Meningitis

Meningitis is a serious infection of the meninges in the brain or spinal cord that is most commonly viral or bacterial in origin. Enteroviruses and herpes simplex virus are the leading causes of viral meningitis, while Neisseria meningitidis and Streptococcus pneumoniae are most commonly responsible for bacterial meningitis. Rarer forms of 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 course of viral meningitis is generally much milder. Diagnostics include physical examination followed by blood cultures and lumbar puncture. If increased ICP is suspected, a cranial CT should be performed first. Bacterial meningitis requires rapid initiation of empiric treatment. A life-threatening complication of bacterial meningitis (particularly meningococcal meningitis) is Waterhouse-Friderichsen syndrome, which is characterized by disseminated intravascular coagulation and acute adrenal gland insufficiency. Bacterial meningitis is fatal if left untreated, whereas viral meningitis usually resolves on its own.

Common causes and risk factors

• Otitis media
• Sinusitis
• CSF leak after head trauma or neurosurgery
• Immunocompromise (e.g., AIDS, asplenia, alcoholism, chronic illness, sickle cell anemia)
• Maternal group B Streptococcus infection during birth
• Crowded living conditions (e.g., college dormitories, military barracks)
• Close contact with an infected person

Common pathogens by patient group

Newborns	Group B Streptococcus (most common) Gram-negative bacilli (e.g., Escherichia coli) Listeria monocytogenes Haemophilus influenzae Enterobacter cloacae
Infants (1 month – 2 years)	Streptococcus pneumoniae and Neisseria meningitidis (most common) Listeria monocytogenes Haemophilus influenzae Group B Streptococcus
Children and teens	Neisseria meningitidis (most common) Streptococcus pneumoniae Listeria monocytogenes Haemophilus influenzae Enteroviruses: particularly coxsackievirus and echovirus Herpes simplex virus (HSV-2)
Adults (18–60 years)	Streptococcus pneumoniae (most common) Neisseria meningitidis Listeria monocytogenes Haemophilus influenzae Enteroviruses: particularly coxsackievirus and echovirus Herpes simplex virus (HSV-2)
Elderly (> 60 years)	Streptococcus pneumoniae (most common) Gram-negative bacilli (e.g., E. coli) Listeria monocytogenes Enteroviruses Herpes simplex virus (HSV-2)
Immunocompromised patients	Listeria monocytogenes Gram-negative bacilli Streptococcus pneumoniae Cryptococcus spp. CMV, VZV, HSV, JC virus Mycobacterium tuberculosis, toxoplasma gondii
Pregnant women	Listeria monocytogenes Streptococcus agalactiae
Hospitalized patients	Staphylococci Gram-negative bacilli

Less common pathogens

• Bacterial meningitis
  • Mycobacterium tuberculosis → tuberculous meningitis
  • Borrelia spp. → Lyme meningitis
  • Treponema pallidum → syphilitic meningitis
• Viral meningitis
  • Arbovirus (e.g., West Nile virus)
  • Herpesviruses (CMV, EBV, VZV)
  • Echovirus, Coxsackievirusl, Poliovirus
  • Influenza virus
  • Lymphocytic choriomeningitis virus (LCMV)
  • HIV
  • Mumps virus
  • Tick-borne encephalitis virus (TBEV)
• Fungal meningitis
  • Cryptococcus spp.
  • Coccidioides
  • Candida spp.
  • Aspergillus spp.
• Parasitic meningitis
  • Protozoan: Toxoplasma gondii
  • Helminths: Echinococcus spp.
• Noninfectious meningitis
  • Sarcoidosis
  • Tumor metastases (meningeal carcinomatosis and meningeal leukemia)
  • Medication (e.g., NSAIDs)

References:^{[1][2][3][4][5][6]}

Pathways of infection

Most pathogens that cause meningitis colonize the nasopharynx or the upper airways → entry into the CNS via:

• Hematogenous dissemination
• Contiguous spread of infections in nose, eyes, and ears
• Retrograde transport along or inside peripheral or cranial nerves
• Direct infection (e.g., due to trauma or head surgery)

Incubation times

• Bacterial meningitis: usually 3–7 days
• Viral meningitis: depends on the type of virus; usually 2–14 days

References:^[2][7][4]

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

Children and adults

• Classic triad of meningitis: fever, headache, and neck stiffness (nuchal rigidity)
• Altered mental status
• Photophobia
• Nausea, vomiting
• Malaise
• Seizures
• If due to N. meningitidis: myalgia and possibly petechial or purpuric rash (especially in children); ; see also Waterhouse-Friderichsen syndrome
• Specific symptoms in viral meningitis:
  • Prodrome with flu-like symptoms: low-grade fever, malaise, myalgia, and upper respiratory symptoms
  • Pharyngitis, herpangina, and/or rash

Neonatal meningitis

• Often nonspecific and without the classic triad of meningitis
• Early-onset: lethargy, vomiting, irritability, poor appetite, dyspnea, abnormal breathing patterns
• Late-onset: fontanelle bulging, high-pitched crying, seizures

The classical features of acute bacterial meningitis are fever, neck stiffness, and headache, but they can only be observed in approximately half of those patients.

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

References:^{[1][8][9][10]}

Physical examination

• Signs of meningeal irritation: Kernig sign and Brudzinski sign
• Papilledema (< 5% of cases)

Laboratory tests

• Blood cultures before antibiotic therapy is started
• Blood glucose to assess CSF glucose; (see “Cerebrospinal fluid analysis” table below)
• ↑ WBC
• Coagulation studies if disseminated intravascular coagulation is suspected

Lumbar puncture

• Essential in all patients with suspected meningitis, unless CNS mass effect is suspected (e.g., in case of focal neurological deficits, papilledema, altered mental status, or seizures)
  • → Initiate empiric antibiotic treatment if bacterial meningitis is suspected (within one hour of patient admission)
  • → Perform cranial CT first
• Gram stain and culture to differentiate pathogens
  • Meningococci: gram-negative diplococci
  • Pneumococci: gram-positive diplococci
  • Listeria: gram-positive rods
  • Haemophilus influenzae: gram-negative coccobacilli
• Bacterial antigen detection (latex agglutination test): enables rapid detection of meningococci, pneumococci, Haemophilus influenzae, and Escherichia coli
• Viral PCRs and culture (e.g., in HSV meningitis)

Post-dural puncture headache is the most probable diagnosis in patients complaining of headache, dizziness, hearing loss/tinnitus, and nausea after lumbar puncture!

Cerebrospinal fluid analysis in meningitis

	Normal	Bacterial meningitis	Viral meningitis1)	Tuberculous meningitis2) [11]	Lyme meningitis [12]	Cryptococcal meningitis [13]
Appearance	Clear fluid	Cloudy, purulent fluid	Clear fluid	Clear fluid with spiderweb coagulum	Clear fluid	Cloudy
Cell type	No granulocytes	Significant granulocytosis	Lymphocytosis	Pleocytosis (predominantly lymphocytes, but also granulocytes and mononuclear cells)	Pleocytosis (lymphocytes, mononuclear cells)	Pleocytosis (lymphocytes)
Cell count/μL	< 5	> 1000	10–500	30–300	10–1000	20–200
Opening pressure [14]	50–180 mm H2O	↑↑	↑	↑↑	↑↑	↑↑
Lactate	1.2–2.1 mmol/L	↑↑	Variable	↑	Variable	↑
Protein	15–45 mg/100 mL	↑	Normal or ↑	↑	Normal or ↑	↑
Glucose	40–75 mg/100 mL (∼ ⅔ of blood glucose level)	↓	Normal	↓	Normal or ↓	↓
1) Distinguishing tuberculous meningitis from viral meningitis based on the CSF analysis is often challenging because the cell type and cell count in both forms of meningitis are very similar. However, lactate and glucose levels usually differ, as well as protein levels in some cases. 2)Additional diagnostics in tuberculous meningitis: PCR

References:^{[2][8][14][12][15][11][13]}

Tuberculous meningitis

• Pathogen: Mycobacterium tuberculosis
• Incubation period: approximately 2–8 weeks
• Clinical course
  • Subacute course over several weeks or months
  • Gradual manifestation with intermittent fever
• Clinical features
  • Focal neurological deficits due to hematogenous dissemination of cranial arteritis
  • Cranial nerve deficits (basal meningitis, affecting the base of the brain, is the most common)
• Diagnostics:
  • Acid fast stain; and culture of 3 CSF samples
• Complications
  • Communicating (malabsorptive) hydrocephalus
  • Pituitary gland insufficiency
• Treatment: antituberculosis treatment

Cryptococcal meningitis

• Pathogen: Cryptococcus neoformans (a type of yeast)
• Etiology:
  • AIDS
  • Exposure to pigeon droppings
• Clinical course: subacute onset with (low) fever, fatigue, and headaches
• Clinical features: see “Clinical features” above; meningeal signs are often absent
• Diagnostics: CSF and blood
  • Latex agglutination test detects pathogens (encapsulated fungus, visible via India ink staining) and cryptococcal antigens
  • Cultured on sabouraud agar
  • Staining: India Ink (clear halo), mucicarmine (red inner capsule)
• Treatment:
  • Amphotericin B plus flucytosine; , followed by fluconazole → maintenance therapy with fluconazole for at least 12 months
  • cART therapy should be delayed for at least 2 weeks after initiation of antifungal therapy

If left untreated, cryptococcal meningitis may lead to rapid death within weeks!

Lyme meningitis

• Pathogen: Borrelia burgdorferi
• Etiology:
  • Route of infection: tick-borne
  • At increased risk: campers, hikers, hunters
• Incubation period: symptoms of lyme meningitis develop 3–10 weeks after a tick bite
• Diagnostics: CSF analysis suggests aseptic (lymphocytic) meningitis.
• Clinical features:
  • See “Clinical features” above.
  • Erythema chronicum migrans
  • Lyme arthritis
  • Bell's palsy
• Treatment: IV ceftriaxone

Tick-borne meningoencephalitis

• Pathogen: tick-borne encephalitis virus (TBEV)
• Route of infection: tick-borne
  • Ixodid tick acts as a vector → transmission 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.
• A vaccine is not available in the US.
  • Active immunization with an inactivated TBEV (inactivated vaccination): Large-scale implementation of this vaccination is not generally recommended.
  • The CDC's Advisory Committee on Immunization Practices (ACIP) recommends the vaccination only for individuals living, traveling, or working in high-risk areas (laboratory staff exposed to TBEV, foresters, etc.).

References:^{[2][12][16][17][18][19][20][11]}

Acute bacterial meningitis

Management algorithm

1. Blood cultures
2. Lumbar puncture for CSF Gram stain and culture
3. Immediate empirical treatment

Empiric treatment

• IV antibiotics for different patient groups
  • < 1 month: ampicillin PLUS aminoglycoside (e.g., gentamicin) PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone )
  • > 1 month to < 50 years: vancomycin PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone)
  • > 50 years: vancomycin PLUS ampicillin PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone)
  • Immunocompromised: vancomycin PLUS ampicillin PLUS cefepime OR meropenem
  • Hospital-acquired: vancomycin PLUS ceftazidime OR cefepime OR meropenem
• Possibly dexamethasone: only beneficial in some cases
  • In adults: when pneumococcal meningitis is strongly suspected or confirmed
  • In children: for suspected or confirmed HiB meningitis
• Doxycycline (during tick-bite season in endemic areas only!)

Acute viral meningitis

• Symptomatic therapy only
• For severe cases of HSV, EBV, and VZV meningitis, consider antiviral therapy with acyclovir (IV or PO).

References:^{[1][8][21][22]}

Neurologic

• Most common: sensorineural hearing loss (transient or permanent)
• Focal neurological deficits
• Seizures
• Cognitive impairment
• Spasticity or paresis
• Cerebral edema and elevated ICP
• Cerebrovascular abnormalities
• Rare: brain abscess, subdural empyema, arteritis (risk of cerebral infarction and cerebral venous sinus thrombosis), ventriculitis, cerebritis

Waterhouse-Friderichsen syndrome

• Predominantly affects small children and asplenic patients
• Dangerous complication of a number of diseases but most commonly associated with meningococcal meningitis
• Pathophysiology: coagulopathy triggered by endotoxins, which often leads to hemorrhagic necrosis of the adrenal glands
• Clinical features
  • Myalgia
  • Non-blanching, petechial rash (mostly on trunk and legs); in severe cases even purpura fulminans with extensive necrosis of the skin
  • Severe malaise; or even shock
  • Findings of disseminated intravascular coagulation
  • Findings of acute adrenal gland failure
  • Respiratory failure
• Treatment
  • Empiric antibiotic treatment (see “Treatment” above)
  • Parenteral fluid therapy and management of disorders of sodium balance
  • Treatment of coagulopathy
• Prognosis
  • Fatal if left untreated and often even despite adequate treatment, particularly in meningococcal infection (> 40% mortality rate)

Other

• Sepsis, coagulopathy
• ARDS

References:^{[1][8][21][23][24][25][26][27]}

We list the most important complications. The selection is not exhaustive.

• Bacterial meningitis
  • Fatal if left untreated
  • Prognosis in treated patients depends on age, overall condition, immune status and the pathogen(s) involved
• Viral meningitis
  • Resolves spontaneously in the majority of cases
  • Residual symptoms such as sensorineural hearing loss, epilepsy, and cognitive deficits are rare
• Fungal meningitis:
  • Associated with neurological sequelae and a high mortality rate
  • Treatment adherence is very important to avoid relapse.

References:^[21]

For meningococcal vaccination (a polysaccharide conjugate vaccine) see the immunization schedule.

Postexposure measures in bacterial meningitis

• Postexposure vaccination: may be considered if the particular serogroup is known and available as a vaccine
• Postexposure chemoprophylaxis:
  • Indicated in cases of meningitis caused by H. influenzae, N. meningitidis, or S. pneumoniae
  • Indicated for all individuals exposed to the index case
  • Drugs of choice: rifampin, ciprofloxacin, or ceftriaxone

Post-exposure prophylaxis	Drugs of choice (monotherapy)
Adults	Rifampin Ciprofloxacin Ceftriaxone
Infants, children, and adolescents	Rifampin Ceftriaxone
Pregnancy	Ceftriaxone

References:^[8][14][26]