Central Nervous System Infections

Central Nervous System Infections

Heidi L. Smith

Alan L. Rothman

The central nervous system (CNS) infections of major interest in the intensive care unit (ICU) are bacterial meningitis, encephalitis, brain abscess, and other parameningeal foci of infection. The clinical presentations of these diseases may overlap. Meningitis means inflammation of the leptomeninges; its hallmark is stiff neck. Encephalitis is a syndrome consisting of disturbance of cerebral function and cerebrospinal fluid (CSF) pleocytosis. Many cases of bacterial meningitis also fit this definition of encephalitis due to the occurrence of mental status changes, seizures, or coma. Focal infections, such as brain abscesses, may present more as space-occupying lesions than with classical infectious signs or symptoms.

CSF examination is the major tool used in diagnosis of CNS infections. The terms purulent and aseptic describe contrasting CSF formulas, though overlap exists. The typical purulent CSF has a white blood cell count of more than 1,000 cells per mm3 (most of which are neutrophils), a depressed glucose concentration (< 40 mg per dL), and an elevated protein level (> 100 mg per dL); it is most commonly seen in bacterial meningitis. In contrast, an “aseptic” formula has a lower total leukocyte count with a predominance of mononuclear cells, a glucose concentration greater than 40% to 50% of the blood level, and less marked elevation of protein; this picture characterizes most other CNS infections. An intermediate CSF formula, in which a moderate lymphocytic pleocytosis is accompanied by depressed glucose and elevated protein, suggests granulomatous disease.

General Clinical Approach

Initial evaluation of the patient with suspected CNS infection should focus on defining the nature of the symptoms (meningitic vs. encephalitic) and the presence and pattern of neurologic involvement (focal vs. diffuse).

If bacterial meningitis is suspected, expeditious analysis of CSF is critical. This must be balanced with the need to administer antibiotics promptly, because delays as short as 3 hours have been shown to lead to unfavorable outcomes [1,2]. If lumbar puncture (LP) is delayed for any reason, antibiotics (and dexamethasone; see later) should be started as soon as blood cultures have been obtained while efforts to obtain CSF proceed [3].

LP is not without risk. In patients with bleeding disorders, it should be delayed until the defect(s) can be corrected [4]. LP may be hazardous in the settings of intracranial mass lesion with edema and lumbar spinal epidural abscess. Concern for cerebral herniation as a consequence of the procedure has led to the common practice of routinely performing computed tomography (CT) scanning prior to LP. This practice is not well founded, however [5,6]. A prospective study has confirmed that CT scans rarely discover abnormalities that would represent a contraindication to LP except in patients who have a prior history of CNS disease, an immunosuppressive disorder, seizures, moderate-to-severe impairment of consciousness, papilledema, or focal neurological findings [7].

Bacterial Meningitis

Bacterial meningitis is perhaps the most clear-cut emergency in the field of infectious diseases. Delayed or inadequate treatment increases the risk of death or significant neurologic impairment [1].


The predominant organisms vary based on the age and underlying condition of the host. Historically, bacterial meningitis in the United States has been primarily caused by five organisms: Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzae, and group B streptococcus. However, immunization of young children against H. influenzae and S. pneumoniae has had a marked impact on meningitis in the United States, raising the average age of meningitis due to these five pathogens from 15 months old to 25 years old [8].

S. pneumoniae accounts for almost half of the cases of community-acquired bacterial meningitis in the United States in all age groups beyond the neonatal period [8]. It is associated with a sixfold higher risk of unfavorable outcome (death, neurologic sequelae) than other pathogens [9]. Pneumococcal meningitis is more common in the setting of a CSF leak, hypogammaglobulinemia, asplenia, alcoholism, head trauma, or cochlear implant [10,11]. Routine infant immunization against S. pneumoniae has also reduced the incidence of pneumococcal meningitis in older children and adults due to a reduction in S. pneumoniae carriage in the younger population [12,13]. N. meningitidis accounts for approximately one fourth of cases of meningitis in the United States [8]. Nasal carriage of N. meningitidis gradually increases from infancy and peaks in the teenage years [14]; it is the most common cause of meningitis in older children and young adults. It is the one form of bacterial meningitis associated with epidemic spread. A polysaccharide-protein conjugate vaccine is available in the United States but does not provide protection against serogroup B strains. The vaccine is currently recommended for preadolescents, freshman entering college, and military recruits [15]. L. monocytogenes is a common cause of meningitis in the neonatal period or in the setting of malignancy, immunosuppression, or alcoholism. Approximately 30% of patients have no apparent immunocompromising condition; most of these individuals are older than 50 years [8,16,17]. H. influenzae type B was formerly the most common cause of bacterial meningitis in young children. Vaccination of children has reduced the incidence of invasive H. influenzae type B
disease by more than 80% [8,18]. Sporadic cases have recently been reported in unimmunized and partially immunized children, however [19]. H. influenzae in adults is uncommon and is usually associated with predisposing factors, such as anatomic defects (head trauma, CSF leaks) or defects in humoral immunity [20].

Gram-negative bacillary meningitis occurs in the neonatal period or after neurosurgery or trauma [21]. Community-acquired Gram-negative bacillary meningitis is rare in adults [21]. When it occurs, it is usually a complication of bacteremia from a distant site, often the urinary tract.

Staphylococcus aureus meningitis is associated with neurosurgery or trauma. Community-acquired cases occur in the presence of a focus of infection outside the CNS, such as endocarditis or soft tissue infections, and have a worse prognosis [22]. Meningitis in patients with CSF shunts is most commonly caused by skin flora (S. aureus, Staphylococcus epidermidis, Propionibacterium acnes) and Gram-negative bacilli [23]. These infections can have an indolent presentation and milder CSF abnormalities [3,23]. Use of shunt catheters impregnated with antibiotics has shown some promise in reducing the incidence of infection [24].

Several additional species of streptococci can cause meningitis. Group B streptococcus, Streptococcus agalactiae, is the most common cause of neonatal meningitis [8]. Rates of group B streptococcal invasive disease in adults are increasing, particularly in diabetic patients, but only a small proportion present as meningitis [25]. Streptococcus suis is an increasingly common cause of meningitis in Asia and should be considered in travelers, particularly those who may have ingested raw pork or had contact with pigs [26,27]. LP associated with the use of catheters for anesthesia and imaging procedures has been associated with the introduction of α-hemolytic streptococci in rare cases [28]. Anaerobic bacteria and other streptococci are otherwise uncommon causes of meningitis that are usually related to spread from brain abscess or parameningeal foci [29].


Bacterial seeding of the meninges usually arises from hematogenous spread. Spread from contiguous foci of infection is more often a cause of intracranial abscess. Bacteremia can arise from simple colonization of the nasopharynx, though colonization alone is obviously not sufficient, since 10% of the population is colonized with N. meningitidis at any given time [30]. The bacterial species most commonly associated with meningitis bind the laminin receptor on microvascular endothelial cells, potentially facilitating entry to the CNS [31]. Most meningitis pathogens also secrete immunoglobulin A proteases, facilitating immune evasion at mucosal sites [14]. Inadequate levels of antibody specific for the invading organism (such as occurs at the extremes of age or in acquired immunodeficiencies) and opsonophagocytic deficiencies (such as in asplenia, diabetes, or alcoholism) are the most commonly recognized risk factors for meningitis [32]. Individuals with terminal complement component deficiencies may experience recurrent episodes of meningococcal meningitis, though with lower mortality rates [33].

Once bacteria reach the CSF, both bacterial and host factors contribute to disease. Recognition of bacterial components, including cell wall molecules and bacterial DNA, leads to elaboration of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1, and interleukin-6 by leukocytes and endothelial cells. One of the major consequences is the disruption of the tight junctions of the blood–brain barrier. Additional inflammation, caused in part by increased migration and activation of neutrophils, triggers release of tissue factor (which aids thrombus formation and disrupts cerebral perfusion), nitric oxide (which disrupts autoregulation of blood flow and can have direct toxic effects on neurons), and matrix metalloproteinases (which can also disrupt endothelial junctions and impair neuronal function). Neuronal damage is further worsened by resulting increases in intracranial pressure [34,35].

Antibiotics that rapidly lyse bacteria generate a transient increase in inflammation as a response to the release of bacterial cell wall components [36]. Adjunctive steroid therapy acts to decrease inflammation associated with bacterial lysis [37]. The body also deploys endogenous immunomodulators such as TNF-related apoptosis-inducing ligand (TRAIL), which has been shown to reduce neuronal damage in animal models [38].

The clinical consequence of these pathologic processes is a generalized disturbance of cerebral function. An early phase of agitation or mania may be noted. Lethargy progresses to obtundation and sometimes coma. Seizures occur early in 20% to 30% of adults with meningitis [21]. Hyponatremia, caused by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, may contribute to obtundation and seizures. Focal neurologic deficits may be observed; sensorineural deafness is particularly common. Neurologic impairment persists in approximately 30% of survivors of meningitis in adulthood [6].



Patients with meningitis may be unable to give a coherent history. Patients found unresponsive should be evaluated with a high level of suspicion for meningitis. Patients with fever and derangement of cerebral function, even if there is another cause for the latter, must have meningitis excluded. Persons with coexistent alcoholism, general debility, head trauma, or neurosurgery are at higher risk for meningitis.

Classic meningeal symptoms are headache (often with photophobia), neck pain, fever, and mental status changes; in a recent case series, 95% of patients with bacterial meningitis had at least two of these four symptoms [9]. Symptoms of other foci of infection, such as pneumonia, otitis, or sinusitis, may also be present [39]. Any history of head trauma (including remote events) or recent clear nasal or ear discharges should be obtained. Recent antibiotics, which could interfere with culture results, should be noted. A history of exposure to a patient with known meningococcal disease is usually forthcoming if present. In children, immunization history and history of school or daycare exposures should be elicited. Travel history may aid the identification of regionally endemic pathogens.

Physical Examination

Nuchal rigidity suggests meningitis when present. Limitation of motion caused by degenerative cervical arthritis may be a confounding variable in the elderly. Kernig’s and Brudzinski’s signs have low sensitivity but high specificity [40]. The initial neurologic examination should evaluate the mental status and the presence of focal deficits. Papilledema is rarely observed in meningitis [21,41] but alters the approach to LP when present. Serial examinations document any functional progression or improvement.

The systemic examination may give clues to the cause of meningitis. A thorough ear, nose, and throat examination can reveal possible foci leading to contiguous extension to the meninges. Petechiae or purpuric lesions strongly suggest meningococcal disease, though they may also be seen in S. pneumoniae and H. influenzae meningitis [39]. Petechiae may also be seen in aseptic meningitis caused by enteroviruses or Rocky Mountain spotted fever. Needle aspiration or punch biopsy of skin lesions should be used to obtain material
for Gram stain and culture. In one series of patients with N. meningitidis infection, bacteria were detected on either culture or stain in more than 60% of skin specimens. In addition, the Gram stain was positive in samples obtained as late as 45 hours after initiation of antibiotics [42].

Laboratory Tests

Evaluation of the CSF is essential for the diagnosis of meningitis. The typical features of purulent CSF have been noted earlier. Neutrophils constitute more than 50% of the cells in nearly all bacterial meningitis cases and more than 80% in the majority [21]. In rare cases, the CSF shows many organisms on Gram stain but few cells, implying rapidly progressive disease [9]. Elevated protein is also almost always present [21]. Severe depression of the CSF glucose (< 20 mg per dL) is strong evidence for a pyogenic process, but CSF glucose is normal in up to 50% of patients with bacterial meningitis [21]. Patients with L. monocytogenes meningitis may have milder CSF abnormalities with relatively modest changes in glucose and protein and white blood cell counts of less than 2,000 cells per mm3 [16,17]. Treatment with antibiotics prior to LP may alter CSF chemistries, resulting in higher glucose levels and lower protein levels, though cell counts are usually unaffected [43].

Cultures remain the mainstays of diagnosis. Blood cultures can be useful in identifying the causative agent of meningitis in cases where CSF cultures are unrevealing [44,45]. Ultimately, 60% to 90% of patients with community-acquired meningitis and purulent CSF have an organism isolated in culture [21,39]. Antibiotic administration is more likely to render cultures negative [43,46]. Bacterial antigen detection tests offer little additional information [47]. Newer techniques such as polymerase chain reaction (PCR) detection of bacterial DNA may provide more rapid and sensitive diagnosis, particularly in the setting of antibiotic pretreatment; however, these assays are not yet widely available [48].

Imaging studies are of secondary importance in the diagnosis of meningitis. Imaging of the chest and paranasal sinuses may identify other foci of infection. CT and magnetic resonance imaging (MRI) of the brain are most useful for evaluating complications of meningitis. Rapid deterioration should lead to consideration of subdural empyema, a collection between the dura and the arachnoid membrane, best visualized on MRI [6,49]. A new focal neurologic abnormality, decreased level of consciousness, or cerebrovascular accident with a nonarterial distribution should prompt imaging for venous thrombophlebitis, also best seen on MRI [6,49].

Differential Diagnosis

Several pathogens other than pyogenic bacteria can cause clinical presentations and/or spinal fluid formulas that overlap with bacterial meningitis.

Viral meningitis can have initial clinical presentations similar to bacterial meningitis. It can be caused by a wide range of pathogens including enteroviruses, arboviruses such as West Nile virus (WNV) [50], herpes viruses such as herpes simplex virus (HSV) [51], and acute HIV infection [52]. Mumps and lymphocytic choriomeningitis are the viruses most often associated with low CSF glucose levels. Very high CSF white blood cell counts and a high proportion of neutrophils occur in a few cases of enteroviral meningitis and eastern equine encephalitis. PCR assays for detection of enteroviruses can provide timely clarification [53]. Recurrent culture-negative meningitis, sometimes referred to as Mollaret’s meningitis, can have an early neutrophil predominance; most cases have a positive HSV PCR in the CSF [51]. Other types of viral meningitis may also display an early neutrophil predominance, with a shift to lymphocytes taking place with time [3].

Tuberculous meningitis most commonly presents with a mononuclear predominance in the CSF along with low glucose and high protein. However, some cases have a total leukocyte count in the range of purulent meningitis with a polymorphonuclear predominance [54]. A history of tuberculosis, risk factors for exposure, or the presence of an immunocompromising condition should raise suspicion. If an initial diagnosis of bacterial meningitis is not confirmed by culture and the patient’s condition does not improve, repeat LP with studies for acid-fast bacilli should be performed. A switch to lymphocytic predominance, additional decrease in CSF glucose and increase in protein, positive chest radiograph, or well-founded clinical suspicion mandates institution of antituberculous therapy [54,55]. The reported yield of acid-fast stains of CSF ranges from 15% to 60% but improves with repeat sampling [56,57]. Nucleic acid amplification tests may facilitate earlier diagnosis, but there is a wide variability in their availability and sensitivity [58]. MRI is more likely than CT to visualize tuberculomas [59].

Parasitic infections can cause purulent meningitis. Primary amebic meningitis with Naegleria fowleri is acquired through freshwater swimming and presents similarly to acute bacterial meningitis. Diagnosis is made on wet mount of CSF [60]. The nematode Strongyloides stercoralis is capable of establishing a cycle of autoinfection in immunosuppressed hosts, including those on oral corticosteroids. Migration of larvae from the gut can result in the deposition of enteric bacteria in the CNS, causing Gram-negative or polymicrobial meningitis [61].

Fungal meningitis may present with hypoglycorrhachia. An indolent course and lymphocytic CSF pleocytosis usually distinguish these from pyogenic infections, but Coccidioides immitis, an endemic fungus of the southwest United States, can have neutrophil predominance [62]. Cryptococcus neoformans is a major cause of meningitis in patients with immunosuppressive conditions, though it can occur in normal hosts. Cryptococcal antigen assay of the CSF provides a sensitive means of diagnosis [63].

Parameningeal foci of infection, including epidural abscess, can present a purulent picture, usually with elevated protein and a normal glucose concentration [64]. Brain abscess that has ruptured into the ventricles may duplicate the clinical picture of bacterial meningitis. Localizing neurologic findings or isolation of an anaerobe or multiple organisms from the CSF should suggest one of these diagnoses.

Noninfectious conditions can cause meningeal signs and CSF findings that overlap with those of bacterial meningitis. Hypoglycorrhachia may be seen in carcinomatous meningitis. Drug-induced meningitis may have a CSF formula indistinguishable from pyogenic infection; the most commonly implicated agents are nonsteroidal anti-inflammatories, antibiotics, and intravenous immunoglobulin [65]. Postneurosurgical chemical meningitis, believed to be an inflammatory reaction to surgical manipulation, blood, or bone dust, can present with a CSF profile similar to bacterial meningitis. Although symptoms, CSF leukocytosis, and hypoglycorrhachia are usually less severe, no single parameter has been proven to distinguish between the two conditions. Given the risk of postsurgical bacterial meningitis in this population, antibiotics are often administered until CSF culture results are finalized [66,67,68].


The appropriate management of patients with bacterial meningitis involves prompt initiation of antimicrobial and anti-inflammatory therapy, aggressive control of the potential complications, and prevention of spread of disease [3]. Overall mortality from bacterial meningitis is in the range of 20% to 30% [9,21,69]. However, mortality rates are significantly influenced by both the pathogen, with S. pneumoniae among the most deadly, and the host, with elderly patients among the most
susceptible [9,21]. Consequently, most patients should be treated in an intensive care setting.

Antimicrobial Therapy

The principal consideration in choosing an antibiotic regimen for bacterial meningitis is that the agent(s) reach the CSF in concentrations that are bactericidal for the likely pathogens. Table 79.1 lists recommendations for therapy of bacterial meningitis in a variety of clinical settings. Initial therapy is usually selected empirically based on the age and underlying condition of the patient. Once the result of Gram stain of CSF is available, antimicrobial therapy can be targeted appropriately.

The third-generation cephalosporins (ceftriaxone or cefotaxime) are the mainstays of therapy for community-acquired meningitis. These agents are active against most strains of S. pneumoniae and provide excellent coverage against N. meningitidis and Gram-negative bacilli (except Pseudomonas aeruginosa). S. pneumoniae with reduced susceptibility to the cephalosporins has increased in frequency; this organism remains universally susceptible to vancomycin [70]. If the CSF Gram stain suggests pneumococci or is unrevealing, vancomycin should be given in addition to the cephalosporin until culture and sensitivity results are available [3]. Meropenem also demonstrates activity against many, but not all, cephalosporin-resistant strains of S. pneumoniae and has demonstrated clinical effectiveness for treatment of meningitis [70,71].

Ampicillin (or penicillin) should be included in the regimen for empiric therapy in neonates (< 1 month old), individuals older than 50 years, patients with alcoholism, or those who are debilitated or immunosuppressed, for coverage of L. monocytogenes [16,72]. Initial therapy for postneurosurgical bacterial meningitis should include vancomycin plus either ceftazidime or cefepime to provide adequate coverage for methicillin-resistant staphylococci and P. aeruginosa. Resistance to antimicrobials, either at the outset or developing during treatment, can complicate therapy for Gram-negative organisms [73]. An increasing number of cases due to multidrug-resistant hospital-acquired organisms such as Acinetobacter sp have been reported [74].

Few good treatment regimens exist for the cephalosporin-intolerant patient. Consequently, a trial of the third-generation cephalosporins (or meropenem) should be strongly considered unless there is a documented, serious intolerance. Vancomycin is the preferred alternative for treatment of pneumococcal meningitis. The fluoroquinolone moxifloxacin has activity against pneumococci, meningococci, and H. influenzae and has shown promise in animal models of meningitis, but clinical experience is limited [3]. Trimethoprim–sulfamethoxazole is effective for the treatment of meningitis caused by L. monocytogenes and many Gram-negative bacilli other than P. aeruginosa [75].

If S. pneumoniae is isolated, adjustment of therapy should be based on the results of drug susceptibility testing. Fully susceptible organisms can be treated with third-generation cephalosporin alone. For resistant organisms, vancomycin and cephalosporin should be continued and the addition of rifampin considered [76]. Repeated examination of the CSF after 24 to 36 hours of therapy is warranted to monitor sterilization of the CSF in these cases [77]. Regardless of the causative organism, continued clinical instability after 48 hours of appropriate antibiotic therapy is also an indication for repeat LP [3]. Repeat CSF samples should have a negative Gram stain and culture after at least 24 hours of effective antibiotic therapy [6].

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Sep 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Central Nervous System Infections
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