Acute Bacterial Infections of the Central Nervous System

Acute bacterial infections of the central nervous system (CNS) include meningitis, brain abscess, subdural empyema, epidural abscess, and septic intracranial thrombophlebitis. The etiology, clinical presentation, diagnosis, and treatment of each of these bacterial infections are discussed in this chapter.

Acute Bacterial Meningitis

Bacterial meningitis is an acute purulent infection in the subarachnoid space, associated with an inflammatory reaction in the brain parenchyma and cerebral vasculature. During its treatment, not only must the meningeal pathogen be eradicated, but also the neurologic complications resulting from an often robust inflammatory reaction must be anticipated and managed. The most common causative organisms of bacterial meningitis are Streptococcus pneumoniae , Neisseria meningitidis , Listeria monocytogenes , Staphylococcus aureus , group B streptococci, and gram-negative bacilli. The current epidemiology of acute bacterial meningitis, the best diagnostic tests to perform on cerebrospinal fluid (CSF), the use of dexamethasone as adjunctive therapy, and the present recommendations for the use of chemoprophylaxis and vaccination are discussed here.

Etiology

The most common etiologic organisms of acute bacterial meningitis in children and adults are S. pneumoniae and N. meningitidis. Prior to the routine use of the Haemophilus influenzae type b conjugate vaccine, H. influenzae type b was the most common cause of bacterial meningitis in children in the United States. Use of this vaccine has dramatically reduced the incidence of bacterial meningitis due to H. influenzae type b in children. H. influenzae type b, however, remains an important cause of bacterial meningitis in older adults, immunocompromised patients, and patients with chronic lung disease, splenectomy, leukemia, or sickle cell anemia. Children too young to have completed a primary H. influenzae type b vaccination course are also at risk.

S. pneumoniae is the most common cause of community-acquired meningitis in both children and adults in the United States and Europe. A number of predisposing conditions increase the risk of pneumococcal meningitis, the most common of which is pneumonia. Acute and chronic otitis media, sinusitis, immunodeficiency from alcoholism, diabetes, cancer, and immunosuppressive drugs are also important risk factors. Given the rise of multidrug-resistant strains of S. pneumoniae to both penicillin and third-generation cephalosporins, vancomycin is added to the initial empiric antimicrobial therapy, with specific antibiotic therapy based on culture susceptibilities.

N. meningitidis is the second most common cause of meningitis in adults, but has a predilection for those younger than age 60. The quadrivalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine is recommended for all 11- to 18-year-olds, and is a requirement for attending most colleges and universities in the United States. A vaccine for serogroup B became available in 2015 and is increasingly recommended for college-bound students.

The Enterobacteriaceae ( Proteus species, Escherichia coli , Klebsiella species, Serratia species, and Enterobacter species) cause meningitis in older adults; in adults with underlying diseases such as cancer, diabetes, alcoholism, congestive heart failure, chronic lung disease, and hepatic or renal dysfunction; and in neurosurgical patients.

L. monocytogenes is a cause of meningitis in individuals with impaired cell-mediated immunity from older age (adults greater than 55 years old), organ transplantation, pregnancy, malignancy, chronic illness, immunosuppressive therapy, and neonates. Outbreaks have occurred from eating contaminated foods. The incidence amongst pregnant women and neonates has decreased, likely from education on foodborne infections during pregnancy. In addition, the routine use of trimethoprim-sulfamethoxazole as a prophylactic agent for the prevention of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS) has the added benefit of reducing the risk of L. monocytogenes infection, including meningitis.

S. aureus and coagulase-negative staphylococci are the predominant organisms causing meningitis as a complication of invasive neurosurgical procedures, particularly shunting procedures for hydrocephalus and with subcutaneous Ommaya reservoirs or following lumbar puncture for the administration of intrathecal chemotherapy. Hematogenous spread accounts for 25 percent of S. aureus meningitis cases and is seen in patients with endocarditis, pneumonia, and skin or soft-tissue infections. Intravenous drug use accounts for an increasing number of methicillin-resistant (MRSA) infections.

Streptococcus agalactiae , or group B streptococcus, is a leading cause of bacterial meningitis and sepsis in neonates and is increasingly recognized in two groups of adults: puerperal women and patients with serious underlying disease.

Clinical Presentation

The classic triad of symptoms and signs of bacterial meningitis consists of fever, headache, and stiff neck. An altered level of consciousness, such as lethargy or stupor, may deteriorate rapidly, and should be added to the classic triad for potential bacterial meningitis. Approximately 95 percent of patients will have at least two of the four symptoms and signs of fever, stiff neck, headache, or altered mental status, but less than 50 percent will have all three components of the classic triad. Nausea, vomiting, and photophobia are common complaints, which often reflect elevated intracranial pressure (ICP). Seizure activity occurs in approximately 20 percent of patients, although in neonates this can approach 40 percent, typically either at the onset or within the first few days of the illness; seizures are a poor prognostic indicator.

A stiff neck, or meningismus, is the pathognomonic sign of meningeal irritation. Meningismus is present when the neck resists passive flexion. Kernig and Brudzinski signs are classic signs of meningeal irritation with high specificities but relatively low sensitivities, and therefore their absence does not exclude the diagnosis. Kernig sign is elicited with the patient in the supine position; the thigh is flexed on the abdomen, with the knee flexed. Attempts to passively extend the leg elicit pain when meningeal irritation is present. Brudzinski sign is elicited with the patient in a supine position and is positive when passive flexion of the neck results in spontaneous flexion of the hips and knees.

Increased ICP is an expected complication of bacterial meningitis and is the major cause of obtundation and coma. The most common signs of increased ICP in bacterial meningitis are an altered level of consciousness and papilledema. Cerebral arteritis and septic venous thrombosis of the cerebral dural sinuses and cortical veins are also complications of bacterial meningitis, often presenting as focal neurologic deficits or as new-onset seizure activity.

The rash of meningococcemia begins as a diffuse erythematous maculopapular rash resembling a viral exanthem, but the lesions rapidly become petechial. This rash can be differentiated from the rash of a viremia in that petechiae are found on the trunk and lower extremities in meningococcemia. Petechiae may also be found in the mucous membranes and conjunctiva and occasionally on the palms and soles. Other infectious diseases that may manifest with a petechial, purpuric, or erythematous maculopapular rash resembling that of meningococcemia include enteroviral meningitis, Rocky Mountain spotted fever, West Nile virus encephalitis, bacterial endocarditis, echovirus type 9 viremia, and, more rarely, pneumococcal or H. influenzae meningitis.

Diagnosis

The diagnosis of bacterial meningitis is made by examination of the CSF. The necessity of neuroimaging prior to lumbar puncture has been debated for years. The presence of any of the following necessitate neuroimaging prior to lumbar puncture: an altered level of consciousness, papilledema, focal neurologic deficits, an immunocompromised state, or new-onset seizure activity. When the clinical presentation is suggestive of bacterial meningitis, two sets of blood cultures should be obtained and dexamethasone and empiric antimicrobial therapy initiated immediately. If the patient is being treated with antibiotics, there is no risk in delaying lumbar puncture until after neuroimaging has been performed. While antibiotics do decrease the likelihood of a positive CSF culture, the culture is still positive in approximately 75 percent of cases if obtained less than 4 hours after antibiotic initiation, since it takes time to sterilize the cultures once antibiotics have been initiated. Antibiotic therapy for several hours prior to lumbar puncture has little effect on CSF white blood cell count or glucose concentration, so even if the specific organism is not isolated, the overall suspicion of bacterial meningitis based on CSF abnormalities will remain. Blood cultures are positive at least 60 percent of the time, making them particularly helpful if CSF culture is negative. Serum procalcitonin is elevated in bacterial, but not viral, meningitis.

The classic CSF abnormalities in bacterial meningitis are: (1) an increased opening pressure (>18 cm water); (2) a pleocytosis of polymorphonuclear leukocytes (10 to 10,000 WBCs/mm ³ ); (3) a decreased glucose concentration (<40 mg/dL or CSF/serum glucose ratio of <0.31); and (4) an increased protein concentration. A CSF sample should be analyzed using Gram stain and bacterial culture, which can identify the causative pathogen in approximately 80 percent of patients. CSF PCR assays detect bacterial nucleic acid in CSF. A 16S rRNA conserved sequence broad-based bacterial PCR can detect small numbers of viable and nonviable organisms in the CSF, but this assay has been replaced by newer nucleic acid assays.

A commonly used PCR panel is the FilmArray Meningitis/Encephalitis panel which tests six bacterial meningeal pathogens, including S. pneumoniae , N. meningitidis , H. influenzae , E. coli , group B streptococcus and L. monocytogenes . Specific advantages of this PCR panel are its rapid turnaround time, which can be as short as 1 hour, and that antibiotics do not interfere with its results. The sensitivity and specificity of the FilmArray Meningitis/Encephalitis panel for bacterial pathogens is not known at this time as further studies are still required for verification along with further refinements to reduce false-positive rates. Metagenomic next-generation sequencing (mNGS) is a newer nucleic acid assay to identify the meningeal pathogen. A limitation to mNGS is that the results take time. Metagenomic next-generation sequencing is particularly helpful in those instances when the pathogen is difficult to detect. PCR assays have eliminated the need for previously used tests, such as the latex particle agglutination test, which had high specificities but variable sensitivities. A false-positive PCR is a possibility with meningitis/encephalitis panels and mNGS. The results of a PCR assay can be confirmed by a conventional test, such as culture, CSF IgM, acute and convalescent serology, or some combination of these tests. In clinical practice, when bacterial meningitis is a possibility, most physicians treat with empiric therapy until CSF analysis suggests an alternative diagnosis.

If there are petechial skin lesions, biopsies should be performed. While the occurrence of a rash is only modestly sensitive, it is highly specific for meningococcal meningitis if present. The rash of meningococcemia results from the dermal seeding of organisms with vascular endothelial damage, and biopsy may reveal the organism on Gram stain.

Lumbar puncture should be performed with a 22- or 25-gauge needle. The amount of CSF recommended for testing is 10 to 15 ml, which includes saving 5 ml for future testing. Cell count with differential, glucose and protein concentrations, Gram stain and culture, and viral culture and PCR assays all should be sent and more advanced testing including panels and mNGS should be considered as above in some clinical situations.

Differential Diagnosis

Viral meningitis and herpes simplex virus (HSV) encephalitis are the leading diseases in the differential diagnosis of bacterial meningitis. Arthropod-borne viral encephalitis should be considered during the summer and early fall months while mosquitoes are biting. Focal intracranial mass lesions and subarachnoid hemorrhage also need to be included in the differential diagnosis when approaching patients with suspected meningitis.

Viral Meningitis

In a patient with fever, headache, and a stiff neck, the leading consideration in addition to bacterial meningitis, is viral meningitis. The key difference is that patients with viral meningitis do not typically have an altered level of consciousness and are both awake and alert. Patients with viral meningitis will often be sitting up and concerned about the severity of their headache. Patients with viral meningitis also do not have seizures or focal neurologic deficits. In addition to clinical differences, viral meningitis will have a distinct CSF profile from bacterial meningitis. In comparison to the predominantly polymorphonuclear pleocytosis and low glucose concentration of bacterial meningitis, patients with viral meningitis will exhibit a lymphocytic pleocytosis with a modest white cell count (often 100 to 500 WBCs) and normal glucose concentration. Treatment for viral meningitis is largely supportive, except when the organism is herpes simplex virus (HSV) or varicella zoster virus (VZV), in which case acyclovir, valacyclovir, or famciclovir should be used. Viral meningitis is typically a self-limited disease, but the headache may take months to resolve.

Herpes Simplex Virus Encephalitis

The clinical presentation of HSV encephalitis (discussed in detail in Chapter 42 ) often includes hemicranial headache, fever, behavioral abnormalities, focal or generalized seizure activity, and focal neurologic deficits (e.g., dysphasia, usually hemiparesis with greater involvement of the face and arm, and superior visual field defects). The symptoms of HSV encephalitis typically evolve over several days, and the presentation is often less acute than bacterial meningitis. In patients with HSV encephalitis, fluid-attenuated inversion recovery (FLAIR), T2-, and diffusion-weighted magnetic resonance imaging (MRI) sequences demonstrate lesions in the medial and inferior temporal lobe, inferior frontal lobe, and insular cortex that begin unilaterally and remain asymmetric if contralateral involvement occurs. Lesions will have associated edema, restricted diffusion (particularly early in the course), hemorrhage, or some combination of these features. The absence of an abnormality on MRI 48 hours after symptom onset should prompt consideration of another diagnosis.

There is a distinctive electroencephalographic (EEG) pattern in HSV encephalitis, consisting of periodic, stereotyped complexes from one or both temporal areas that occur at regular intervals of 1 to 2 seconds and are typically observed between day 2 and day 15 of the illness. Examination of the CSF reveals an increased opening pressure, a lymphocytic pleocytosis of 5 to 500 cells/mm ³ , a mild to moderate elevation in the protein concentration, and a normal or mildly decreased glucose concentration. There may be red blood cells or xanthochromia, findings that reflect the hemorrhagic nature of the encephalitis but are neither sensitive nor specific markers of the disorder. Results of CSF viral cultures for HSV-1 are almost always negative.

HSV PCR is the gold standard for diagnosis with a sensitivity of 96 percent and specificity of 99 percent. Nonetheless, a false-negative PCR is possible within the first 72 hours of symptom onset. If an initial CSF HSV PCR is negative within the first 72 hours of symptoms and HSV remains a major diagnostic consideration, patients should be continued on empiric treatment and repeat lumbar puncture with HSV PCR should be performed 3 to 7 days later. CSF and serum samples can also be sent for HSV IgG antibody titers if neurologic symptoms are present for more than 1 week at the time of presentation, since the sensitivity of HSV PCR begins to decline after the first week and antibodies to HSV appear in the CSF approximately 8 to 12 days after onset of symptoms. A serum to CSF HSV-1 antibody ratio of less than 20 to 1 is considered diagnostic of intrathecal synthesis of antibodies and HSV encephalitis in the appropriate clinical context.

Arthropod-Borne Virus Encephalitis

During the summer and early fall months when mosquitoes are active, arthropod-borne virus (also known as arbovirus) encephalitis (see Chapter 42 ) should be included in the differential diagnosis of patients with meningitis. In the United States, the most common arbovirus is West Nile virus with the number of neuroinvasive cases ranging from a few hundred to a few thousand cases per year. The other arboviruses occur much less frequently, and include St. Louis encephalitis virus, Powassan virus, La Crosse virus, western equine encephalitis virus, Jamestown Canyon virus, and eastern equine encephalitis virus. Eastern equine encephalitis virus causes the most severe arthropod-borne viral encephalitis, and the fatality rate is as high as 40 percent; recent outbreaks of this rare disease have raised awareness of the entity. Japanese encephalitis virus is the most common cause of arboviral encephalitis worldwide and occurs mainly in Asia. Venezuelan equine encephalitis virus is endemic in South America and is a rare cause of encephalitis in Central America and the southwestern United States, particularly in Texas.

The clinical presentation of arthropod-borne viral encephalitis, regardless of the specific virus, is fairly characteristic. The onset of encephalitic symptoms may be preceded by an influenza-like prodrome of fever, malaise, myalgias, nausea, and vomiting followed by headache, confusion, stupor, and occasionally convulsions. Focal neurologic deficits and focal seizure activity have been reported in cases of encephalitis caused by eastern equine encephalitis virus and La Crosse virus. Patients with West Nile virus encephalitis may have conjunctivitis or a maculopapular or roseolar rash. Patients with West Nile virus or St. Louis encephalitis virus may present with a polio-like acute asymmetric flaccid weakness or a syndrome of tremors, myoclonus, or parkinsonian features. The flaviviruses, including St. Louis encephalitis virus, Japanese encephalitis virus, and West Nile virus, tend to infect the basal ganglia and the thalamus, leading to tremors during the acute disease and a parkinsonian-like syndrome in survivors.

On neuroimaging, bilateral and symmetric T2-FLAIR hyperintensities with associated mass effect in the basal ganglia and thalamus are a characteristic finding in eastern equine encephalitis virus, St. Louis encephalitis virus, Japanese encephalitis virus, and West Nile virus encephalitis.

Examination of the CSF demonstrates a polymorphonuclear leukocytic pleocytosis if tested very early in the course, and this typically evolves to a moderate lymphocytic pleocytosis (i.e., several hundred cells). The CSF glucose concentration and protein concentration are usually normal. Based on criteria established by the US Centers for Disease Control and Prevention, a confirmed case of arboviral encephalitis is defined as a febrile illness with encephalitis during a period when arboviral transmission is likely to occur, plus at least one of the following: (1) fourfold or greater rise in serum antibody titer between the time of acute illness and 4 weeks later; (2) isolation of virus from tissue, blood, or CSF; or (3) a specific immunoglobulin M (IgM) antibody identified in the CSF. However, La Crosse virus has not been isolated from CSF and St. Louis encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus are rarely isolated from CSF; therefore antibody titers are typically the diagnostic test of choice. A CSF PCR assay is available for the detection of West Nile virus nucleic acid and has a high specificity; however, it has a low sensitivity so a negative test does not exclude the disorder. The detection of West Nile virus IgM in CSF is considered the most sensitive diagnostic test for West Nile virus encephalitis. West Nile virus IgM antibodies may persist in serum (not the CSF) for a year or more after exposure to the virus and therefore cannot be used for definitive diagnosis of recent infection.

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever is caused by the bacterium Rickettsia rickettsii . The disease begins with high fever, prostration, myalgias, headache, nausea, and vomiting. The rash is characteristic and presents initially as a diffuse erythematous maculopapular eruption appearing 2 to 4 days after the onset of symptoms, usually beginning at the wrist and ankles and then spreading distally, including to the palms and soles, and then proximally within a matter of a few hours. Diagnosis is made by immunofluorescent staining of skin biopsy specimens or by the detection of IgM and IgG antibodies. If a tick-borne etiology is suspected, then empiric treatment with doxycycline should be initiated.

Focal Infectious Intracranial Mass Lesions

Focal infectious intracranial mass lesions, including brain abscess, subdural empyema, and epidural abscess, are discussed later in this chapter but should be included in the differential diagnosis of bacterial meningitis. The presence of a focal infectious intracranial mass lesion is suggested by focal or generalized seizure activity or focal neurologic deficits on examination. This possibility is ruled out by neuroimaging.

Subarachnoid Hemorrhage

The possibility of a subarachnoid hemorrhage should also be included in the differential diagnosis of acute bacterial meningitis. The clinical presentation is characterized by the explosive onset of a severe headache or a sudden transient loss of consciousness followed by a severe headache. Because of the presence of blood in the subarachnoid space, nuchal rigidity is frequently present, leading to diagnostic confusion with infectious meningitis. A dilated nonreactive pupil is suggestive of a subarachnoid hemorrhage from an aneurysm of the posterior communicating artery. Computed tomography (CT) of the brain may demonstrate blood in the basal cisterns. If the CT scan is normal, the spinal fluid should be examined for red blood cells and xanthochromia. Red blood cells are present in the CSF within minutes of the rupture of an intracranial aneurysm and usually fail to clear in successive tubes of CSF. A sample of the blood-tinged CSF should be centrifuged; a yellow or xanthochromic color in the supernatant is present 6 to 12 hours following subarachnoid hemorrhage and lasts for 2 to 3 weeks. Xanthochromic spinal fluid may also be seen when the CSF protein concentration is elevated (above 150 to 200 mg/dL), and therefore it can be seen in bacterial meningitis.

Treatment

Empiric Antimicrobial Therapy

When bacterial meningitis is suspected, antimicrobial therapy is initiated immediately after blood cultures are obtained and before the results of CSF Gram stain, culture, and antimicrobial susceptibility tests are known. Empiric therapy should be based on the possibility that the patient has penicillin- and cephalosporin-resistant pneumococcal meningitis and should include a combination of a third- (ceftriaxone or cefotaxime) or fourth-generation cephalosporin (cefepime) plus vancomycin. Acyclovir is added to the empiric regimen to cover HSV ( Table 38-1 ). Ampicillin should be added to cover L. monocytogenes if the patient is over the age of 55 years or is immunosuppressed. When the patient has been treated with trimethoprim-sulfamethoxazole for prophylaxis of toxoplasmosis or P. carinii pneumonia, it is less likely that the meningitis is due to L. monocytogenes. Meningitis that complicates a neurosurgical procedure, epidural anesthesia, head trauma with skull base fracture, or intrathecal chemotherapy should be treated empirically with a combination of vancomycin plus ceftazidime, cefepime, or meropenem. Vancomycin is used to cover staphylococci and ceftazidime, cefepime, or meropenem to cover gram-negative bacilli, specifically Pseudomonas aeruginosa. The doses of each of the antimicrobial agents are provided in Table 38-2 , which shows both pediatric and adult dosing ranges.

Table 38-1

Empiric Therapy for Acute Bacterial Meningitis in Children and Adults

Community-acquired (immunocompetent child or adult)	Cefotaxime or ceftriaxone or cefepime plus Vancomycin plus
	Acyclovir
Community-acquired (immunosuppressed individual)	Cefotaxime or ceftriaxone or cefepime plus Vancomycin plus
	Acyclovir plus
	Ampicillin
Iatrogenic (associated with neurosurgery, epidural anesthesia, intrathecal chemotherapy)	Vancomycin plus Ceftazidime or meropenem

Table 38-2

Doses of Antimicrobial Agents

Antimicrobial Agent	Total Daily Pediatric Dose (Dosing Interval)	Total Daily Adult Dose (Dosing Interval)
Acyclovir	30 mg/kg daily (every 8 h)	30 mg/kg daily (every 8 h)
Ampicillin	300 mg/kg daily (every 6 h)	12 g/day (every 4–6 h)
Cefepime	150 mg/kg daily (every 8 h)	6 g/day (every 8 h)
Cefotaxime	225–300 mg/kg daily (every 6–8 h)	12 g/day (every 4–6 h)
Ceftazidime	150–200 mg/kg daily (every 8 h)	8 g/day (every 8 h)
Ceftriaxone	80–100 mg/kg daily (every 12 h)	4 g/day (every 12 h)
Meropenem	120 mg/kg daily (every 8 h)	6 g/day (every 8 h)
Metronidazole	30 mg/kg daily (every 6 h)	2 g/day (every 6 h)
Nafcillin	200 mg/kg daily (every 6 h)	12 g/day (every 4 h)
Penicillin G	0.3 million U/kg/day (every 4–6 h)	24 million U/day (every 4–6 h)
Vancomycin	60 mg/kg daily (every 6 h)	45–60 mg/kg daily (every 6 h)
Intrathecal vancomycin	10 mg/day	20 mg/day

Specific Antimicrobial Therapy

All CSF bacterial isolates should be tested for antimicrobial susceptibility. In experimental models of bacterial meningitis, the maximal bactericidal activity occurs when the antibiotic concentration is 10 to 30 times greater than the minimal bactericidal concentration of the microorganism in vitro.

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