidemiology The incidence of bacterial meningitis in children has significantly decreased over the past decades in countries that have introduced Pathogenesis Tissue injury and subsequent morbidity in acute bacterial meningitis is caused collectively by multiple factors, including bacterial proliferation in the subarachnoid space, release of bacterial products, local immune response from CNS tissue, and leukocyte migration into infected tissue These factors then can lead to injury to the brain parenchyma via (1) ischemia from loss of autoregulation of cerebral blood flow, thrombosis of arteries, veins, or dural venous sinuses secondary to vasculitis, microvascular thrombosis, and/or increased intracranial pressure (ICP); and (2) direct cytotoxicity from bacterial products or the host immune response that may damage neurons and other cell types in the brain.7 Relatively recent colonization of the nasopharynx by the causative microbe, often in conjunction with a viral respiratory tract infection, is frequently the antecedent event in bacterial meningitis After entrance into the bloodstream, microbes reach the CSF most likely via the blood-CSF barrier of the choroid plexus, and possibly other sites, including the intraparenchymal cerebral capillaries of the blood-brain barrier Magnitude (i.e., higher CFU/mL) and duration of bacteremia may be factors in development of meningitis Experimental data show that various pathogens pass between or through cerebral capillary endothelial cells 823 823.e1 Epidemiology of Common Organisms Causing Pediatric Meningitis Many bacterial species can cause meningitis The most common etiologies historically have been Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, Neisseria meningitidis, Streptocococus agalactiae (Group B streptococcus; GBS), Escherichia coli, and Listeria monocytogenes,1,2,4 with the latter three causing disease primarily, but not exclusively, in the first month of life Staphylococcus aureus meningitis usually occurs within the context of neurosurgical procedures or head trauma, but newly detected strains can cause meningitis in the absence of other risk factors.5 In the United States, the incidence of Hib, which was the most common cause of bacterial meningitis, has decreased from 22 to 24 per 100,000 children younger than years in the mid-1980s to fewer than per 100,000.6 This success has been attributed to vaccine induction of concentrations of serum immunoglobulin G antibodies against the Hib capsular polysaccharide that were sufficient to eradicate nasopharyngeal colonization with this microbe.7 Meningitis due to other capsular types of H influenzae occur sporadically worldwide but have not emerged to the level of Hib in the prevaccine era.8 Rates of all types of infection due to the more than 90 serotypes of S pneumoniae have decreased since the introduction of a 7-valent vaccine in 2000, followed by a 13-valent vaccine in 2010.4,9–11 The majority of pneumococcal meningitis cases now are caused by nonvaccine serotypes, although cases due to the vaccine serotype 19a remain proportionately common.12 The frequency of pneumococcal isolates with reduced susceptibility to penicillin and ceftriaxone has declined to date since the introduction of the 13-valent vaccine There remains potential for nonvaccine serotypes to emerge with subsequent increases in incidence of invasive pneumococcal infections, including meningitis, toward prevaccine levels.13 N meningitidis has been the second most common cause of sepsis and meningitis beyond the neonatal period.4 Following the introduction of conjugated meningococcal vaccines against capsular serogroups A, C, Y, and W-135, the incidence of N meningitidis meningitis decreased from 0.7 per 100,000 people in 1997 to 0.1 per 100,000 people in 2010 Globally, N meningitidis causes around 500,000 cases of meningitis and septic shock every year, although incidence rates vary from fewer than per 100,000 per year in North America to 10 to 1000 per 100,000 per year in sub-Saharan Africa.7 The peak incidence of invasive meningococcal disease occurs in children between months and years of age, with a second smaller peak in adolescents and young adults In N meningitidis infections, capsular group B is the major disease-causing group in most countries, causing the highest rates of disease in North America and Europe Serogroup Y strains have become more common in the United States in recent years Serogroup A strains are more common in parts of Africa and Asia.7 Vaccines using various serogroup B protein antigens are now available but not yet widely used.14 Among infants younger than 90 days, GBS and E coli remain the most common etiologies of bacterial meningitis, each accounting for about one-third of cases, especially among neonates.15 From 1997 to 2017, early-onset neonatal GBS infections in the United States declined from about 0.60 to 0.22 per 1000 live births due to implementation of guidelines for maternal screening and intrapartum antimicrobial prophylaxis Rates of late-onset GBS cases have remained relatively stable at about 0.3 per 1000 live births over this time period.16,17 Klebsiella, other Enterobacteriaceae species, L monocytogenes, and S aureus can also cause meningitis in this age group.18,19 Viral meningitis, as in older age groups, is more common than bacterial meningitis in young infants.20 Lymphocytic meningitis can be a manifestation of early Lyme disease This entity should be considered for patients in endemic areas or those who have traveled to such areas Presentation usually involves cranial nerve deficits, especially Bell palsy, and papilledema, as well as the clinical finding of erythema migrans Most patients with Lyme meningitis are not as acutely ill as with other bacterial etiologies of CNS infection.21 Mycobacterium tuberculosis (TB) is a rare but still important cause of pediatric meningitis in the United States TB meningitis disproportionately affects young children and is the most common form of childhood extrapulmonary tuberculosis after scrofula Before antituberculosis drugs, tuberculous meningitis invariably caused death, usually within weeks A meta-analysis in 2014 showed that risk of death from tuberculous meningitis was 19.3%, with risk of neurologic sequelae among survivors greater than 50%.22 Use of effective antimicrobials and adjunctive corticosteroids, along with advances in management of intracranial hypertension, has improved outcomes Longer duration of symptoms (days to weeks) before diagnosis is associated with poorer outcomes Early diagnosis remains a substantial challenge because the earliest stage of TB meningitis often manifests with nonspecific signs and symptoms 824 S E C T I O N V I Pediatric Critical Care: Neurologic or potentially traverse the blood-CSF barrier within phagocytic cells This ingestion causes a nonfatal phagocytosis, often labeled a “Trojan horse.”7,23 Bacterial strains that cause hematogenous meningitis usually have one or more traits that facilitate their invasion into the CSF Examples include the following • E coli: Type fimbriae, outer membrane protein A, and flagella • Group B streptococcus (GBS): Laminin-binding protein, fibrinogen-binding protein A, and pilus protein A • S pneumoniae: Phosphorylcholine and pneumococcal surface protein C • N meningitidis: Type IV pili and neisserial adhesin A These and other identified microbial structures interact with various host cell receptors that connect with host-signaling pathway molecules.7 A recently identified mutation in pneumococcal penicillin-binding protein, pbp1bA641C, was associated with increased risk of meningitis via increased microbe tolerance of antimicrobial therapy.24 Host factors also are important in pathogenesis There is a general lack of immune defenses in the subarachnoid space, which can allow for rapid multiplication of bacteria within the CSF Children with asplenia, congenital immunodeficiencies, cochlear implants, human immunodeficiency virus (HIV), and CSF leakage secondary to trauma are at increased risk for pneumococcal meningitis Patients with asplenia or complement deficiencies are at increased risk for meningococcal meningitis On rare occasions, acute otitis media has been associated with Streptococcus pyogenes meningitis.25 Infections by S aureus and coagulase-negative staphylococci are generally associated with neurosurgery or head trauma Human genetic determinants of infectious diseases are increasingly recognized risk factors for infection.26 In invasive meningococcal disease, several mutations and polymorphisms have been associated with a higher susceptibility and severity of illness To date, the genetic markers with the strongest supportive evidence are specific polymorphisms in the coding genes of plasminogen activator inhibitor (PAI-1) and receptors of the Fc fraction of immunoglobulins.27 Deficiencies in the interleukin-1 (IL-1) receptor–associated kinase (IRAK-4) and MyD88, both components of toll-like receptor (TLR) pathways, appear to be associated with increased risk of pneumococcal meningitis.28 Analysis of 11 single-nucleotide polymorphisms (SNPs) in seven genes involving host immune response suggests a potential cumulative risk when multiple such SNPs are present.29 These genes included complement factor H, mannose-binding lectin, and toll/interleukin-1 receptor domain containing adaptor protein (TIRAP) In another study, nine candidate SNPs in TLRs 2, 4, and were not associated with increased risk of pneumococcal or meningococcal meningitis.30 Clinical Manifestations No constellation of clinical signs and symptoms is 100% predictive of meningitis.31 The classic clinical presentation of meningitis is characterized by fever, headache, nuchal rigidity, and altered mental status Clinical symptoms can be ambiguous in the pediatric patient such that the triad of fever, neck stiffness, and a change in mental status is present in less than 50% of pediatric cases Most but not all children with meningitis have fever Nuchal rigidity is frequently absent, and changes in mental status such as irritability can often be misattributed to other causes, especially in young infants On admission, less than 25% will have focal neurologic signs (often cranial nerve involvement), and 15% will be obtunded or comatose.7 The classic signs of Kernig and Brudzinski frequently go unrecognized or are absent and appear to have limited utility in the diagnosis of bacterial meningitis in children.15,32,33 The presence of petechiae and purpura may suggest meningococcus as the causative agent, but similar findings can occur when S pneumoniae and Haemophilus influenzae type b (Hib) are etiologies.34 Poorly reactive pupils, a bulging fontanel, diplopia, papilledema, and uncontrollable vomiting can be present and are indications of increased ICP Acute bacterial meningitis patients can present with seizure activity A multiyear retrospective study from South America evaluated risk factors in pediatric patients with confirmed bacterial meningitis for the subsequent development of seizure activity Risk factors for seizure development included age less than years, pneumococcal etiology, altered mental status at admission, and CSF leukocyte count less than 1000 cells Generalized seizures were present in 20% to 30% of patients within the first days of illness The presence of focal seizures and onset past the third day of illness was associated with long-term neurologic sequelae Development of seizure activity in these patients also was associated with a ninefold increase in mortality.35 Laboratory Diagnosis The microbiology laboratory plays a critical role in early identification of the causative bacterium in meningitis When clinically feasible, the diagnosis of meningitis should include examination of CSF In most cases of bacterial meningitis, the diagnosis is made on the basis of isolation of pathogenic bacteria from CSF CSF white blood cell (WBC) count and differential, protein, glucose, Gram stain, and culture are essential in confirming the diagnosis In the past few years, multiplex polymerase chain reaction (PCR) panels for the most common bacterial, viral, and fungal etiologies of meningitis have become available Evidence is growing to support the clinical utility of rapid identification of the etiology of meningitis using these technologies.36 Molecular tests using specific, universal (e.g., 16S ribosomal ribonucleic acid [rRNA] sequence analysis), or multiplex PCR tests may provide evidence of the causative microbes, especially when antibiotics have been given before obtaining material for culture Many meningitis patients will have concurrent bacteremia, but the use of blood culture alone as an initial screening test is not appropriate Prior oral antimicrobial therapy will not significantly alter CSF cell counts, differential, and chemistries in children with bacterial meningitis However, sensitivity of the CSF Gram stain and culture are greatly reduced.37 Bacterial antigen tests not have sufficient diagnostic validity for routine use Measurement of opening pressure when performing lumbar puncture may help guide decision-making regarding need for acute neurosurgical interventions in some cases Lumbar puncture should be postponed in children with an ongoing coagulopathy, elevated ICP (such as altered mental status or hydrocephalus seen on head computed tomography [CT] scan or brain magnetic resonance imaging [MRI]), cardiorespiratory difficulty, and patients with suspected mass-occupying lesions Head CT imaging is indicated before lumbar puncture in those with focal neurologic findings or signs of elevated ICP It is important to remember that even when head CT scans are reported as normal, herniation may still occur in both children and adults with meningitis.38,39 CHAPTER 67 Central Nervous System Infections and Related Conditions CSF with pleocytosis, usually greater than 1000/mL, and a predominance of polymorphonuclear (PMN) leukocytes are highly suggestive of bacterial meningitis High protein and low glucose (usually less than half serum value) concentrations also support the diagnosis A predominance of lymphocytes and monocytes suggests a viral pathogen This can also be observed in patients with rickettsial and tuberculous meningitis Pleocytosis also can occur in Kawasaki disease and various autoimmune disorders CSF eosinophils are commonly observed in patients with CSF shunt devices, but also can be found in parasitic CNS infections CSF pleocytosis is also observed in adverse reactions to numerous drugs, including nonsteroidal antiinflammatory agents, trimethoprim-sulfamethoxazole, and intravenous (IV) gammaglobulin Meningitis caused by enterovirus and related strains can be associated with PMN predominance early in the clinical course, but these patients usually have normal CSF protein and glucose concentrations Interestingly, hypoglycorrhachia can be observed with certain viral pathogens, such as enterovirus and mumps virus On occasion, a small percentage of patients may have an initial normal-appearing CSF analysis, especially with N meningitidis Gram stains demonstrate organisms in 50% to 75% of patients with bacterial meningitis The clinician must be cautioned not to make significant changes in antimicrobial therapy solely based on a Gram stain result, as differences in CSF staining during slide preparation sometimes occur Interpretation of CSF WBC count when there is significant blood contamination of the specimen (the “bloody tap”) is often difficult Rules such as allowance of WBC for every 500 to 1000 red blood cells (RBCs) in the specimen or determination of expected versus observed CSF WBCs using concurrent ratio of peripheral blood WBCs to RBCs can be applied, but none of these approaches are well validated Comparison of the CSF to peripheral blood WBC differential proportions may be useful at times Reasonable data exist to adjust the CSF protein concentration for blood contamination, with an allowance of 1.1 mg/dL for every 1000 RBCs.40 Serum procalcitonin and C-reactive protein assays have been studied as a means of estimating the likelihood of invasive bacterial infections and differentiating between bacterial and aseptic (usually viral) meningitis To date, the utility of these serum tests for these purposes is unclear Numerous CSF biomarkers also have been evaluated for ability to distinguish between bacterial and viral meningitis Sufficient data to provide clinical confidence regarding predictive values for any specific marker, including CSF lactate, are still lacking.41–44 Repeated lumbar punctures during antibiotic therapy are no longer routinely recommended However, repeat lumbar puncture after 48 hours of therapy should be considered in cases caused by S pneumoniae when the isolate is (1) nonsusceptible to third-generation cephalosporins; (2) the condition of the patient is not improving; or (3) dexamethasone has been administered, which may affect interpretability of the clinical response since this agent can suppress fever.45 Repeat lumbar puncture also should be considered in infants with meningitis caused by gram-negative enteric bacteria until sterility of the CSF is documented Treatment Once meningitis is suspected, antimicrobial therapy must be initiated promptly Antibiotic therapy and other supportive measures must be started early when meningitis is suspected and should not 825 be delayed while awaiting CSF results when clinical suspicion is high Delays in antibiotic administration have been repeatedly shown to increase mortality, with delays as short as hours associated with unfavorable outcomes The risk for poor outcome increases by up to 30% per hour of antibiotic treatment delay.46 Initial therapies for bacterial meningitis in children are based on achievable CSF concentrations of various antimicrobial agents and the likelihood of antimicrobial resistance among the most likely pathogens based on age and other clinical circumstances Hospital antibiograms can serve as a partial guide to antimicrobial resistance considerations Critical care clinicians should be familiar with recommendations for antibiotic management in bacterial meningitis eTables 67.1 to 67.3 list the most frequent meningeal pathogens and recommended antimicrobial regimens along with dosage information The duration of antimicrobial therapy varies according to causative pathogen Children with gram-negative bacterial meningitis require a minimum of weeks of therapy Classically, infants with GBS meningitis require 14 to 21 days; with S pneumoniae, 10 to 14 days; with N meningitidis, days; and with H influenzae, to 10 days of therapy For treatment of tuberculosis (TB) meningitis in children, up-to-date guidance from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) should be reviewed due to changing antimicrobial sensitivities In neonates, empiric therapy using a combination of ampicillin with either gentamicin or cefotaxime has been a longstanding recommendation Currently, cefepime is often substituted for cefotaxime owing to a manufacturing-related shortage of the latter Some have recently proposed that a third- or fourth-generation cephalosporin alone, without ampicillin, may be sufficient in this age group given the rarity of meningitis due to L monocytogenes and enterococcal species in recent case series.18,19 If more frequent expression of extended-spectrum b-lactamases emerges among E coli and other gram-negative enteric bacteria at the population level over time, this may require consideration of inclusion of alternative agents such as carbapenems in empiric regimens for neonatal meningitis Because of the ongoing potential for reduced susceptibility to penicillin and cephalosporins among pneumococcal strains, empiric therapy beyond the neonatal period (or if S pneumoniae is suspected or confirmed as the etiology in the neonate) should include vancomycin and a third-generation cephalosporin (i.e., ceftriaxone or cefotaxime) If the isolate is shown to be susceptible to penicillin, therapy may be completed with penicillin or a thirdgeneration cephalosporin If the isolate is nonsusceptible to penicillin but susceptible to third-generation cephalosporin, the latter should be continued If the isolate is nonsusceptible both to penicillin and third-generation cephalosporins, vancomycin plus either ceftriaxone or cefotaxime should be continued If the patient is not improving after 24 to 48 hours of therapy, follow-up CSF culture remains positive, or the microbe is fully resistant to third-generation cephalosporins, addition of rifampin should be considered if the microbe is susceptible to this agent.45 Additional empiric agents could be added according to epidemiologic exposures, underlying conditions, and the presence of resistant organisms in the community or hospital Once a specific pathogen has been identified and susceptibility data are available, antimicrobial therapy could be narrowed to specifically target the offending pathogen Carbapenems may offer a treatment option in antibiotic-resistant strains causing meningitis or in cases of hypersensitivity to penicillins or cephalosporins Meropenem is as 825.e1 eTABLE Initial Empiric Antimicrobial Therapy for Bacterial Meningitis Based on Presumptive Pathogen(s) 67.1 Age and/or Predisposing Condition Pathogen Antimicrobial Therapy ,1 mo Escherichia coli, Streptococcus agalactiae, Klebsiella species, Listeria monocytogenes Ampicillin plus cefotaximea aminoglycoside 1–2 mo S pneumoniae, Neisseria meningitidis, S agalactiae, Haemophilus influenzae, E coli Vancomycin plus third-generation cephalosporinb mo–5 y S pneumoniae, N meningitidis, H influenzae Vancomycin plus third-generation cephalosporinb y S pneumoniae, N meningitidis Vancomycin plus third-generation cephalosporinb Humoral immunodeficiency, HIV, asplenia S pneumoniae, N meningitidis, H influenzae, Salmonella spp Vancomycin plus third-generation cephalosporinb Complement deficiencies N meningitidis, S pneumoniae Vancomycin plus third-generation cephalosporinb Basilar skull fractures S pneumoniae, N meningitidis, Streptococcus pyogenes Vancomycin plus third-generation cephalosporinb Cerebrospinal fluid shunt–related Coagulase-negative staphylococci, Staphylococcus aureus (methicillin-susceptible, methicillinresistant), aerobic gram-negative bacilli (including Pseudomonas aeruginosa), Propionibacterium acnes Vancomycin plus ceftazidime or vancomycin plus cefepime or vancomycin plus meropenemc Postneurosurgery Coagulase-negative staphylococci, Staphylococcus aureus (methicillin-susceptible, methicillinresistant), aerobic gram-negative bacilli (including Pseudomonas aeruginosa), Propionibacterium acnes Vancomycin plus ceftazidime or vancomycin plus cefepime or vancomycin plus meropenemc Cochlear implants S pneumoniae Vancomycin plus third-generation cephalosporinb HIV, Human immunodeficiency virus a Cefepine may be substituted when cefotaxime is unavailable b Cefotaxime or ceftriaxone c The choice of anti-gram-negative bacillary agent should be based on the institution’s susceptibility patterns ... Vancomycin plus third-generation cephalosporinb mo–5 y S pneumoniae, N meningitidis, H influenzae Vancomycin plus third-generation cephalosporinb y S pneumoniae, N meningitidis Vancomycin plus third-generation... pyogenes Vancomycin plus third-generation cephalosporinb Cerebrospinal fluid shunt–related Coagulase-negative staphylococci, Staphylococcus aureus (methicillin-susceptible, methicillinresistant),... Generalized seizures were present in 20% to 30% of patients within the first days of illness The presence of focal seizures and onset past the third day of illness was associated with long-term neurologic