Meningeal Infections
The clinical presentation of fever, headache, and stiff neck raises the clinical suspicion of meningeal infection in most cases, while biochemical, cellular, and microbiological analysis of the cerebrospinal fluid (CSF) confirms the presence of inflammatory cells and biochemical perturbations and identifies the etiologic agent. Acute bacterial meningitis is a medical emergency, and before the antibiotic era it was almost always a fatal infection. The incidence and demographics of meningeal infections vary by age and geographic location. Many of these differences are the direct result of effective immunization measures for the common causes of bacterial meningitis that have been introduced across the developed world.
Incidence and Demographics
Bacterial meningitis is a significant global health problem with dramatic differences in infection rates when developed countries are compared with underdeveloped regions of the world. In Senegal, Africa, the average incidence of bacterial meningitis during the 1970s was 50 cases per 100,000 people, with an alarming 1 in 250 children developing meningitis during their first year of life.1–3 Sub-Saharan Africa is commonly referred to as the meningitis belt because of epidemics of meningococcal meningitis, with incidence rates as high as 100 cases per 100,000 people.4,5 Epidemiologic and surveillance studies from the United States, Europe, Brazil, Israel, and Canada show that bacterial meningitis is less common in developed parts of the world but is generally caused by the same groups of microorganisms found in underdeveloped regions.
The development and implementation of vaccines to prevent infections caused by the three most common agents of bacterial meningitis (Haemophilus influenzae type B [HIB], Streptococcus pneumoniae, and Neisseria meningitidis) have had profound effects on the epidemiology of meningitis in children from all regions of the world where these vaccines are routinely available.
Etiology and Pathogenesis
Most cases of bacterial meningitis result from hematogenous seeding of the meninges. Direct extension of a bacterial infection from the sinuses, middle ear, or mastoid air cells is another route of spread. Such a source is immediately obvious on neuroimaging. The most common microbiological causes and pathogenesis of bacterial meningitis differ based on the age of the affected patient ( Table 9.1 ). Common etiologic agents of bacterial meningitis in the first week of life include Streptococcus agalactiae (group B streptococci), Escherichia coli, and Listeria monocytogenes.6–10 Late-onset neonatal meningitis occurs after the first week of life and up to 3 months of age and may be caused by the agents listed above, other enteric gram-negative bacilli, Pasteurella after animal exposure,11 pneumococci, meningococci, and staphylococci.12
During late infancy and early childhood, S. pneumoniae and N. meningitidis account for 80% of cases of bacterial meningitis.13–16 The remaining 20% are caused by L. monocytogenes, Streptococcus pyogenes (group A streptococci), S. agalactiae (group B streptococci), H. influenzae (type B and nontypeable isolates), E. coli, and other enteric gram-negative rods (including Salmonella species). Bacterial meningitis in adolescents and younger adults is usually caused by either S. pneumoniae or N. meningitidis 17–19; however, after the age of 50 years, L. monocytogenes becomes more prevalent.20 In elderly individuals, S. pneumoniae, N. meningitidis, and L. monocytogenes remain the more common microbiological etiologic agents21; however, a broad array of other pathogens has been described, depending on the presence of comorbidities, travel, and unusual exposures.22 Neuroimaging studies of patients with uncomplicated bacterial meningitis will usually demonstrate leptomeningeal enhancement ( Fig. 9.1 ) if a contrast image is performed.
Haemophilus influenzae Type B Meningitis
HIB is a gram-negative organism that invades via the respiratory tract. The primary virulence factor is the polysaccharide capsule, which allows it to evade the host′s innate immune defenses. Other encapsulated types of H. influenzae (types A, C, D, E, and F) and nontypeable, or unencapsulated, forms of the bacterial species are rare causes of meningitis, usually seen in patients with humoral immune deficiencies. A primary site of infection, such as the lung or middle ear, may precede the bacteremia that is ultimately responsible for hematogenous seeding of the meninges. Once the most common bacterial form of meningitis during childhood, HIB infection is now a rare occurrence in countries where vaccination programs are in place. A diagnosis of HIB meningitis in a vaccinated child merits special attention. Although primary vaccine failure with breakthrough infection can occur, every such child should be evaluated for the possibility of an immunodeficiency condition. Based on the enormous success of HIB vaccination programs in children, HIB meningitis has become a disease found predominately in adults in the United States and Europe.23–25
Pneumococcal Meningitis
S. pneumoniae is now the leading cause of bacterial meningitis in the United States and Europe, accounting for more than 60% of all cases.26 The polysaccharide capsule functions as a primary virulence factor, and more than 90 different capsular serotypes have been described. The serotypes differ in prevalence and their tendency for antibiotic resistance. Some serotypes are more likely to cause invasive disease, including meningitis. Like HIB meningitis, pneumococcal meningitis is usually secondary to hematogenous seeding of the meninges, with a primary focus in the sinopulmonary tract. After introduction of the conjugate vaccine in 2000, U.S. population–based data from the Active Bacterial Core surveillance (ABCs), published by the Centers for Disease Control and Prevention, showed a 59% decline in pneumococcal meningitis in children younger than 2 years of age,27 and Nationwide Inpatient Sample data showed that the incidence rate fell by 33% in children younger than 5 years of age (from 0.8 to 0.55 cases per 100,000 population).28
Meningococcal Meningitis
N. meningitidis is a gram-negative diplococcus. Major virulence factors include the presence of lipopolysaccharide (endotoxin), expression of an immunoglobulin A protease, and the presence of a polysaccharide capsule that allows the organism to evade the host′s innate immune response. The 12 serogroups of N. meningitidis known to infect humans are characterized by the polysaccharide expressed on the capsule: A, B, C, 29-E, H, I, K, L, W-135, X, Y, and Z. Clinically, the most relevant and most prevalent serogroup types are A, B, C, Y, and W-135. Invasive disease caused by the other types is unusual. Asymptomatic nasopharyngeal carriage of the bacterium is relatively common. In the United States, carrier prevalence in the general population is estimated to be between 5 and 10%. During adolescence, this prevalence can increase to as high as 35%. In situations of close contact, such as military barracks and college dormitories, carriage rates may approach 100%.29 The balance between carriage and the development of disease is affected by a combination of host and environmental factors, along with the characteristics of the infecting organism.30,31 Several social factors may also increase risk, such as close contact with an infected person and living or working in crowded conditions. It would appear that changes in behavior are the driving force behind the increased risk for meningococcal carriage in adolescents, particularly with regard to smoking and alcohol consumption.32,33
The proportion of cases of meningococcal disease caused by individual serogroups A, B, C, W-135, and Y varies by geographic region. In developed countries, serogroup distribution also differs within regions. In Great Britain, for example, serogroups B and C account for over 90% of cases, whereas in New Zealand, serogroup B alone causes 87% of all cases. In contrast, meningococcal meningitis diagnosed in the African meningitis belt is usually caused by serogroup A. Attack rates during epidemics in Africa approach 1% of the population.34–36 In Saudi Arabia, where serogroup W-135 predominates, attack rates have been described at 25 cases per 100,000 population during the Hajj.37–40 The country of Niger has recently experienced the emergence of serogroup X, where it caused half of 1,139 cases in 2006.41 In the United States, between 1,200 and 3,500 cases of meningococcal disease occur annually (0.9 to 1.5 cases per 100,000 population). Data for 2006 through 2008 show that serogroups B, Y, and C account for most of the U.S. cases.42
Meningitis Caused by Streptococcus agalactiae (Group B Streptococci)
Group B streptococci are gram-positive organisms possessing several virulence factors, including a polysaccharide capsule, several adherence proteins, and cytolytic toxins. The organism remains a common cause of meningitis in newborns, with more than two-thirds of these infections occurring during the first 3 months of life.43 Several studies have shown that administration of intravenous antibiotics to women in labor who are known to be colonized by group B streptococci is highly effective at reducing subsequent neonatal colonization. A meta-analysis of seven clinical trials demonstrated a 30-fold reduction of neonatal group B streptococcal invasive disease when antibiotics were delivered in this manner.44 In the United States during the decade of the 1990s, the incidence of neonatal group B streptococcal infection dropped from 1.7 to 0.6 cases per 1,000 live births, likely as a result of the increased use of peripartum antibiotics in women in labor.45,46 By 2004, rates dropped further, to approximately 0.3 per 1,000 following the implementation of formal obstetric screening guidelines.47 Meningitis caused by group B streptococci is unusual beyond infancy but has been described.
Meningitis Caused by Streptococcus pyogenes (Group A Streptococci)
S. pyogenes accounts for approximately 1% of all cases of bacterial meningitis in children and adults.48 Primary infection of the middle ear, lung, or sinuses is the rule, with bacteremic spread to the central nervous system (CNS), but cases also occur following recent head injury, after neurosurgical procedures, in the presence of a neurosurgical device, and in patients with CSF leaks.49,50 Reported mortality rates vary from 4 to 27%, with neurologic sequelae in 28%. Common complications in children include learning difficulties and other cognitive deficits, visual field defects, and hearing loss.51 The largest published adult series demonstrated a rate of neurologic sequelae (43%) higher than that reported in children.48
Meningitis Caused by Staphylococcus aureus
Unlike the community-acquired meningitis caused by H. influenzae, pneumococci, meningococci, and group A streptococci, S. aureus meningitis is almost always a nosocomial infection, occurring most commonly after a neurosurgical procedure, such as CSF shunt placement.52,53 In the unusual circumstance of community-acquired S. aureus meningitis, the patient should be questioned about possible intravenous drug use and assessed for the presence of an underlying immunodeficiency. In addition, patients with staphylococcal endocarditis frequently develop metastatic infection of the CNS, including brain abscess and meningeal infection.54,55 The mortality rate for nosocomial S. aureus meningitis is approximately 14%.56 Mortality secondary to community-acquired S. aureus meningitis exceeds 50% because of underlying, predisposing diseases.54
Meningitis Caused by Listeria monocytogenes
L. monocytogenes is a food-borne bacterium responsible for causing meningitis and other serious invasive illness in humans and other animals. L. monocytogenes is a gram-positive bacillus with the unusual ability to thrive intracellularly based on a host of characterized virulence factors.57 L. monocytogenes causes approximately 2% of all cases of meningitis in the United States, a proportion that has grown smaller in recent years, likely as a result of a decrease in the contamination of ready-to-eat foods.58 Infection is often associated with the presence of infectious foci in the brain parenchyma, especially in the brainstem.59 The organism remains one of the principal causes of bacterial meningitis in neonates.60–63
Meningitis Caused by Enteric Gram-Negative Bacteria
E. coli, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and other aerobic gram-negative bacteria have been shown to cause meningitis following head trauma or neurosurgical procedures.64–67 Meningitis caused by members of this group of organisms tends to occur late after surgery, with a median time until presentation of 12 days. Some infections may be detected more than a month after craniotomy. Community-acquired meningitis caused by aerobic gram-negative rods is unusual in adults but can occur in the context of immune-compromising conditions such as human immunodeficiency virus (HIV) infection. In contrast, enteric gram-negative bacteria as a group are second in frequency to group B streptococci during the neonatal period.68 Most of these infections are caused by E. coli, Klebsiella species, and Citrobacter species. Citrobacter koseri infections are almost universally complicated by the development of parenchymal abscesses. Young infants may also develop meningitis caused by Pasteurella multocida, almost always after direct or indirect exposure to cats or dogs in the household.11 Salmonella species have also been shown to cause meningitis. Approximately 15% of pediatric and adult patients who develop bacteremia during gastrointestinal salmonellosis will develop a metastatic infection of the joints, bone, or CNS. CNS seeding may cause meningitis but can also be complicated by subdural empyema and brain abscess.69,70
Lyme Meningitis
Lyme disease is an infection caused by the spirochete Borrelia burgdorferi. This infection is transmitted via an infected tick bite in areas of endemicity. The pathogenesis of Lyme meningitis is secondary to spirochetemia during the early disseminated stage of infection.
Tuberculous Meningitis
Worldwide, tuberculous meningitis remains a serious health threat, particularly in children residing in resource-poor areas of the world. Morbidity among survivors is the rule; death occurs in approximately 60% of patients.71 The agent of tuberculosis, Mycobacterium tuberculosis, is an extremely common cause of pulmonary infection. CNS complications occur following dissemination in the highest-risk groups, including children and patients infected with HIV. Prediction of outcome early in the illness is difficult because the infection runs a protracted course. Clinical indices such as cranial nerve palsy or other focal findings, seizures, and coma at the time of presentation have been assessed as predictors of long-term morbidity. Radiologic findings of hydrocephalus, cerebral infarction, or tuberculomas65 may offer a more realistic predictive value for long-term sequelae, particularly among children.72–75
Specific Risk Factors for the Development of Bacterial Meningitis
Alcoholism, diabetes mellitus, asplenia, cancer, and other secondary immune compromising conditions all increase the risk for invasive CNS infections, including meningitis. Other risk factors for the development of meningitis can be divided into two broad categories: anatomic and immunologic. Patients who present with recurrent bacterial meningitis need to be evaluated for underlying factors because direct surgical or medical intervention for the underlying cause may be required to prevent further episodes.
Anatomic Risk Factors
Anatomic abnormalities that predispose patients to bacterial meningitis include neural tube defects, epidermoid cysts, dermoid cysts, dermal sinus tracts, neurenteric cysts, and congenital inner ear malformation, including Mondini defects.76 Most of these defects become evident during a careful physical examination and/or fairly routine neuroimaging; however, the detection of inner ear malformations requires specialized high-resolution images when suspicion is strong.
Mondini Dysplasia
The Mondini defect consists of three main features: (1) instead of a cochlea with the normal two and one-half turns, a cochlea with one and one-half turns, comprising a normal basal turn and a cystic apex in place of the distal one and one-half turns; (2) an enlarged vestibule with normal semicircular canals; and (3) an enlarged vestibular aqueduct containing a dilated endolymphatic sac77 ( Fig. 9.2 ). In most cases, Mondini dysplasia is associated with some degree of hearing impairment and can be associated with CSF otorrhea and meningitis.78,79 It is thought that a fistula between the CSF spaces and the middle ear predisposes patients to the development of meningitis. The underlying CSF fistula in some patients with Mondini defects can occur in such places as through a deficient oval window or stapes footplate.
Cochlear Implant
In most cases of meningitis in patients with a cochlear implant, the initial infection is acute otitis media on the side of the implant. Bacteria enter the inner ear through the surgical cochleostomy. Pathways of bacterial access to the CSF from the inner ear include entry into the labyrinth, infiltration of the cochlea along the implanted electrode, and/or perivascular pathways into the internal auditory canal to the meninges.80 In a case-control study performed in children younger than 6 years of age, 26 cases of meningitis were identified among 4,264 patients with cochlear implants.81 During a 2-year follow-up of the same cohort, an additional 12 episodes of meningitis occurred.82 This finding represents a more than 30-fold increase in the risk for meningitis compared with the general population. The mortality rate of meningitis in the context of a cochlear implant is approximately 16%. Not surprisingly, S. pneumoniae is the most commonly identified etiologic agent of implant-associated bacterial meningitis.
Immunologic Risk Factors
Primary immune deficiencies, particularly those that impair humoral immunity, and secondary immune deficiencies resulting from alcoholism, HIV infection, diabetes mellitus, asplenia, the use of immunosuppressive medications, and malignancy all increase a patient′s risk for developing an invasive systemic infection, including meningitis.83–85 The most common infecting bacterial pathogen in patients with immunodeficiency is S. pneumoniae,86 but other bacterial, viral, fungal, and even parasitic opportunistic infections must be considered based on the degree of the patient′s immunocompromised state. Specifically, HIV-infected individuals have up to a 324-fold higher risk for invasive pneumococcal infection.87–89 Even following therapy with highly active antiretroviral medications, when HIV replication is controlled, the risk for developing pneumococcal meningitis remains approximately 35-fold higher than that in the general population.90,91 This increased risk has a profound public health effect in the underdeveloped world, where up to 95% of patients with pneumococcal meningitis are also infected with HIV.92–95 Opportunistic infections are seen more frequently in those individuals with severe immunodeficiencies, but some immune defects are directly associated with an increased risk for specific offending organisms.
Hypogammaglobulinemia
Patients with humoral immunodeficiencies are especially prone to develop sinopulmonary infections and meningitis caused by encapsulated bacterial pathogens (pneumococci, meningococci, H. influenzae). Although patients with hypogammaglobulinemia have no increased susceptibility to most viral infections, there is one exception. Although immunologically normal individuals develop a self-limited “aseptic meningitis” when enteroviruses infect the CNS, patients with hypogammaglobulinemia can develop chronic meningoencephalitis.96 Enterovirus-directed therapies are not available, and despite aggressive supportive care, many of these patients lose substantial neurologic function, and some die.
IRAK-4 and MyD88 Deficiency
Impairments in innate immune responses are also known to increase the risk for developing meningitis. The autosomal recessive interleukin-1 receptor–associated kinase (IRAK)-4 and myeloid differentiation (MyD) factor 88 deficiencies impair toll-like receptor (TLR)–mediated and interleukin-1 receptor–mediated immunity. These defects lead to a predisposition to the development of recurrent life-threatening bacterial diseases, especially during infancy and early childhood. In the single largest clinical report of infections in patients with these deficiencies, approximately half of all invasive bacterial infections were meningitis, although the frequency and types of long-term sequelae were similar to those seen in immunocompetent patients.97 Infecting agents included S. pneumoniae, HIB, S. aureus, and group B streptococci.
Complement Deficiency
Complement deficiencies are rare disorders of immune function afflicting 0.03% of the population. Because complement activation pathways converge at the activation of C3, patients who are deficient in C3 have serious deficiencies in complement-mediated opsonization, phagocyte recruitment, and bacteriolysis. Such patients are prone to invasive infection caused by encapsulated bacteria such as pneumococci, meningococci, and H. influenzae. Most infections in patients with C3 deficiency involve the sinopulmonary tract (otitis, sinusitis, and pneumonia), but C3-deficient patients are also predisposed to the development of sepsis and meningitis.98 An increased incidence of invasive meningococcal disease has been observed in patients with deficiencies or defects in terminal complement components C5–C9 and dysfunctional properdin.99–101 Any patient who presents with recurrent infections (including meningitis) caused by Neisseria species should be evaluated for a terminal complement defect.
Clinical Presentation
The clinical presentation of acute bacterial meningitis varies by patient age and immune status as well as the etiology of the infection.102 The classic triad of fever, neck stiffness, and altered mental status is not always present. Only in patients with severe meningeal inflammation (white blood cell [WBC] count ≥ 1,000/mL of CSF) is nuchal rigidity 100% sensitive and specific for the diagnosis of acute meningitis.103
Neonatal meningitis is difficult to identify because newborns tend to present with nonspecific symptoms, including temperature instability, respiratory distress, jaundice, poor suck, and lethargy.102,104,105 Approximately 50 to 88% of neonates present with fever, two-thirds with irritability and/or a bulging fontanelle, one-third with lethargy, and 25 to 40% with seizures before admission.102,104,105 The presence of a bulging fontanelle is strongly predictive of neonatal meningitis.106
Infants beyond the neonatal period and children younger than 5 years of age with meningitis present with fever, irritability, altered mental status, and decreased oral intake.104,107–109 Seizures occur in 42 to 81% of these children.104,107 Other symptoms may include neck stiffness, headache, vomiting, lethargy, “staring eyes,” and rash.104,107–109 Children older than 5 years of age are more likely to present with classic meningismus.104,110 Other symptoms that are seen include a petechial or purpuric rash, change in muscle tone, vomiting, and decreased oral intake. Of note, a change in a child′s state of alertness is one of the most important signs of meningitis, although the finding may be subtle.102
A nationwide study in the Netherlands prospectively evaluated 696 episodes of community-acquired bacterial meningitis in adults. They found that the classic triad of fever, neck stiffness, and altered mental status was present in only 44% of the episodes. However, when headache was added to this list, 95% of the patients had at least two of the four symptoms.19 The classic triad was more likely to be present in pneumococcal meningitis than in meningococcal meningitis.19,111 Rash was present in 26% of cases and focal neurologic deficit in 33%. Seizures were present in 5% of patients.19 Neurologic abnormalities seen on presentation in adults with meningitis can include generalized deficits, such as confusion, lethargy, and unresponsiveness, as well as focal neurologic signs, such as cranial nerve palsies, hemiparesis, aphasia, and visual field defects.17,112
Elderly patients are another group whose clinical diagnosis can be challenging. Presenting signs and symptoms are quite variable and are often nonspecific.22 It is important to note that nuchal rigidity can be present for reasons other than meningitis in elderly patients, such as previous cerebrovascular accidents, Parkinson disease, and cervical spondylosis.113 The elderly are more likely to present with depressed mental status, hemiparesis, and seizures than with headache, nausea, vomiting, and nuchal rigidity.20,113 Acute complications of pyogenic bacterial meningitis include the development of cerebritis with parenchymal infarcts, subdural empyema, ventriculitis, and hydrocephalus ( Fig. 9.3 ). Neuroimaging should not be delayed because emergent surgical intervention may be necessary.
Unlike the other common types of bacterial meningitis, Lyme disease is associated with aseptic meningitis, more closely mimicking mild forms of viral meningitis rather than fulminant, pyogenic bacterial meningitis. One study showed that the duration of headache secondary to Lyme meningitis was three times longer, lasting on average for more than a week.114 More than half of adults with Lyme meningitis will exhibit symptoms of parenchymal involvement, such as somnolence, memory loss, poor concentration, emotional lability, and behavioral changes. In contrast, a series in children with CNS Lyme infection showed that most young patients have a fairly benign, mild course of aseptic meningitis.115 Seventh nerve palsy is seen in approximately half of patients with Lyme meningitis but can also be an isolated neurologic finding of Borrelia infection.116 Rare complications and some less common presentations of CNS Lyme infection include other cranial nerve palsies, particularly cranial nerves III and VI, pseudotumor cerebri, chorea, cerebellar ataxia, mononeuritis multiplex, myelitis, and opsoclonus-mycolonus.117–119
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
