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Meningitis

Summary

Meningitis is a serious infection of the meninges in the brain or spinal cord that is most commonly viral or bacterial in origin, although fungal, parasitic, and noninfectious causes are also possible. Enteroviruses and herpes simplex virus are the leading causes of viral meningitis, while Neisseria meningitidis and Streptococcus pneumoniae are the pathogens most commonly responsible for bacterial meningitis. Rarer forms of bacterial meningitis include tuberculous meningitis and Lyme-associated meningitis. The classic triad of meningitis is fever, headache, and neck stiffness. In infants and young children, the presentation is often nonspecific. Patients may also present with neurological deficits, altered mental status, and seizures, indicating increased intracranial pressure (ICP). The diagnosis is confirmed with lumbar puncture (LP) and CSF analysis. If increased ICP is suspected, a CT of the head should be performed first. Bacterial meningitis requires rapid initiation of empiric treatment. A life-threatening complication of bacterial meningitis (especially meningococcal meningitis) is Waterhouse-Friderichsen syndrome, which is characterized by disseminated intravascular coagulation and acute adrenal gland insufficiency. Viral meningitis typically resolves on its own and has a far less severe course than bacterial meningitis, which is generally fatal if left untreated. When N. meningitidis or S. pneumoniae are identified as the pathogen, the CDC should be notified and preventative measures taken to prevent dissemination of the infection.

Epidemiology

  • In the pediatric population, meningitis most often occurs in children < 1 year of age. [1]
  • The median age of adult patients with meningitis is 43 years. [2]
  • Worldwide, the incidence of meningitis caused by N. meningitidis is highest in sub-Saharan Africa, collectively referred to as the “meningitis belt.” [3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Common causes

Risk factors

  • Immunocompromise (e.g., due to AIDS, asplenia, heavy alcohol use disorder, chronic illness, cancer, sickle cell anemia, old age, pregnancy)
  • Crowded occupational or living conditions (e.g., college dormitories, military barracks, retirement homes, kindergartens)
  • Close contact with an infected person

Common bacterial pathogens by patient group [4][5]

Patient population Pathogen
By age
< 1 month [1]
1 month – 2 years [2]
2–50 years [2][8]
  • Neisseria meningitidis (most common in individuals aged 11–17 years)
  • Streptococcus pneumoniae (most common in adults)
> 50 years [2][9]
By underlying state
Immunocompromized [10]
Basilar skull fracture [9]
Penetrating trauma [9]
Healthcare-associated [11]

Less common bacterial pathogens

Other etiologies

Causes of meningitis in immunocompromised individuals

References:[19][20][21][22][23][24]

Pathophysiology

Pathways of infection

  • Most pathogens that cause meningitis colonize the nasopharynx or the upper airways before entering the CNS via:
    • Hematogenous dissemination . [25]
    • Contiguous spread of infections in nose, eyes, and ears
    • Retrograde transport along or within peripheral or cranial nerves
  • Direct infection (e.g., due to trauma or head surgery) [26]

Incubation periods

  • Bacterial meningitis: usually 3–7 days [27]
  • Viral meningitis: usually 2–14 day, depending on the type of virus

References:[20][27][22]

Clinical features

Clinical features of bacterial and viral meningitis are similar, although viral meningitis is less acute and usually self-limiting within 7–10 days.

Neonates (neonatal meningitis)

In neonates, meningitis often manifests with nonspecific symptoms and without the classic triad of meningitis.

Children and adults

Subarachnoid hemorrhage can manifest with the classic triad of meningitis but has a more sudden onset and patients often lose consciousness.

The classical features of acute bacterial meningitis are fever, neck stiffness, and headache. However, this triad of symptoms only manifests in approx. 50% of cases.

Physical examination [20][31]

Features suggestive of meningoencephalitis [34][35]

In addition to the features of meningitis, meningoencephalitis is characterized by signs of inflammation of the brain parenchyma (encephalitis).

References:[19][31][36][37]

Management

General approach

Do not delay empiric antibiotic therapy in patients suspected of having bacterial meningitis.

Challenges
  • Diagnosis
    • There is a significant overlap in presentation between bacterial and other etiologies.
    • LP and CSF analysis can be time-consuming and risky.
    • Patients may present with relative contraindications to LP (e.g., signs of elevated ICP).
  • Treatment
    • Bacterial meningitis can be rapidly progressive and life-threatening.
    • Patients may present as critically ill and with complications (e.g., sepsis, multiorgan failure) requiring early aggressive supportive care.
    • Empiric antibiotic treatment must be initiated as soon as possible (i.e., often prior to diagnosis).

Diagnostics

Approach [38][39][29][30][5]

  • Obtain samples immediately for blood cultures, routine laboratory tests, and screening for organ dysfunction.
  • Confirm the diagnosis with LP and CSF analysis (if no contraindications are present).


Start empiric antibiotics immediately after obtaining blood cultures and CSF samples. If LP is delayed for any reason (e.g., the need for a CT or hemodynamic stabilization), obtain blood cultures and administer antibiotics until it can be performed.

Laboratory studies [38][29][30][5]

Neuroimaging [38][39][26]

Imaging is not necessary to establish the diagnosis of meningitis in most patients and should only be considered in patients with significant risk factors for complications.

  • Indications
    • To assess the risk of brain herniation precipitated by LP [38]
    • Identify abscesses or other localized lesions (e.g., in postsurgical patients in whom infection is suspected) [26]
    • Suspected healthcare-associated ventriculitis/meningitis [26]
    • Patients with devices (e.g., CSF shunts) [26]
  • Recommended criteria for imaging prior to LP in suspected meningitis [38][39][40]
  • Modalities
    • CT head (with or without IV contrast): before LP if increased ICP is suspected [41]
    • MRI brain with IV contrast and diffusion: especially useful in patients with devices or after surgery [26]
  • Supportive findings
    • Usually normal or showing mild meningeal enhancement
    • May identify predisposing factors for the infection (e.g., fractures, mastoiditis) or complications (e.g., abscess)
    • See “Subtypes and variants” for characteristic findings of specific pathogens.

To remember the indications for imaging before LP, think of LP FAILS: Focal neurological deficits, Altered mental status, Immunocompromised or ↑ ICP, Lesions (space-occupying lesions in the brain), Seizures.

Cerebrospinal fluid analysis

Lumbar puncture is indicated in all patients with suspected meningitis (see “Lumbar puncture” for details on indications, contraindications, procedural steps, and complications).

Approach to interpretation
  • Confirmatory findings: pathogen identification on CSF OR positive blood cultures in a patient with highly suggestive CSF findings
  • Highly suggestive findings: pleocytosis (granulocytic or lymphocytic), low glucose, high protein
  • Nonspecific findings: high opening pressure

Routine testing [38][39][40]

Cerebrospinal fluid analysis in meningitis [38][40]
Normal Bacterial meningitis Viral meningitis
Appearance
  • Clear fluid
  • Clear fluid
Cell count and differential
  • Cell count < 5/mm3
  • Variable cell count (leukocyte count 10–500/mm3)
  • ↑ Lymphocytes
Opening pressure [42]
  • 5–18 cm H2O
  • ↑↑
  • Normal or ↑
Lactate [39]
  • 1.2–2.1 mmol/L
  • ↑↑
  • Variable
Protein
  • 15–45 mg/dL
  • ↑
  • Normal or ↑
Glucose
  • 40–75 mg/dL
  • ↓
  • Normal
Gram stain and culture [39][40]
  • No organisms present
  • No organisms present

Atypical pathogen testing

Atypical pathogen testing is not necessary for all patients and should be performed as directed by clinical suspicion.

Cerebrospinal fluid analysis in meningitis due to atypical pathogens [40]
Tuberculous meningitis [43] Lyme meningitis [44] Cryptococcal meningitis [45]
Appearance
  • Clear fluid with a spiderweb clot
  • Clear fluid
  • Cloudy fluid
Cell count and differential
Opening pressure
  • ↑↑
  • ↑↑
  • ↑↑
Lactate [39]
  • ↑
  • Variable
  • ↑
Protein
  • ↑
  • Normal or ↑ [44]
  • ↑ [45]
Glucose
  • ↓
  • Normal or ↓
  • ↓ [45]

Additional microbiological testing

  • Special microbiological stains
  • Special cultures [40]
  • PCR for viral meningitis and specific bacterial subtypes [38][39]
    • Indications
      • Confirmation of viral meningitis/encephalitis (e.g., HSV)
      • Detection of intracellular bacteria (e.g., TB, rickettsial infections)
    • Disadvantages
      • No antibiotic sensitivity data for bacterial infections
      • Not readily available for unusual pathogens (especially bacteria)
  • Latex agglutination test [38]
    • Bacterial antigen detection
      • Not routinely used because of variable accuracy [38]
      • Consider in patients in whom there is strong suspicion for bacterial meningitis despite negative Gram stain or culture after 48 hours
    • Fungal latex agglutinations: especially relevant for cryptococcal antigen testing (see cryptococcal meningitis)

Treatment

Approach

Do not delay administering antibiotics if neuroimaging is indicated prior to LP. Obtain blood cultures, start antibiotics (and steroids, if needed) immediately, then proceed with the CT and LP.

Patient stabilization

Antimicrobial therapy

Empiric antibiotic therapy [38]

  • The choice of initial empiric therapy depends primarily on the prevalence of organisms in certain age groups and individual patient risk factors for resistant organisms.
  • Factors to consider:
    • Epidemiological factors (e.g., local flora, resistance patterns)
    • Bioavailability: Antimicrobial agents should cross the blood-brain barrier and higher doses may be needed.
    • Individual patient risk factors and comorbidities
Empiric antibiotic therapy for bacterial meningitis [38]
Patient characteristics Recommended regimen

Age < 1 month
Age > 1 month to < 50 years
Age > 50 years

Immunocompromised

(E.g., as a result of HIV, AIDS, use of immunosuppressants, or following transplantation) [47]
Healthcare-associated infections [26]

Suspected rickettsial (e.g., RMSF) or ehrlichial infection [48]
Basilar skull fracture
Penetrating head trauma

Ampicillin is added if patients are at risk of Listeria spp. infection (e.g., newborns, pregnant women, the elderly, or immunocompromised patients) because cephalosporins are ineffective against Listeria spp.

Ceftriaxone is contraindicated in patients aged < 1 month because of a higher risk of biliary sludging and kernicterus. Cefotaxime or ceftazidime can be used instead. [46]

Empiric therapy for viral meningitis [48][19]

Most cases of viral meningitis (e.g., caused by enteroviruses) can be treated supportively. Specific antiviral therapy is only warranted if viral encephalitis is also suspected (see HSV encephalitis for further details).

  • Indications
    • Concern for HSV encephalitis, for example:
      • Risk factors (e.g., neonates with a mother who has active genital HSV lesions)
      • Suggestive clinical features (e.g., focal neurological deficits, altered mental status; , seizures, behavioral changes, coma)
      • Imaging findings (e.g., temporal lobe enhancement)
      • CSF: ↑ RBCs despite a nontraumatic LP (suggestive of hemorrhagic encephalitis)
    • Concern for other herpesviruses, e.g., VZV, EBV
  • Recommended empiric antiviral agent: acyclovir
    • Continue treatment if either HSV or VZV is detected, otherwise discontinue.

Treatment with acyclovir should be started in all patients who present with typical clinical signs of viral meningoencephalitis and only discontinued after PCR and antibody tests are negative for HSV and VZV, even if CSF is initially normal.

Pathogen-specific therapy

The decision to narrow therapy should be guided by final culture and sensitivity results, as well as local resistance patterns. We list a few examples of antimicrobial agents that may be used against specific pathogens.

Pathogen-specific therapy in meningitis [38]
Pathogen Examples of antimicrobial agents

S. pneumoniae (penicillin-resistant strains)
MRSA
S. epidermidis
H. influenzae
N. meningitidis
L. monocytogenes
S. agalactiae
E. coli
Enterococcus spp.
P. aeruginosa
R. rickettsii
Herpesviruses
Less frequent pathogens, e.g., M. tuberculosis, C. neoformans, B. burgdorferi
  • See “Subtypes and variants”.

Corticosteroids [39][49]

Do not delay antibiotics to administer adjuvant therapy. If dexamethasone is not readily available, start antibiotics immediately.

Supportive therapy

Monitoring and disposition
  • Most patients with meningitis require admission; select patients may be considered for outpatient therapy with close follow-up. [38]
  • Serial neuro examinations
  • Consultations:
    • Infectious disease
    • Consider also ICU , neurology, neurosurgery as needed.

Acute management checklist

Subtypes and variants

Tuberculous meningitis

Cryptococcal meningitis

  • Pathogen: Cryptococcus neoformans (a type of encapsulated yeast)
  • Risk factors
    • AIDS
    • Exposure to pigeon droppings
  • Clinical course: subacute onset with (low) fever, fatigue, and headaches
  • Clinical features
    • See section on “Clinical features” above
    • Meningeal symptoms are often absent
  • Diagnostics [50]
    • Cryptococcal antigen testing of CSF and serum
      • Highly specific and sensitive [50]
      • Typically performed via latex agglutination or enzyme immunoassay
    • CSF culture (Sabouraud agar)
    • CSF gram staining: India Ink (clear halo), mucicarmine (red inner capsule)
    • MRI: gelatinous pseudocysts (soap bubble appearance)
  • Treatment
    • Intrathecal amphotericin B with or without flucytosine (induction therapy lasting 10–14 days)
    • Followed by fluconazole (consolidation therapy lasting 8–10 weeks and maintenance therapy lasting at least 12 months)
    • cART therapy should be delayed for at least 2 weeks after initiation of antifungal therapy.


Tick-borne diseases

North America

Eurasia: Tick-borne meningoencephalitis

  • Pathogen: tick-borne encephalitis virus (TBEV)
    • TBEVs are part of the Flaviviridae family and occur predominantly in parts of Europe, Russia, and Asia.
    • TBEV is very closely related to the Powassan virus in the US and Russia, which is a rare cause of encephalitis.
  • Route of infection: tick-borne
    • Ixodid tick acts as a vector; therefore, transmission is predominantly in June/July and September/October.
    • Occasional transmission via unpasteurized dairy products from infected livestock
  • Incubation period: usually 7–14 days
  • Clinical features:
    • Nearly 90% of cases are asymptomatic.
    • Biphasic course: initial flu-like symptoms and fever, followed (after ∼ 8 days) by a fever-free interval and subsequent increase in temperature, which is associated with the onset of meningoencephalitis
  • Treatment: symptomatic
  • Prognosis:
    • Full recovery is common (particularly in children and adolescents).
    • In symptomatic disease, residual symptoms may occur.
  • Prevention: A vaccine is not available in the US.

Primary amoebic meningoencephalitis [51]

  • Pathogen: Naegleria fowleri (colloquially referred to as “brain-eating amoeba”), found in warm freshwater (e.g., ponds, hot springs)
  • Route of infection: via contaminated water entering the nose (e.g., while swimming) → invades the CNS directly via the cribriform plate
  • Clinical features: causes fulminant meningoencephalitis with rapid onset
  • Diagnosis
  • Treatment: amphotericin B, miltefostine
  • Prognosis: nearly always fatal [52]

References:[20][53][54][55][56][57][58][59][60]