Bacterial Infections of the Central Nervous System

Paul A. LaPenna, DO; Karen L. Roos, MD

Disclosures

Semin Neurol. 2019;39(3):334-342. 

In This Article

Bacterial Meningitis

Acute bacterial meningitis is a life-threatening neurological emergency. It is defined as a purulent infection within the subarachnoid space and is often associated with inflammation of the meninges, brain parenchyma, and cerebral vasculature. Hence, this condition is often referred to as meningoencephalitis. Mortality and complication rates are high. Therefore, prompt recognition of clinical manifestations, early introduction of empiric therapy, proper diagnostic testing, and awareness of common complications are essential in the management of those who suffer from bacterial meningitis.

Epidemiology

Bacterial meningitis remains the most common purulent central nervous system (CNS) infection. With the introduction of conjugate vaccines, cases of community-acquired bacterial meningitis have substantially declined since the 1990s; however, mortality rates remain high.[1] In developing countries, most notably sub-Saharan Africa, bacterial meningitis is significantly more common than in industrialized nations. Meningococcal meningitis epidemics have swept through sub-Saharan Africa. In Niger from 1981 to 1996, the incidence of meningococcal meningitis was 101 cases per 100,000 population.[2]

The epidemiologic history of bacterial meningitis is a major triumph of public health efforts and underscores the role of prevention. Haemophilus influenzae type b was once the most common cause of bacterial meningitis, especially in young children and neonates. After vaccination against this pathogen, cases of Haemophilus influenzae type b meningitis declined more than 90%.[2] Later, vaccination against Streptococcus pneumoniaeand Neisseria meningitidis further reduced the burden of community-acquired bacterial meningitis. The use of prophylactic antimicrobials in pregnant women colonized with Group B streptococcus has decreased the mother-to-child transmission of this pathogen, preventing meningitis in neonates and infants.[2] These efforts have decreased the overall incidence of bacterial meningitis and shifted the mean age of this disease into adulthood.[1]

Etiological Organisms

Despite the success of vaccination in the prevention of community-acquired bacterial meningitis, nonvaccine serotype strains have emerged in the pathogenesis of bacterial meningitis. The most common organisms responsible for bacterial meningitis in adults are Streptococcus pneumoniae and Neisseria meningitidis.

Streptococcus pneumoniae accounts for more than 50% of community-acquired bacterial meningitis, and pneumococcal pneumonia is the most common predisposing condition for developing pneumococcal meningitis. Additional risk factors include sinusitis and otitis media, immunodeficiency, cochlear implants, and skull fracture accompanied by cerebrospinal fluid (CSF) leak. Of the common causes of community-acquired bacterial meningitis, Streptococcus pneumoniae carries the highest fatality rate and has a significantly greater risk of complications relative to other organisms (see the "Complications and Prognosis" section).

Neisseria meningitidis is the second most common cause of bacterial meningitis and is the leading cause in children and adolescents aged 2 to 18 years of age. The meningococcal tetravalent vaccine contains serotypes A, C, W-135, and Y, but does not contain serogroup B. In children less than 5 years of age, serogroup B causes 60% of meningococcal meningitis, and in those 11 years of age and older, serogroup B causes one-third of meningococcal meningitis.[3] Neisseria meningitidis colonizes the nasopharynx, which either results in an asymptomatic carrier state or invasive meningococcal disease, depending on the immune response of the host. Those with a complement component deficiency or asplenia are especially at risk for meningococcal meningitis, as are those who live in close quarters such as military barracks or college dormitories.

Several meningeal pathogens can be predicted based on predisposing factors. Listeria monocytogenes should be considered in patients who are neonates, elderly, diabetics, immunocompromised, or pregnant. Listeria monocytogenes is the only bacteria that causes a brainstem encephalitis. Staphylococcus aureus species should be considered in those who recently underwent a neurosurgical procedure such as intraventricular drain placement, or in those with endocarditis. Postneurosurgical patients are also at risk for meningitis due to gram-negative bacilli. Patients with otitis, sinusitis, or mastoiditis are at risk for meningitis due to Streptococci species and gram-negative anaerobic organisms. Viridans streptococcus, Streptococcus bovis, and the HACEK organisms should be considered in endocarditis. Chronically ill or immunocompromised patients are at risk for meningitis due to Streptococcus pneumoniae, Listeria monocytogenes, Haemophilus influenzae, gram-negative bacilli, and Streptococcus agalactiae (Group B streptococcus).

Clinical Presentation

The classic triad of bacterial meningitis is fever, stiff neck (nuchal rigidity), and headache. Although these signs and symptoms are individually common, the triad may be absent. Additional signs and symptoms include vomiting, a decreased level of consciousness, and photophobia. Of these symptoms, temperature greater than or equal to 37.7°C (100°F) is most sensitive, present in 95% of patients at presentation and 99% within 24 hours of presentation.[4] Nearly all patients with bacterial meningitis will have two of the four following symptoms: fever, headache, decreased level of consciousness, or stiff neck.[5]

Physical examination should include testing for nuchal rigidity, which is present in approximately 80%.[5,6] Nuchal rigidity is tested by passively flexing the neck and is positive when the examiner notes significant resistance to forward flexion. Kernig's sign and Brudzinski's sign are classic signs, but have low sensitivity and questionable diagnostic utility.[7] The skin of patients should be examined for a petechial rash, which is highly suggestive of meningococcemia.

Diagnostic Studies

Emergency department personnel should obtain blood cultures and initiate empiric adjunctive and antimicrobial therapy (Table 1) within 60 minutes of patient arrival. Serum biomarkers may assist in the diagnosis of bacterial meningitis. Two such biomarkers, C-reactive protein and procalcitonin, are helpful in differentiating between bacterial and viral meningitis. Procalcitonin has been widely studied and when elevated is considered an excellent predictor of bacterial rather than viral meningitis.[8,9] C-reactive protein is a reliable biomarker but is not as specific as procalcitonin.[8,9]

The diagnosis of bacterial meningitis is established by analysis of CSF. The clinician determines if a computed tomography (CT) scan is required prior to performing a lumbar puncture. Focal neurological deficits, new-onset seizure, papilledema (or poorly visualized fundi), altered level of consciousness, or immunocompromised state are reasons to obtain CT prior to lumbar puncture.[10–12] Hemodynamic instability, coagulopathy, and signs of sepsis or serious rash may also result in the decision to delay lumbar puncture.[11] The meningeal pathogen may be identified by blood cultures, allowing time to stabilize the patient prior to lumbar puncture.

Lumbar puncture is performed with the patient placed in the lateral decubitus position. An opening pressure > 180 mm of water is an expected finding in bacterial meningitis.

The CSF leukocyte count is significantly elevated in the majority of patients with bacterial meningitis, with a predominance of polymorphonuclear leukocytes. A normal CSF leukocyte count is 0 to 5 cells/mm3. In bacterial meningitis, the CSF leukocyte count may exceed 1,000 mm3.[5] Patients who are on immunomodulating therapy[13] or are septic[14] or neutropenic[15] often have lower CSF leukocyte counts, or in the case of neutropenia, may have a normal CSF leukocyte count.

Hypoglycorrhachia (low CSF glucose concentration) is a cardinal feature of bacterial meningitis.[16] CSF glucose concentration < 40 mg/dL or CSF-to-serum ratio < 0.40 is worrisome for bacterial meningitis. A normal CSF-to-serum glucose ratio is 0.6. A CSF-to-serum glucose ratio of less than 0.31 is seen in approximately 70% of patients with bacterial meningitis. The differential diagnosis of hypoglycorrhachia also includes leptomeningeal carcinomatosis, neurosarcoidosis, and fungal or mycobacterial causes of meningitis.

Many additional tests are sent from the CSF, including protein concentration, Gram's stain, cultures, and lactate. Protein concentration > 45 mg/dL is common in bacterial meningitis but is nonspecific. Unless acquisition of CSF is significantly delayed after antimicrobial therapy has been initiated, CSF cultures and Gram's stain reveal the causative organism in approximately 80 and 60% of cases, respectively. Measuring CSF lactate concentration is not routinely recommended in community-acquired bacterial meningitis, but likely has utility when considering the diagnosis of postneurosurgical bacterial meningitis.[17]

CSF pathogen panels are often used to diagnose bacterial meningitis. Latex agglutination was a useful test for the detection of several bacterial antigens. It had high specificity but relatively low sensitivity and has been replaced by polymerase chain reaction (PCR) assays. The FilmArray Meningitis/Encephalitis (ME) panel (BioFire Diagnostics, Salt Lake City, UT) is a multiplex molecular PCR panel that tests for 14 pathogens, including 6 bacteria. Bacteria included in this panel are Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus pneumoniae, and Streptococcus agalactiae. This test has a fair sensitivity for the bacteria in the panel and a rapid turnaround time.[18] Although useful, this panel does not rule out bacterial meningitis as it only tests for six bacterial organisms. This panel is not available at all hospitals. In difficult cases, metagenomic next-generation sequencing can be considered. This test, done through the University of California, San Francisco laboratories,[19] detects viral, bacterial, fungal, and parasitic genetic material in CSF and may assist when diagnostic uncertainty exists.

Imaging studies are often performed in patients with bacterial meningitis. Magnetic resonance imaging (MRI) is superior to CT in detection of cerebral ischemia and edema, and is generally the preferred imaging modality, barring no contraindications. With the administration of gadolinium, meningeal enhancement is often seen, and although nonspecific, may aid in diagnosis. MRI postcontrast imaging may detect cerebral venous thrombosis, another potential complication of meningitis. MRI may aid in narrowing the differential diagnosis; for example, demonstrating a brain abscess or findings consistent with herpes simplex encephalitis.

Differential Diagnosis

The differential diagnosis of bacterial meningitis includes meningitis caused by other pathogens such as fungi, viruses, and mycobacteria. Both bacterial meningitis and intracranial abscess can cause headache, fever, focal neurological deficits, and seizures. Infectious encephalitis, especially herpes simplex virus-1 (HSV-1), can be difficult to differentiate on clinical presentation alone. These causes of CNS infection can be further delineated through imaging, CSF analysis, and occasionally electroencephalogram (EEG). For example, a patient with fluid-attenuated inversion recovery and diffusion-weighted imaging (DWI) hyperintensity in the mesial temporal lobe on MRI, CSF lymphocytic pleocytosis with a normal glucose concentration, and periodic lateralizing discharges on EEG is highly suspicious for HSV encephalitis and should prompt the addition of acyclovir to the empiric regimen, as well as trigger HSV PCR testing from the CSF.

Noninfectious etiologies should be considered in the differential diagnosis of bacterial meningitis. Headache and a decreased level of consciousness are common to both bacterial meningitis and aneurysmal subarachnoid hemorrhage. Drug-induced or "aseptic" meningitis, leptomeningeal carcinomatosis, and CNS inflammatory disease such as neurosarcoidosis, can have similar clinical presentations to bacterial meningitis.

Antimicrobial Therapy

Bacterial meningitis is a neurological emergency, and should be considered in every patient with fever and headache. Blood cultures are obtained and then empirical antimicrobial therapy is initiated (Table 1). Antimicrobial therapy should not be delayed for lumbar puncture; however, lumbar puncture should be performed within a few hours to identify the meningeal pathogen by Gram's stain and culture. Empirical antimicrobial therapy is based on the most common pathogens, Streptococcus pneumoniae and Neisseria meningitidis, and the patient's predisposing and associated conditions. In children and adults up to the age of 55, empiric therapy includes a combination of a third- or fourth-generation cephalosporin plus vancomycin. The latter is added due to the possibility of a penicillin and cephalosporin-resistant strain of Streptococcus pneumoniae being the causative organism. Acyclovir is added until HSV encephalitis has been ruled out.

Ampicillin is added to the empirical regimen for Listeria monocytogenes coverage in those < 3 months of age, > 55 years of age, and those who are chronically ill or immunocompromised. Doxycycline should be considered if a tick-borne bacterial etiology is suspected. In patients with mastoiditis, otitis, or sinusitis, metronidazole should be added for coverage against gram-negative anaerobes. Patients with suspected meningitis associated with a neurosurgical procedure require empirical coverage against Staphylococcus aureus and gram-negative bacteria, including Pseudomonas aeruginosa. Empirical treatment in this population should include vancomycin plus ceftazidime or meropenem rather than ceftriaxone or cefotaxime to provide adequate coverage against Pseudomonas aeruginosa.

Antimicrobial therapy is modified after pathogen identification and antimicrobial susceptibility is known. Meningococcal meningitis typically requires 7 days of intravenous treatment with penicillin G or a third- or fourth-generation cephalosporin. Close contacts are treated with 2 days of rifampin. If pregnant, close contacts are treated with intramuscular ceftriaxone. Pneumococcal meningitis requires 14 days of intravenous antibiotics. Repeat CSF analysis is recommended 24 to 36 hours after treatment is initiated to be certain that the bacteria have been eradicated from the CSF. If the CSF cultures remain positive, then one should consider antibiotic resistance and escalate therapy. Listeria meningitis requires 21 days of treatment with ampicillin (plus gentamicin in critically ill patients).

Adjunctive Therapy

Early treatment with dexamethasone has been shown to improve outcomes in patients with bacterial meningitis, and in some series, decreases mortality.[20] This benefit is most apparent in patients with pneumococcal meningitis, showing increased survival.[21] Dexamethasone also decreased the risk of hearing loss in children with Haemophilus influenzae.[21] In addition, there is evidence of a favorable trend toward reduced rates of death and hearing loss, and no evidence that dexamethasone was harmful in patients with meningococcal meningitis.[22]

Dexamethasone should be administered intravenously at a dose of 10 mg every 6 hours for 4 days. Ideally, dexamethasone is administered 15 to 20 minutes prior to antibiotic therapy and no later than concurrent with the first dose of antibiotics. However, the European Society of Clinical Microbiology and Infectious Diseases guidelines allow for administration up to 4 hours after the first dose of antibiotics.[12]

Complications and Prognosis

Complications commonly occur in patients with bacterial meningitis, even with proper initial treatment. Deterioration in clinical status should prompt investigation. The common complications associated with bacterial meningitis are acute hydrocephalus, seizures, cerebral edema, cerebral venous thrombosis, ischemic stroke, and increased intracranial pressure (ICP).

Acute hydrocephalus occurs in 5% of patients with bacterial meningitis and increases the likelihood of unfavorable outcomes, including death.[23] Clinical suspicion of hydrocephalus is heightened for comatose patients.[23] Communicating hydrocephalus is most common; however, obstruction of flow can occur from blockage within the ventricular foramina. An external ventricular drain (EVD) should be considered for patients with hydrocephalus, although it is unclear if this improves outcome.

Seizures occur in 17% of patients with community-acquired bacterial meningitis and is a poor prognostic factor, increasing the risk of death more than twofold.[24] The threshold for starting antiepileptic drugs and monitoring patients on continuous EEG should be low. Status epilepticus is rare but can occur. Epilepsy is a common consequence of pneumococcal meningitis, reported to be as high as 50% in children.[24]

Other complications include ischemic stroke (14–25%), hemorrhagic stroke (3%), subdural empyema (3%), abscess (2%), cerebral venous thrombosis (1%), and cerebral edema.[12] Cerebral edema often leads to increased ICP, and consideration should be given to placement of an ICP monitor or EVD. Management of increased ICP may include osmotic diuretics, treatment of fever, avoidance of hypercarbia, treatment of hyperglycemia, and raising the head of the bed. Sedation to decrease cerebral metabolism can also be considered.

The prognosis in patients with community-acquired bacterial meningitis varies depending on the causative organism and potential complications. Overall mortality is highest in pneumococcal meningitis (~20–30%). Pneumococcal meningitis has the highest rate of persistent complications, including hearing loss, focal deficits such as weakness, cognitive impairment, and epilepsy.[25] The mortality rate for those with meningococcal meningitis was 7% in one large study.[5]

processing....