Meningitis

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). Diagnostics include physical examination followed by blood cultures and lumbar puncture. 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.

Common causes

• Otitis media
• Sinusitis
• CSF leak after head trauma or neurosurgery
• Maternal group B streptococcal infection during birth
• Sepsis

Risk factors

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

Common pathogens by patient group

Population	Pathogens
Newborns	Group B streptococcus (most common but incidence decreasing because of screening and prophylaxis during pregnancy) Escherichia coli Listeria monocytogenes Haemophilus influenzae Enterobacter cloacae
Infants	Streptococcus pneumoniae and Neisseria meningitidis (most common) Haemophilus influenzae Listeria monocytogenes Group B streptococcus
Children and teenagers	Neisseria meningitidis (most common) Streptococcus pneumoniae Listeria monocytogenes Haemophilus influenzae if not immunized Enteroviruses (especially coxsackievirus and echovirus) Herpes simplex virus (HSV-2) Mumps virus
Adults 20–60 years	Streptococcus pneumoniae (most common) Enteroviruses (especially coxsackievirus and echovirus) Herpes simplex virus (HSV-2)
Adults ≥ 60 years	Streptococcus pneumoniae (most common) Neisseria meningitidis Haemophilus influenzae if not immunized Group B streptococcus E. coli Listeria monocytogenes Enteroviruses (especially coxsackievirus and echovirus) Herpes simplex virus (HSV-2)
Immunocompromised individuals	Listeria monocytogenes Gram-negative bacilli Streptococcus pneumoniae Cryptococcus spp. (particularly in individuals with HIV) CMV, VZV, HSV, JC virus Mycobacterium tuberculosis (tuberculous meningitis) Toxoplasma gondii
Pregnant women	Listeria monocytogenes Streptococcus agalactiae
Hospitalized patients	Staphylococci (most frequently S. aureus) [1] Gram-negative bacteria (e.g., Pseudomonas aeruginosa)

Less common pathogens

• Bacterial meningitis
  • Borrelia spp. → Lyme meningitis
  • Treponema pallidum → syphilitic meningitis
• Viral meningitis: often associated with encephalitis (meningoencephalitis)
  • Herpesviruses: HSV1 (meningitis is more commonly caused by HSV2 than HSV1), CMV, EBV, VZV
  • Lymphocytic choriomeningitis virus (LCMV)
  • Mumps virus
  • Some arboviruses (e.g., West Nile virus, TBEV in Eurasia)
  • Influenza virus
  • HIV
• Fungal meningitis
  • Coccidioides
  • Candida spp.
  • Aspergillus spp.
• Parasitic meningitis: helminths such as Echinococcus spp.
• Noninfectious meningitis
  • Sarcoidosis
  • Tumor metastases (meningeal carcinomatosis and meningeal leukemia)
  • Medication (e.g., NSAIDs)

References:^{[2][3][4][5][6][7]}

Pathways of infection

• Most pathogens that cause meningitis colonize the nasopharynx or the upper airways before entering the CNS via:
  • Hematogenous dissemination . ^[8]
  • 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) ^[1]

Incubation periods

• Bacterial meningitis: usually 3–7 days ^[9]
• Viral meningitis: usually 2–14 day, depending on the type of virus

References:^[3][9][5]

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)

Often nonspecific and without the classic triad of meningitis

• Early symptoms
  • Lethargy
  • Muscle hypotonia
  • Irritability
  • Poor appetite, vomiting
  • Hyperthermia or hypothermia
  • Dyspnea, abnormal breathing patterns (e.g., Biot respiration) ^[10]
• Late symptoms
  • Fontanelle bulging
  • High-pitched crying
  • Seizures

Children and adults

• Classic triad of meningitis: fever, headache, and neck stiffness (this triad is often not present in neonates and infants)
• Altered mental status
• Photophobia
• Nausea, vomiting
• Malaise
• Seizures
• Possibly cranial nerve palsies
• In the case of N. meningitidis
  • Myalgia and, possibly, petechial or purpuric rash (especially in children)
  • Possibly Waterhouse-Friderichsen syndrome
• Common symptoms of viral meningitis
  • Prodrome with flu-like symptoms
    • Low-grade fever
    • Malaise, fatigue
    • Myalgia
    • Upper respiratory symptoms (e.g., sore throat)
  • Pharyngitis, herpangina, and/or rash

Physical examination ^[3][11]

• Signs of meningeal irritation
  • Neck stiffness
  • Kernig sign
  • Brudzinski sign
• Systemic signs of inflammation
  • Fever
  • Hypotension
  • Tachycardia
• Signs of increased intracranial pressure: : e.g., papilledema (< 5% of cases) ^[12]
• Signs of underlying infections
  • Bulging and redness of tympanic membrane: acute otitis media
  • Skin manifestations ^[13]
    • Cutaneous petechiae in meningococcal meningitis: suggestive of meningococcemia
    • Maculopapular rash in some viral meningitis (e.g., West Nile virus, enterovirus)

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

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

References:^{[2][11][14][15]}

Blood studies

• Blood cultures should be performed before antibiotic therapy is started
• Blood glucose to assess CSF glucose; (see table on cerebrospinal fluid analysis in meningitis below)
• Serum studies
  • ↑ WBC
  • Coagulation studies if disseminated intravascular coagulation is suspected

Lumbar puncture (LP)

• Approach: essential in all patients with suspected meningitis, unless there are signs of increased intracranial pressure (ICP), which include: ^[16]
  • History of space-occupying CNS lesions, hydrocephalus, CSF shunts, or CNS trauma
  • Focal neurological deficits
  • Altered mental status
  • Seizures
  • Papilledema
• If LP is contraindicated: initiate empiric antibiotic: treatment immediately and conduct CT before LP to rule out ↑ ICP ^[16]
• Complications
  • Headache
  • Dizziness
  • Nausea
  • Hearing loss, tinnitus
• CSF studies: Gram stain and culture, PCR, and CSF analysis should all be conducted. LAT is not routinely recommended but may be considered if antibiotics were given before the LP.
  • Gram stain and culture to differentiate pathogens ^[12]
    • Meningococci: gram-negative diplococci
    • Pneumococci: gram-positive diplococci
    • Listeria: gram-positive rods
    • Haemophilus influenzae: gram-negative coccobacilli
  • PCR: for bacterial (e.g., meningococcus) and/or viral meningitis (e.g., HSV)
  • Latex agglutination test (LAT; for bacterial antigen detection): enables rapid detection of meningococci, pneumococci, Haemophilus influenzae, and Escherichia coli
    • No longer recommended as a routine test.
    • Highly specific but sensitivity ranges from 50–90%.
    • Indicated if a patient has received antibiotics prior to the LP (which could cause a culture to be falsely negative)
  • Cerebrospinal fluid analysis in meningitis

	Normal	Bacterial meningitis	Viral meningitisa	Tuberculous meningitisb[17]	Lyme meningitis [18]	Cryptococcal meningitis [19]
Appearance	Clear fluid	Cloudy, purulent fluid	Clear fluid	Clear fluid with spiderweb coagulum	Clear fluid	Cloudy
Cell type	No granulocytes Primarily lymphocytes	Significant granulocytosis	Lymphocytosis	Pleocytosis (predominantly lymphocytes, but also granulocytes and mononuclear cells)	Pleocytosis (lymphocytes, mononuclear cells)	Pleocytosis (lymphocytes)
Cell count	< 5/μL	> 1000/μl	10–500/μl	30–300/μl	10–1000/μl	20–200/μl
Opening pressure [20]	50–180 mm H2O	↑↑	Normal or ↑	↑↑	↑↑	↑↑
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 ↓	↓
a) Distinguishing tuberculous meningitis from viral meningitis based on the CSF analysis is often challenging because cell type and count in both forms of meningitis are very similar. However, lactate and glucose levels usually differ, as well as protein levels in some cases. b) Additional diagnostics in tuberculous meningitis: PCR

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

Other tests

• Cerebral imaging
  • CT: possible signs of ↑ ICP (e.g., effacement of the ventricles, herniation)
  • MRT: gelatinous pseudocysts in cryptococcal meningitis (soap bubble appearance)
• Fundoscopic examination: papilledema if ↑ ICP

References:^{[3][11][20][18][12][17][19]}

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 (e.g., hemiparesis) due to hematogenous dissemination of cranial arteritis
  • Cranial nerve deficits
    • Most commonly seen in basal meningitis
    • Predominantly involves the facial nerve and oculomotor nerve
• Diagnostics
  • Acid-fast stain and culture of 3 CSF samples
• Complications
  • Communicating (malabsorptive) hydrocephalus
  • Pituitary gland insufficiency
• Treatment: see “Treatment” in tuberculosis

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
  • Laboratory studies (CSF and blood)
  • Latex agglutination test detects C. neoformans and cryptococcal antigens
  • Culture (Sabouraud agar)
  • Staining: India Ink (clear halo), mucicarmine (red inner capsule)
• Treatment
  • Intrathecally 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.

Lyme meningitis

• See Lyme disease.

Tick-borne meningoencephalitis (primarily in Eurasia)

• 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 → 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.
• Prevention: 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.).

Primary amoebic meningoencephalitis ^[21]

• Pathogen: Naegleria fowleri, an amoeba found in warm, still standing 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 (brain-eating amoeba)
• Diagnosis: microscopy of CSF shows amoebas
• Treatment: amphotericin B
• Prognosis: nearly always fatal

References:^{[3][18][22][23][24][25][26][17][27]}

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:^{[2][11][28][16]}

Neurologic

• Most common: sensorineural hearing loss (transient or permanent)
• Focal neurological deficits ^[31]
• Seizures
• Cognitive impairment
• Spasticity or paresis
• Cerebral edema and elevated ICP
• Communicating hydrocephalus
• Cerebrovascular disease
• Rare: brain abscess, subdural empyema, arteritis (risk of cerebral infarction and cerebral venous sinus thrombosis), ventriculitis, cerebritis

Waterhouse-Friderichsen syndrome

• Epidemiology: : predominantly affects small children and asplenic individuals
• Description: acute primary insufficiency of the adrenal gland most commonly caused by adrenal hemorrhage
  • Dangerous complication of a number of diseases but most commonly associated with meningococcal meningitis
  • Rarer causes include DIC, endotoxic shock, and septicemia due to other pathogens (e.g., S. pneumoniae)
• Pathophysiology: coagulopathy triggered by endotoxins, which often leads to hemorrhagic necrosis of the adrenal glands
• Clinical features
  • Fever
  • Myalgia
  • Nonblanching, petechial rash (mostly on trunk and legs); in severe cases, even purpura fulminans with extensive necrosis of the skin
  • Severe malaise
  • Hypotension ; or even shock
  • Findings of disseminated intravascular coagulation
  • Findings of acute adrenal gland failure
  • Respiratory failure
• Treatment
  • Empiric antibiotic treatment (see section on “Treatment” above)
  • Parenteral fluid therapy and management of disorders of sodium balance
  • Coagulopathy treatment
• Prognosis: fatal without treatment and often fatal even with treatment, particularly if associated with meningococcal infection (> 40% mortality rate) ^[32]

References:^{[2][11][28][31][33][34][35][32]}

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:^[28]

• Preexposure prophylaxis: For meningococcal vaccination (a polysaccharide conjugate vaccine), see immunization schedule.
• Postexposure measures in bacterial meningitis ^[35]
  • Postexposure vaccination: may be considered if the particular serogroup is known and available as a vaccine
  • Postexposure chemoprophylaxis
    • Drugs of choice: rifampin, ciprofloxacin, or ceftriaxone
    • Indicated for all individuals exposed to an index case (close contacts) if caused by: ^[11][20]
      • N. meningitidis (e.g., rifampin, ciprofloxacin, or ceftriaxone)
      • H. influenzae (e.g., rifampin)

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

References:^[11][20][35]