on 29-May-2022 (Sun)

The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, primarily in patients over age 50 years or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes.

The major causes of health care-associated bacterial meningitis are staphylococci and aerobic gram-negative bacilli

Patients with bacterial meningitis are usually quite ill and often present soon after symptom onset

The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status, usually of sudden onset. However, an appreciable number of patients do not have all three features

Initial blood tests should include a complete blood count with differential and platelet count and two aerobic blood cultures of appropriate volume (ideally, prior to the initiation of antimicrobial therapy). Serum electrolytes and glucose, blood urea nitrogen, and creatinine concentrations are helpful in determining the cerebrospinal fluid- (CSF) to-blood glucose ratio.

Coagulation studies may be indicated, especially if petechiae or purpuric lesions are noted.

Blood cultures are often positive and can be useful in the event that CSF cannot be obtained before the administration of antimicrobials. Approximately 50 to 90 percent of patients with bacterial meningitis have positive blood cultures.

Every patient with suspected meningitis should have CSF obtained unless a lumbar puncture (LP) is contraindicated. A CT scan is sometimes performed before LP to exclude a mass lesion or increased intracranial pressure, which rarely leads to cerebral herniation during subsequent CSF removal. However, a screening CT scan is not necessary in the majority of patients.

A CT scan of the head before LP should be performed in adult patients with suspected bacterial meningitis who have one or more of the following risk factors (see 'Indications for CT scan before LP' above):

• Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation)

• History of central nervous system (CNS) disease (mass lesion, stroke, or focal infection)

• New onset seizure (within one week of presentation)

• Papilledema

• Abnormal level of consciousness

• Focal neurologic deficit

If LP is delayed or deferred, blood cultures should be obtained and antimicrobial therapy should be administered empirically before the imaging study, followed as soon as possible by the LP. In addition, dexamethasone (0.15 mg/kg intravenously every six hours) should be given shortly before or at the same time as the antimicrobial agents if the preponderance of clinical and laboratory evidence suggests bacterial meningitis with a plan to stop therapy, if indicated, when the evaluation is complete.

Adjunctive dexamethasone should not be given to patients who have already received antimicrobial therapy because it is unlikely to improve patient outcome.

The usual CSF findings in patients with bacterial meningitis are a white blood cell (WBC) count of 1000 to 5000/microL (range of <100 to >10,000) with a percentage of neutrophils usually greater than 80 percent, protein of 100 to 500 mg/dL (1000 to 5000 mg/L), and glucose <40 mg/dL (2.22 mm/L; with a CSF:serum glucose ratio of ≤0.4). Despite these typical CSF findings, the spectrum of CSF values in bacterial meningitis is so wide that the absence of one of more of the typical findings is of little value (table 4).

Acute bacterial meningitis should be suspected in adults who present with fever and signs of meningeal inflammation. Isolation of a bacterial pathogen from the CSF (by culture or other diagnostic techniques) confirms the diagnosis of bacterial meningitis. Isolation of bacteria from blood cultures in a patient with CSF pleocytosis also confirms the diagnosis, even if the CSF culture remains negative.

The clinical and laboratory findings of bacterial meningitis overlap with those of meningitis caused by viruses, mycobacteria, fungi, or protozoa. Differentiation of these disorders from bacterial meningitis requires careful examination of CSF parameters (table 4), neuroimaging (when indicated), as well as consideration of any epidemiologic factors that would raise the possibility of specific bacterial or nonbacterial CNS infections

Meningitis is an inflammatory disease of the leptomeninges, the tissues surrounding the brain and spinal cord, and is characterized by an abnormal number of white blood cells (WBCs) in the cerebrospinal fluid (CSF) in the majority of patients [1].

The meninges consist of three parts: the pia, arachnoid, and dura maters ( figure 1)

Bacterial meningitis reflects infection of the arachnoid mater and the CSF in both the subarachnoid space and the cerebral ventricles.

The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, primarily in patients over 50 years of age or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes (table 1).

The major causes of health care-associated ventriculitis and meningitis are different (usually staphylococci and aerobic gram-negative bacilli) and occur more commonly after neurosurgical procedures (eg, post-craniotomy, ventriculoperitoneal shunts, lumbar shunts, external ventricular drains or following head trauma such as basilar skull fracture with or without clinical evidence of leak of cerebrospinal fluid) [2]

In the largest prospective study of 1412 episodes of bacterial meningitis, for example, approximately half of the patients presented less than 24 hours after onset of illness [3].

Any form of bacterial meningitis that is untreated or treated very late in its course is almost uniformly fatal.

The classic triad of acute bacterial meningitis, which occurs in 41 percent of patients, consists of fever, nuchal rigidity, and a change in mental status, usually of sudden onset [3,4]. Older patients (age >60 years) more commonly present with the triad than younger patients (58 versus 36 percent) [5].

The most common clinical features include a severe headache (84 percent), fever greater than 38°C (74 percent), stiff neck (74 percent), a Glasgow Coma scale <14 (71 percent), and nausea (62 percent) [3,4,6]

In a 2004 prospective study of 696 cases of community-acquired bacterial meningitis, almost all patients (95 percent) presented with at least two of four symptoms (ie, headache, fever, stiff neck, and altered mental status) [ 4]. The absence of all of these findings essentially excludes the presence of bacterial meningitis [7].

Concomitant infections may include sinusitis or otitis (34 percent), pneumonia (9 percent), and endocarditis (1 percent) [3]

In addition to the classic findings, less common manifestations are seizures (23 percent), aphasia or hemi- or monoparesis (22 percent), coma (13 percent), cranial nerve palsy (9 percent), rash (8 percent), and papilledema (4 percent) [3,4,8,9].

In an observational study of 696 patients with community-acquired bacterial meningitis, cerebral infarction occurred in 25 percent of episodes and in 36 percent of patients with pneumococcal meningitis [10]. Delayed cerebral infarctions have been described in 1 to 4 percent of patients with bacterial meningitis with a possible association with adjunctive dexamethasone [11]

Patients with Listeria meningitis have an increased tendency to have seizures and focal neurologic deficits early in the course of infection. In addition, some patients may present with rhombencephalitis affecting the brainstem and cerebellum, manifested as ataxia, cranial nerve palsies, and/or nystagmus.

Certain bacteria, particularly N. meningitidis, can cause characteristic skin manifestations, such as petechiae and palpable purpura. In two large series of patients with community-acquired bacterial meningitis, rash was present in 11 and 26 percent; among those with rash, 75 and 92 percent were associated with meningococcal meningitis [4,8].

However, others have observed a rash in ≤26 percent of cases of meningococcal meningitis and, if present, the rash was more likely to be scanty or more atypical appearing than the rash seen in patients with meningococcal septicemia [15]. A petechial rash is not specific for meningococcal infection, and some patients with meningococcal meningitis have a maculopapular rash [8]

Arthritis occurs in some patients with bacterial meningitis. In a case series of 696 episodes of community-acquired bacterial meningitis, arthritis was diagnosed in 48 (7 percent) of the episodes, with N. meningitidis the etiologic agent in two-thirds of these joint infections [16]. Joint fluid aspiration was performed in 23 patients and was positive by culture in 6 (26 percent). Recognition of the concurrent arthritis is important since prolonged antibiotic therapy is necessary. (See "Septic arthritis in adults".)

Although patients may not complain specifically of a stiff neck, it is important to assess for meningeal irritation. Passive or active flexion of the neck will usually result in an inability to touch the chin to the chest. Difficulty in lateral motion of the neck is a less reliable finding.

Tests to illustrate meningismus (such as Kernig and Brudzinski signs) were originally developed and tested in patients with severe, late-stage untreated bacterial and tuberculous meningitis in the preantibiotic era (table 2)

● The classic Brudzinski sign refers to spontaneous flexion of the hips during attempted passive flexion of the neck.

● The Kernig sign refers to the inability or reluctance to allow full extension of the knee when the hip is flexed 90 degrees. The Kernig test is usually performed in the supine position, but it can be tested in the seated patient.

Nuchal rigidity and the Kernig and Brudzinski signs were described over a century ago. These tests may be less sensitive in modern day community-acquired bacterial meningitis. As an example, in a large, well-designed prospective study of 297 patients with suspected meningitis, the sensitivity was extremely low (5 percent for each sign and 30 percent for nuchal rigidity); the specificity was 95 percent for each sign and 68 percent for nuchal rigidity [17]

Jolt accentuation of headache may be a more sensitive maneuver for the diagnosis of meningitis. A positive test consists of accentuation of headache by horizontal rotation of the head at a frequency of two to three times per second.

The diagnostic value of this maneuver has been evaluated in several studies with mixed results [18-20]. Although one study showed a sensitivity of jolt accentuation for the diagnosis of meningitis of 97 percent, other studies have revealed lower sensitivity and specificity highlighting the limited predictive value of the test in the diagnosis of meningitis.

Serum electrolytes and glucose, blood urea nitrogen, and creatinine concentrations are helpful in determining the cerebrospinal fluid- (CSF) to-blood glucose ratio. It is important to draw the serum glucose within one hour of obtaining the lumbar puncture to have a reliable ratio [21].

In addition, coagulation studies may be indicated, especially if petechiae or purpuric lesions are noted [ 22]

The white blood cell (WBC) count is usually elevated, with a shift toward immature forms; however, severe infection can be associated with leukopenia. The platelet count may also be reduced. Leukopenia and thrombocytopenia have correlated with a poor outcome in patients with bacterial meningitis [23,24].

Coagulation studies may be consistent with disseminated intravascular coagulation

Serum chemistry results are usually commensurate with the severity of the overall process and may reveal an anion gap metabolic acidosis or hyponatremia; in one series, hyponatremia was present in 30 percent of patients but was usually mild and did not require specific treatment [25]

Initial blood tests should include a complete blood count with differential and platelet count and two aerobic blood cultures of appropriate volume (ideally, prior to the initiation of antimicrobial therapy).

Blood cultures are often positive and can be useful in the event that CSF cannot be obtained before the administration of antimicrobials. Approximately 50 to 90 percent of patients with bacterial meningitis have positive blood cultures [3,4,6]; lower yields have been reported in some studies in patients with meningococcal infection [26]

Tests of serum and urine for bacterial antigens, as well as cultures of mucosal surfaces for the causative pathogen, are not generally helpful

Every patient with suspected meningitis should have CSF obtained unless lumbar puncture (LP) is contraindicated

Although there are no absolute contraindications to performing the procedure, caution should be used in patients with (see "Lumbar puncture: Technique, indications, contraindications, and complications in adults", section on 'Contraindications'):

● Possible raised intracranial pressure with risk for cerebral herniation due to obstructive hydrocephalus, cerebral edema, or space-occupying lesion

● Thrombocytopenia or other bleeding diathesis, including ongoing anticoagulant therapy

● Suspected spinal epidural abscess

A head CT should be performed before LP in adults with suspected bacterial meningitis who have one or more of the following risk factors (algorithm 1) [30-32]:

● Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic cell transplantation)

● History of central nervous system (CNS) disease (mass lesion, stroke, or focal infection)

● New onset seizure (within one week of presentation)

● Papilledema

● Abnormal level of consciousness

● Focal neurologic deficit

Patients without these indications should not undergo a CT scan as it is of no clinical benefit and delays therapy [33]

It has been suggested that a normal CT scan does not always mean that performance of an LP is safe and that certain clinical signs of impending herniation (ie, deteriorating level of consciousness, particularly a Glasgow Coma scale <11; brainstem signs including pupillary changes, posturing, or irregular respirations; or a very recent seizure) may be predictive of patients in whom an LP should be delayed irrespective of CT findings (table 3) [36]. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults", section on 'Cerebral herniation'.)

If LP is delayed or deferred — It is essential that antimicrobial therapy not be delayed if there is a contraindication to or inability to perform an LP, or if the LP is delayed by the need for cranial imaging. In any of these situations, blood cultures should be obtained and empiric antibiotics administered as soon as is possible (before the imaging study in patients who require imaging).

In addition, dexamethasone (0.15 mg/kg intravenously every 6 hours) should be given shortly before or at the same time as the antimicrobial agents if the preponderance of clinical and laboratory evidence suggests bacterial meningitis with a plan to stop therapy, if indicated, when the evaluation is complete.

Adjunctive dexamethasone should not be given to patients who have already received antimicrobial therapy because it is unlikely to improve patient outcome even though the European and United Kingdom guidelines recommend administering dexamethasone up to 4 and 12 hours after receipt of antimicrobial therapy, respectively [ 37]. Indications for adjunctive dexamethasone are discussed in greater detail separately. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults" and "Initial therapy and prognosis of bacterial meningitis in adults", section on 'Avoidance of delay'.)

Prior administration of antimicrobials tends to have minimal effects on the chemistry and cytology findings [28,38] but can reduce the yield of Gram stain and culture [26-28].

However, a pathogen can still be cultured from the CSF in most patients up to several hours after the administration of antimicrobial agents [ 27,28], with the possible exception of the meningococcus

Opening pressure — The opening pressure with the patient lying in the lateral decubitus position should be measured and documented. The opening pressure is typically elevated in patients with bacterial meningitis. In the series of 301 adults cited above, the mean opening pressure was approximately 350 mm H₂O (normal up to 200 mm H₂O) [3]. However, there is a wide range of values as illustrated in a report of 296 episodes of community-acquired bacterial meningitis: 39 percent had values ≥300 mm H₂O, while 9 percent had values below 140 mm H₂O [8]

Characteristic findings in bacterial meningitis include a CSF glucose concentration <40 mg/dL (<2.22 mmol/L), a CSF to serum glucose ratio of ≤0.4, a protein concentration >200 mg/dL (>2000 mg/L), and a WBC count above 1000/microL, with a percentage of neutrophils usually greater than 80 percent [3,32,39]

he spectrum of CSF values in bacterial meningitis is so wide, however, that the absence of one or more of the typical findings is of little value [ 4,8].

For example, in a prospective study of 1412 adults with bacterial meningitis, a CSF WBC >1000/microL was seen in only 66 percent of patients [ 3].

Why some patients have milder CSF abnormalities cannot usually be identified. Potential causes include early presentation, recent prior antimicrobial therapy, and neutropenia. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'CSF in CNS infection'.)

An observational study found that bacterial meningitis was highly probable (≥99 percent certainty) when any one of the following parameters was present: a CSF glucose concentration below 34 mg/dL (1.9 mmol/L), a protein concentration above 220 mg/dL (2200 mg/L), a WBC count above 2000/microL, or a neutrophil count more than 1180/microL [40]. However, clinicians must recognize that many exceptions exist and that empiric antimicrobial therapy is warranted when bacterial meningitis is suspected clinically even if the CSF abnormalities are not diagnostic

A false-positive elevation of the CSF WBC count can be found after traumatic LP or in patients with intracerebral or subarachnoid hemorrhage in which both red blood cells (RBCs) and WBCs are introduced into the subarachnoid space. If a traumatic LP is suspected and the peripheral WBC count is not abnormally low or high, a good rule of thumb for estimating the adjusted WBC count is to subtract one WBC for every 500 to 1000 RBCs measured in the CSF. This "corrected" CSF WBC has better diagnostic accuracy in differentiating culture-positive bacterial meningitis than patients with intracerebral hemorrhage alone [41]. The formula in the following calculator can also be used to determine the adjusted WBC count in the presence of CSF RBCs (calculator 1) [41,42]

Two meta-analyses that included 25 studies (1692 patients) and 31 studies (1885 patients) concluded that the diagnostic accuracy of CSF lactate was superior to that of CSF WBC count, glucose, and protein concentration in differentiating bacterial from aseptic meningitis [43,44], although sensitivity was lower in patients who received antimicrobial treatment prior to LP [43], and CSF lactate may be elevated in patients with other CNS diseases.

A CSF lactate may help differentiate health care-associated ventriculitis from chemical meningitis in patients with recent neurosurgical procedures, but it is only performed in approximately 50 percent of the patients [ 45]

● Gram-positive diplococci suggest pneumococcal infection (picture 1).

● Gram-negative diplococci suggest meningococcal infection (picture 2).

● Small pleomorphic gram-negative coccobacilli suggest Haemophilus influenzae infection (picture 3).

● Gram-positive rods and coccobacilli suggest listerial infection (picture 4).

The Gram stain is positive in 10 to 15 percent of patients who have bacterial meningitis but negative CSF cultures [8]. As noted above, the yield of both Gram stain and culture may be reduced by prior antibiotic therapy [26-28]

The reported sensitivity of Gram stain for bacterial meningitis has varied from 50 to 90 percent; however, the specificity approaches 100 percent [4,11,46]

A rapid multiplex PCR that tests for the most common viruses, bacteria, and fungi is now widely available and has been shown to be useful, especially in those with a negative-CSF Gram stain or culture, or in those who have received prior antimicrobial therapy.

Problems with false-positive results have been reported with PCR but false negatives are very uncommon [52]

Molecular diagnosis of bacterial meningitis is discussed in greater detail separately. (See "Molecular diagnosis of central nervous system infections", section on 'Meningitis'.)

Isolation of bacteria from blood cultures in a patient with CSF pleocytosis also confirms the diagnosis, even if the CSF culture remains negative

Differentiation of these disorders from bacterial meningitis requires careful examination of cerebrospinal fluid (CSF) parameters (table 4) and neuroimaging (when indicated), as well as consideration of any epidemiologic factors that would raise the possibility of specific bacterial or nonbacterial central nervous system infections

Viral meningitis – Aseptic (usually viral) meningitis is a less severe disease that is often monitored in the outpatient setting without antimicrobial therapy, whereas bacterial meningitis is a life-threatening illness that requires hospital admission. Similar to bacterial meningitis, viral meningitis presents acutely with classic signs and symptoms of meningitis. Unlike bacterial meningitis, the CSF normally has a lymphocytic pleocytosis, normal glucose, moderate elevation of protein, and negative-CSF Gram stain and culture. Definitive diagnosis of viral meningitis is generally made by CSF polymerase chain reaction (PCR), although serologies are typically used for the diagnosis of meningitis due to arboviruses (eg, West Nile virus).

TB meningitis – Patients with tuberculous (TB) meningitis may have classic signs and symptoms of meningitis at presentation, however, it is generally a subacute process. CSF exam typically reveals a lymphocyte predominant pleocytosis with elevated protein and decreased glucose. Certain scoring systems (eg, the Lancet consensus scoring system and the Thwaites system) have been developed to help differentiate bacterial from TB meningitis [54]; these are based primarily on clinical and CSF findings. A definitive diagnosis of TB meningitis is made by identification of mycobacterium from the CSF either by culture or PCR.

Fungal meningitis – Several fungal species may cause meningitis including Candida, Cryptococcus, Histoplasma, Blastomyces, and Coccidioides. Although fungal meningitis may present with classic symptoms of meningitis, it often is a subacute process in patients with epidemiologic risk factors for fungal disease (eg, immunocompromise, HIV).

Generalized seizures without meningitis – Generalized seizures may also induce a mild transient CSF pleocytosis, although this has not been well studied [55-57]. However, CSF pleocytosis should not be ascribed to seizure activity alone unless the fluid is clear and colorless, the opening pressure and CSF glucose are normal, the CSF Gram stain is negative, and the patient has no clinical evidence of bacterial meningitis

When the Gram stain is negative, studies in both adults and children have concluded that, in the setting of an elevated CSF white blood cell (WBC) count, no single CSF biochemical variable can reliably exclude bacterial meningitis [40,46,58]

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