A. Introduction. Meningitis—inflammation of the meninges—may result from infection, malignancy (i.e., carcinomatous meningitis), or systemic illness (e.g., lupus, sarcoidosis). Infectious etiologies (particularly acute bacterial meningitis) are life-threatening, but treatable causes of meningitis and are the major focus of this chapter. Infectious meningitis can be classified as easy as “A, B, C.”
MNEMONIC: Classification of Infectious Meningitis (“A, B, C”)
Bacterial meningitis (acute)
B. Causes of Meningitis
a. Aseptic meningitis (inflammatory cerebrospinal fluid [CSF] with negative cultures)
i. Viral infections, including enterovirus, mumps, herpes simplex virus 1 (HSV-1), Coxsackie virus, Epstein-Barr virus, West Nile virus, and cytomegalovirus (CMV), are common causes of aseptic meningitis.
ii. Spirochetal infections. Secondary syphilis, Lyme disease, and leptospirosis may also cause aseptic meningitis.
iii. Parameningeal focus. An infection near the arachnoid layer—but not invading it—may produce inflammation in the CSF (e.g., spinal epidural abscess, intracranial abscess) despite persistently negative CSF cultures.
b. Acute bacterial meningitis
i. Streptococcus pneumoniae is the most common cause of meningitis in adults.
ii. Neisseria meningitidis infection may be epidemic or sporadic. It is rare in adults older than 50 years.
iii. Haemophilus influenzae infection, previously common in children younger than 6 years, has been significantly reduced by the H. influenzae vaccine in adults.
iv. Listeria monocytogenes infection is most often seen in infants, but can older, debilitated, alcoholic, and immunosuppressed (including pregnant) patients.
Think Listeria when taking care of patients from nursing homes or chronic care facilities with suspected meningitis.
v. Staphylococcus aureus, Staphylococcus epidermidis, and gram-negative bacilli. Infections with these organisms may occur after neurosurgical procedures, head trauma, or shunt infections. Aortic and mitral valve endocarditis should always be considered when the infecting organism is S. aureus.
i. Fungal infections, including Coccidioides immitis and Cryptococcus neoformans infections, are especially common causes of chronic meningitis. More virulent fungi and acute presentations may be seen in immunocompromised patients.
ii. Mycobacterial infections.Mycobacterium tuberculosis is the most common mycobacterial cause of chronic meningitis.
iii. Spirochetal infections.Treponema pallidum and Borrelia burgdorferi, the causes of syphilis and Lyme disease, respectively, may cause aseptic or chronic meningitis.
C. Clinical Manifestations of Infectious Meningitis
a. Fever with headache should always raise the suspicion of meningitis.
b. Neck stiffness, positive Kernig’s and Brudzinski’s signs, and photosensitivity are also common findings but are less likely with certain infections (e.g., cryptococcal meningitis).
c. Altered mental status (rare in aseptic meningitis), focal neurologic abnormalities, seizures, and evidence of increased intracranial pressure (e.g., papilledema) may all be seen.
d. Signs related to the causative organism may be present. For example, a petechial or purpuric rash caused by meningococcus infection is present in approximately 50% of patients with meningococcal meningitis.
Infants, older adults, and immunosuppressed patients may not generate a fever or signs of meningitis. The sensitivities of neck stiffness and related signs are not high enough to rule out meningitis clinically. Therefore, all patients with a fever and altered mental status or fever with headache require further evaluation.
D. Approach to the Patient
a. Patient history. The time course of the patient’s illness may provide a clue as to the type of meningitis; however, a lumbar puncture is always necessary to confirm the diagnosis.
i. Aseptic meningitis often presents acutely after a “flu-like” prodrome. More than 90% of patients are younger than 30 years.
ii. Acute bacterial meningitis presents acutely (usually within hours to days) and typically with symptoms that are more severe than patients with aseptic meningitis.
iii. Chronic meningitis is usually more indolent; symptoms may not appear for days to weeks.
b. Blood cultures and empiric therapy. If acute meningitis is suspected, draw two sets of blood cultures and start empiric therapy with antibiotics (and possibly steroids) immediately; the yield on Gram stain and culture of the CSF is unlikely to decrease within 4 hours of starting therapy. Blood cultures are positive in approximately 50% of patients with bacterial meningitis and should always be obtained because they may be diagnostic in patients with a negative CSF culture.
c. Lumbar puncture and CSF fluid analysis. Acute bacterial meningitis often cannot be distinguished from more benign processes (e.g., aseptic meningitis, common viral syndromes) on the basis of clinical criteria alone; therefore, a lumbar puncture should be performed as early as possible whenever meningitis is a consideration.
i. Lumbar puncture
1. Contraindications. A lumbar puncture can usually be done safely in the presence of normal mental status and a nonfocal neurologic examination with no evidence of increased intracerebral pressure (e.g., papilledema). If there is evidence of altered mental status, a focal neurologic examination, papilledema, an immunocompromised state, a history of central nervous system disease, or a new seizure, empiric therapy should be initiated and a computed tomography (CT) scan obtained before lumbar puncture.
a. Measure the opening pressure. Opening pressure elevation is nonspecific, but common in patients with acute bacterial meningitis. Normal (~10–20 cm H2O) or minimal elevations predominate in aseptic meningitis. The legs must be straightened to obtain an accurate opening pressure.
b. Draw four samples. You will usually have four pre-numbered, clear CSF tubes in your kit. Use all four as follows:
i. A cell count is usually performed on the CSF sample in tubes 1 and 4. If the last tube has a significantly decreased number of red blood cells (RBCs) in comparison with the first tube, a traumatic tap may be more likely than a true disease process associated with bleeding into the CSF (e.g., subarachnoid hemorrhage, herpes encephalitis).
ii. Protein and glucose levels are often obtained from the sample sent in tube 1 or tube 4.
iii. Gram staining and culture. The CSF sample in tube 2 is usually used for Gram staining and culture. Only a small amount of CSF (e.g., 1 mL) is required.
iv. Cryptococcal antigen (CrAg) titer, an India ink preparation, and fungal culture can also be performed on the tube 2 sample in HIV-positive or immunocompromised patients; however, a serum CrAg is more sensitive than a CSF CrAg.
v. Other studies may be needed. Tube 3 is often filled and refrigerated pending the results of the standard tests.
ii. CSF analysis
1. Cell count. The normal cell count is 0–5 lymphocytes/µL. If pleocytosis is found, the predominant cell type helps to prioritize the differential diagnoses.
a. Neutrophilic (polymorphonuclear neutrophil [PMN]) pleocytosis
i. The patient should be considered to have acute bacterial meningitis until proven otherwise.
ii. Early viral infections can also be neutrophil predominant, but the worst (i.e., bacterial infection) should always be assumed first and empiric antibiotic therapy initiated.
iii. PMN counts greater than 50,000 cells/µL should alert you to a possible brain abscess with rupture into a ventricle.
b. Lymphocytic pleocytosis. An elevated lymphocyte count can occur with all three categories of infectious meningitis (i.e., the ABCs) as well as with other processes.
i. ABCs. Aseptic and chronic meningitis typically have a lymphocytic predominance. Certain types of bacterial infections (e.g., early or partially treated bacterial meningitis, brain abscesses, parameningeal infections) may also cause lymphocytic pleocytosis.
MNEMONIC: Other Causes of Lymphocytic Meningitis (“2 ICE”)
Infections (malaria, toxoplasmosis, fresh-water amebiasis, cysticercosis, Rocky Mountain spotted fever)
Intoxications (salicylates, barbiturates, heavy metals, nonsteroidal antiinflammatory drugs [NSAIDs])
Cancer (carcinomatous meningitis)
Collagen vascular disease (systemic lupus erythematosus [SLE])
Endocrine disorder (pheochromocytoma)
2. Protein level. The normal protein level in adults is 15–45 mg/dL. Approximately 90% of patients with acute bacterial meningitis have an elevated CSF protein level, whereas patients with aseptic meningitis often have a normal or minimally elevated protein level.
3. Glucose level. The normal glucose level is 45–85 mg/dL. The CSF glucose may vary with the serum glucose.
a. The ratio of CSF to serum glucose is less than 0.4 (assuming that the serum glucose level is less than 250 mg/dL) in most patients with acute bacterial meningitis but is often normal (greater than 0.4) in patients with aseptic meningitis.
b. Carcinomatous, fungal, and tuberculous meningitis are other common causes of reduced CSF glucose.
4. Gram stain and culture
a. Gram stain. The Gram stain is positive in most cases of untreated acute bacterial meningitis. (L. monocytogenes, however, is notorious for not being identified.)
b. Culture. The CSF culture is positive in most cases of bacterial meningitis.
d. Ancillary tests
i. Patients with neutrophilic pleocytosis (i.e., a high probability of bacterial meningitis)
1. Latex agglutination tests for bacterial antigen can be done in patients who may have a partially treated culture-negative bacterial meningitis.
2. Head CT scan or magnetic resonance imaging (MRI). Acute bacterial meningitis may be caused by direct extension from sinusitis, otitis, or mastoiditis. An imaging study is necessary if extension is suspected.
ii. Patients with lymphocytic pleocytosis. By considering the possible causes of a lymphocytic pleocytosis (i.e., the ABCs and the 2 ICE cubes) and the clinical setting, you can determine which diagnostic tests may be useful.
a. Aseptic meningitis. Mumps virus, HSV, varicella-zoster virus, and CMV can be recovered from the CSF.Monospot test can be done for Epstein-Barr virus, but in most cases, the viral agent is not recovered. A Venereal Disease Research Laboratory (VDRL) test should always be done. Lyme titers and polymerase chain reaction (PCR) testing for HSV. should be considered in cases of aseptic meningitis.
b. Bacterial meningitis. Acute bacterial infection resulting from a parameningeal focus is a possibility, and depending on the presentation, a CT scan or MRI may be considered. Common sources may include the sinus cavities or infection within the bony part of the ear canal.
c. Chronic meningitis.M. tuberculosis infection and fungal infection are possible etiologies. Commonly ordered tests include a purified protein derivative (PPD) test, a CSF acid-fast bacillus stain and culture, CSF and serum CrAg titers, and Coccidioides serology (other fungal serologies and cultures may also be ordered).
i. Multiple CSF samples of up to 20 mL of CSF increase the yield on acid-fast bacillus staining and culture, but the culture may still be negative in up to 25% of patients with tuberculous meningitis. PCR-based tests are more rapid alternatives that require less CSF, although data supporting their diagnostic accuracy in tuberculous meningitis are limited.
ii. A history of tuberculosis (TB), active TB, or basilar meningitis on MRI may support the diagnosis of tuberculous meningitis.
2. Other causes. CSF cytology is frequently done when carcinomatous meningitis is a consideration. Multiple (often three) CSF samples and performing CSF flow cytometry can increase the yield.
E. Treatment. Medication doses are given for adults with normal renal function.
a. Empiric antibacterial therapy for acute bacterial meningitis is critical.
i. No penicillin allergy
1. Ceftriaxone (2 g by intravenous (IV) route every 12 hours) or cefotaxime (2 g IV every 4 hours) is the best choice because these drugs cover gram-negative organisms (including H. influenzae) as well as the emerging penicillin-resistant S. pneumoniae.
2. Vancomycin (30–45 mg/kg/day divided every 8 to 12 hours) is usually recommended given the high prevalence of drug-resistant S. pneumoniae. Vancomycin should be added to cover S. aureus in cases involving head trauma or recent neurosurgery or in which a CSF shunt is placed or has been recently manipulated.
3. Ampicillin (12–18 g/day in divided doses every 4 hours) or penicillin G (18–24 million units/day IV divided or with continuous therapy) should be added in patients with epidemiologic risk factors for L. monocytogenes (immunocompromised, older than 50 years).
4. Acyclovir should be added for cases suspicious for HSV (while awaiting results of HSV PCR).
5. Fungal coverage should be considered in any immunocompromised patient.
ii. Penicillin allergy
1. In patients who are allergic to penicillin and have a history of anaphylaxis, chloramphenicol may be used. Chloramphenicol is also effective against Listeria. Aztreonam (2 g IV every 8 hours) is a potentially less toxic alternative and also crosses the blood-brain barrier.
2. If the patient is allergic to penicillin but has no history of anaphylaxis, ceftriaxone or cefotaxime may be tried. Trimethoprim/sulfamethoxazole (TMP/SMX) can be added if Listeria infection is a possibility.
b. Steroids may be appropriate in the following situations:
i. To decrease the incidence of deafness in children with H. influenzae infection.
ii. In most cases of adult bacterial meningitis, dexamethasone 0.15 mg/kg IV every 6 hours for 4 days is typically administered before or concomitant to the start of antibiotics. Steroids are probably only beneficial in pneumococcal meningitis and should only be continued if this diagnosis is confirmed by Gram stain or culture. Steroids may be harmful in patients with HIV.
iii. In some cases of tuberculous meningitis of moderate severity.
F. Prevention. Rifampin prophylaxis (600 mg orally twice daily for 2 days for adults) is appropriate for close contacts of a patient with meningococcal meningitis. Household and group child care center contacts and hospital workers with intense exposure should all be given prophylaxis.
Suggested Further Readings
Phan A-D, Benchetrit L, Jacobs FM. Acute bacterial meningitis in adults. Lancet 2017;389:1609–10.Find this resource:
Ropper AE, Ropper AH. Acute spinal cord compression. N Engl J Med 2017;376:1358–69.Find this resource:
Shapiro ED. Lyme disease. N Engl J Med 2014;370:1724–31.Find this resource:
van Ettekoven CN, van de Beek D, Brouwer MC. Update on community-acquired bacterial meningitis: guidance and challenges. Clin Microbiol Infect 2017;23:601–6.Find this resource:
Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. A risk score for unfavorable outcome in adults with bacterial meningitis. Ann Neurol 2008;63:90–7.Find this resource: