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.

Epidemiology
• In the pediatric population, meningitis most often occurs in children < 1 year of age.
• Improved vaccination coverage has helped to reduce the incidence of bacterial meningitis in
all age groups except in children < 2 months of age.
• The median age shifted from <5 years to approximately 30 to 40 years, though the incidence
remains highest among infants <2 months old .
• The incidence of bacterial meningitis in neonates (infants <1 month) ranges from 0.25 and
0.32 per 1000 live births .

✓ Risk factors for neonatal sepsis and meningitis include :

o Low birth weight (<2500 g)
o Preterm birth (<37 weeks gestation, with the highest risk in infants <28 weeks
gestation)
o Premature and/or prolonged rupture of membranes
o Septic or traumatic delivery
o Fetal hypoxia
o Maternal peripartum infection
o Galactosemia
o Urinary tract abnormalities

Etiology

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 occupational or living conditions (e.g., college dormitories, military barracks,
retirement homes, kindergartens)
• Close contact with an infected person.
• Congenital or acquired immunodeficiency (eg, asplenia, complement deficiency,
hypogammaglobulinemia, HIV infection, glucocorticoid use, diabetes mellitus, other innate
immune defects)
• Anatomic defects of the spinal cord (eg, dermal sinus), brain, or inner ear .
• Acquired cranial defects due to basilar skull fracture or surgery .
• Presence of a medical device (eg, CSF shunt, cochlear implant)
• Parameningeal infections (eg, sinusitis, mastoiditis)
• Recent infection (especially respiratory and ear infections)
• Recent exposure to someone with meningitis
• Recent travel to an area with endemic meningococcal disease, such as sub-Saharan Africa

Causative organisms :
• The relative frequency of different causative pathogens varies by age and by geographic region.
In addition, certain pathogens may be more likely depending upon the route of acquisition and
underlying host factors.
Age – The most frequent pathogens vary according to age as follows :
Infants <3 months old – Group B streptococcus (GBS) and Escherichia coli are the most
common pathogens in neonates and young infants. Other enteric gram-negative
bacilli, Streptococcus pneumoniae, and Neisseria meningitidis are less common in this
age group. Other uncommon pathogens
include Enterococcus, Staphylococcus aureus, Listeria monocytogenes, group A
streptococcus, and Haemophilus influenzae.
Older infants and children – S. pneumoniae and N. meningitidis are the most common
pathogens in this age group, together accounting for approximately 60 to 70 percent of
cases . As discussed below, the relative frequencies of these two pathogens vary
somewhat in different geographic regions. Less common pathogens in this age group
include group A streptococcus and GBS, H. influenzae, and other gram-negative
organisms.
Adolescents – N. meningitidis is the most common pathogen in adolescents, accounting
for more than one-half of all cases.
S. pneumoniae remains among the most common causes of bacterial meningitis in
children, though the overall incidence of pneumococcal meningitis in children in the
United States declined by 50 to 60 percent after widespread pneumococcal vaccination.
Most common causative agents of bacterial meningitis by age group and
underlying condition

Patient population Pathogen

By age

• Group B streptococcus (esp. Streptococcus agalactiae)

o The most common cause of bacterial meningitis

and sepsis in neonates aged ≤ 72 hours

< 1 month o The incidence of group B streptococcus infections in neonates is

decreasing because of screening and prophylaxis during pregnancy.

• Gram-negative bacilli (e.g., Escherichia coli)

• Listeria monocytogenes

• Streptococcus pneumoniae

• Neisseria meningitidis
1 month–2 years
• Group B streptococcus (esp. Streptococcus agalactiae)

• Hemophilus influenzae type b (if not immunized)

• Neisseria meningitidis (most common at the age of 11–17 years)

2–50 years
• Streptococcus pneumoniae (most common in adults)

• Streptococcus pneumoniae (most common)

• Aerobic gram-negative bacilli (e.g., Escherichia coli)

> 50 years
• Listeria monocytogenes

• Haemophilus influenzae type b (if not immunized)

 Patient population Pathogen

• Neisseria meningitidis

• Group B streptococcus

By underlying condition

• Listeria monocytogenes

• Streptococcus pneumoniae
Immunocompromise
• Haemophilus influenzae type b

• Gram-negative bacilli (e.g., Escherichia coli, Salmonella spp.)

• Streptococcus pneumoniae

Basilar skull fracture • Haemophilus influenzae type b

• Group A beta-hemolytic streptococci

• Staphylococcus aureus

Penetrating trauma • Coagulase-negative staphylococci (e.g., Staphylococcus epidermidis)

• Aerobic gram-negative bacilli (including Pseudomonas aeruginosa)

• Coagulase-negative staphylococci (e.g., Staphylococcus epidermidis)

• Staphylococcus aureus
Health care-
• Gram-negative bacteria (e.g., Pseudomonas
associated
aeruginosa, Enterobacter cloacae, Serratia marcescens, Klebsiella spp.)

• Propionibacterium acnes

Less common bacterial pathogens

• Borrelia spp. (Lyme meningitis)
• Treponema pallidum (syphilitic meningitis)
• Mycobacterium tuberculosis (tuberculous meningitis)
• Actinomyces israelii
• Leptospira (leptospirosis)
 Other etiologies
• Viral meningitis: often associated with encephalitis (meningoencephalitis)
o Enteroviruses (especially coxsackieviruses and echoviruses): the most common cause of all
types of meningitis in all patient groups
o Herpesviruses: HSV (meningitis is more commonly caused
by HSV2 than HSV1) , CMV, EBV, VZV
o Lymphocytic choriomeningitis virus (LCMV)
o Mumps virus
o Measles virus
o Some arboviruses (e.g., West Nile virus, TBEV in Eurasia)
o Poliovirus (nonparalytic poliomyelitis: aseptic meningitic form)
o St. Louis encephalitis virus
o California encephalitis virus
o Western equine encephalitis virus
o Influenza virus
o HIV
JC virus
o
• Fungal meningitis
o Coccidioides
o Candida spp.
Aspergillus spp.
o
• Parasitic meningitis
o Helminths (e.g., Echinococcus spp., Strongyloides stercoralis, Angiostrongylus
cantonensis, Baylisascaris procyonis)
Protozoa (e.g., Naegleria fowleri, Acanthamoeba)
o
• Noninfectious meningitis
o Sarcoidosis
o Tumor metastases (meningeal carcinomatosis and meningeal leukemia)
o Medication (e.g., NSAIDs, sulfa drugs)

Causes of meningitis in immunocompromised individuals

• Bacterial
o Certain immune deficiencies can predispose to certain types of meningitis.
▪ Defects in humoral immunity (including splenectomy): encapsulated bacteria (N.
meningitidis, S. pneumoniae, H. influenzae, etc.)
 ▪ Defects in cell-mediated immunity (e.g., in HIV, drug-induced immunosuppression): M.
tuberculosis, L. monocytogenes
o Immunocompromised individuals are at increased risk of recurrent bacterial meningitis
compared to those with intact immunity.
• Viral: Risk is higher in individuals with cell-mediated immune deficiencies (e.g., in HIV
infection).
o Herpesviruses: CMV, EBV, VZV, and HSV6
o HIV
o Adenovirus
o JC virus
➢ Although JC virus is primarily associated with primary progressive
leukoencephalopathy, it can cause meningitis in rare cases.
• Fungal: Risk is higher in individuals with cell-mediated immune deficiencies (e.g., HIV
infection).
o Cryptococcus spp.
o Candida spp.
o Histoplasma capsulatum
o Aspergillus spp.
• Protozoal: Toxoplasma gondii (rare)

Pathophysiology

Pathways of infection
• Most pathogens that cause meningitis colonize the nasopharynx or the upper airways before
entering the CNS via:
o Hematogenous dissemination .
➢ About 5–10% of the US adult population are colonized with Neisseria meningitidis.
The bacteria attach to the nasopharyngeal mucosa, where they can persist for long
periods of time. Hematogenous dissemination may then occur subsequent to
mucosal infiltration facilitated by infection with another pathogen capable of
infiltrating the mucosa, e.g., adenovirus
o Contiguous spread of infections in nose, eyes, and ears
o Retrograde transport along or within peripheral or cranial nerves
• Direct infection (e.g., due to trauma or head surgery)
 Incubation periods
• Bacterial meningitis: usually 3–7 days
• Viral meningitis: usually 2–14 days, depending on the type of virus.

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.
Course — Acute bacterial meningitis has two patterns of presentation :
Gradually progressive course – Most children with meningitis have a preceding
febrile illness and then develop signs and symptoms of meningeal inflammation
progressively over one to several days.
Fulminant course – Patients with acute and fulminant meningitis present with
manifestations of sepsis and meningitis that develop rapidly over several hours.
The fulminant presentation is often complicated by severe brain edema.

Neonates (neonatal meningitis)

In neonates, meningitis often manifests with nonspecific symptoms and without the classic
triad of meningitis.
• Early symptoms
o Lethargy
o Muscle hypotonia
o Irritability
o Poor appetite, vomiting
o Hyperthermia or hypothermia
➢ Temperature instability — Temperature instability is the most common finding.
Temperature instability encompasses fever (rectal temperature >38°C) or hypothermia
(rectal temperature <36°C).
Dyspnea, abnormal breathing patterns (e.g., Biot respiration)
o
• Late symptoms
o Fontanelle bulging
o High-pitched crying
o Seizures
 Children and adults (meningismus)
• 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
o Myalgia and, possibly, petechial or purpuric rash (especially in children)
o Possibly Waterhouse-Friderichsen syndrome
• Common symptoms of viral meningitis
o Prodrome with flu-like symptoms
▪ Low-grade fever
▪ Malaise, fatigue
Myalgia
▪
▪ Upper respiratory symptoms (e.g., sore throat)
o Pharyngitis, herpangina, and/or rash
✓ 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
• Signs of meningeal irritation
o Neck stiffness
o Kernig sign
kernig sign is present if the patient, in the supine position with the hip and knee flexed at
90°, cannot extend the knee more than 135° and/or there is flexion of the opposite knee
o Brudzinski sign
Brudzinski sign is present if the patient, while in the supine position, flexes the
lower extremities during attempted passive flexion of the neck .
• Systemic signs of inflammation
o Fever
 o Hypotension
o Tachycardia
• Signs of increased intracranial pressure: e.g., papilledema (< 5% of cases)
In infants, signs of increased ICP may include bulging fontanel or diastasis of the
cranial sutures. In older children, signs of increased ICP may include headache,
vomiting, and altered mental status . The constellation of systemic
hypertension, bradycardia, and respiratory depression (Cushing triad) is a late
sign of increased ICP.
Papilledema on funduscopic examination is suggestive of increased ICP at any
age, but it is an uncommon finding in acute bacterial meningitis. The finding of
papilledema should prompt evaluation for venous sinus occlusion, subdural
empyema, or brain abscess.
• Signs of underlying infections
o Bulging and redness of tympanic membrane: acute otitis media
o Skin manifestations
▪ Cutaneous petechiae in meningococcal meningitis: suggestive of meningococcemia
▪ Maculopapular rash in some viral meningitis (e.g., West Nile virus, enterovirus)
▪ Nonblanching rash: should raise suspicion for meningococcal meningitis or Rocky
Mountain spotted fever .

✓ Systemic findings – Children with bacterial meningitis frequently present with systemic
manifestations, which can range from fever and chills to septic shock, disseminated
intravascular coagulation, acute respiratory distress syndrome, pericardial effusion, and
septic or reactive arthritis. Most of these systemic complications are consequences of
the bacteremia that frequently accompanies meningitis.

✓ Arthritis is most common with meningococcal disease but may occur with other
infections

Features suggestive of meningoencephalitis

In addition to the features of meningitis, meningoencephalitis is characterized by signs
of inflammation of the brain parenchyma (encephalitis).
• Focal neurological signs (e.g., paresis, extrapyramidal symptoms, aphasia)
• Seizures (focal-onset or generalized)
• Behavioral changes, psychosis
• Altered consciousness

Management
• Bacterial meningitis is a medical emergency and requires immediate treatment.
• Diagnostic and treatment steps should be initiated simultaneously and empiric treatment
should not be delayed for diagnostic steps.
o If the patient is stable and has no LP contraindications: Perform LP as soon as possible
before starting empiric antibiotics.
o If the patient is unstable, requires neuroimaging (see criteria for imaging prior to LP in
suspected meningitis), or has relative contraindications to LP (e.g., coagulopathy):
Defer LP and start empiric antibiotic treatment (see empiric antibiotic therapy for bacterial
meningitis)

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

Diagnostics
Approach
• Obtain samples immediately for blood cultures, routine laboratory tests, and screening for
organ dysfunction.
• Confirm the diagnosis with LP and CSF analysis (if no LP 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
• Routine tests
o Blood cultures (two sets): obtain before starting antibiotic therapy
o CBC
▪ Normal/↑ WBC count
▪ In severe infections, ↓ WBC count and thrombocytopenia
o BMP: Blood glucose is needed to analyze CSF glucose.
▪ Common finding: mild electrolyte disturbances (e.g., hyponatremia from SIADH)
▪ In critically ill patients: possible signs of acute kidney injury
 o CRP: elevated
• Additional tests
o Assess for organ damage and complications.
▪ Coagulation panel: especially if there is suspicion for disseminated intravascular
coagulation (e.g., petechiae, purpura)
▪ Blood gas: metabolic acidosis may be present in critically ill patients
o Consider testing for atypical infections

Neuroimaging
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
o To assess the risk of brain herniation precipitated by LP
o Identify abscesses or other localized lesions (e.g., in postsurgical patients in whom
infection is suspected)
o Suspected healthcare-associated ventriculitis/meningitis
Patients with devices (e.g., CSF shunts)
o
• Recommended criteria for imaging prior to LP in suspected meningitis
o Focal neurological deficits
o Altered mental status
o Immunocompromised status (e.g., HIV, post-transplant, taking immunosuppressants)
o Papilledema
o History of CNS disease (e.g., mass, stroke, abscess)
o Seizures (new-onset)
• Modalities
o CT head (with or without IV contrast): before LP if increased ICP is suspected
o MRI brain with IV contrast and diffusion: especially useful in patients with devices or
after surgery
• Supportive findings
o Usually normal or showing mild meningeal enhancement
o May identify predisposing factors for the infection (e.g., fractures, mastoiditis) or
complications (e.g., abscess)
o 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.

Cerebrospinal fluid analysis in meningitis

Normal Bacterial meningitis Viral meningitis

• Clear
Appearance • Cloudy, purulent fluid • Clear fluid
fluid

• Cell
• Elevated cell count • Variable cell count
Cell count count
with significant pleocytosis (leuk (leukocyte count 10–
and <
ocyte count > 1000/mm3) 500/mm3)
differential
5/mm
• ↑ Granulocytes (> 80%) • ↑ Lymphocytes
3

• 5–18
Opening
cm • ↑↑ • Normal or ↑
pressure
H2O

• 1.2–

2.1
Lactate [39]
• ↑↑ • Variable
mmol

/L

• 15–45
Protein • ↑ • Normal or ↑
mg/dL

Glucose • 40–75 • ↓ • Normal

 mg/dL

• Positive gram stain and culture

o Meningococci: gram-

• No negative diplococci

Gram organi o Pneumococci: gram-

stain and sms positive diplococci • No organisms present

culture
prese o Listeria: gram-positive rods

nt o Haemophilus

influenzae: gram-

negative coccobacilli

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

Cryptococcal
Tuberculous meningitis Lyme meningitis
meningitis

Appearan
• Clear fluid with a spiderweb clot • Clear fluid • Cloudy fluid
ce
 Cerebrospinal fluid analysis in meningitis due to atypical pathogens

Cryptococcal
Tuberculous meningitis Lyme meningitis
meningitis

• Variable cell count (30–300/mm3)

Cell count • Variable cell count (10– • Variable cell count
• Pleocytosis (predominantly lymph
and 1000/mm3) (20–200/mm3)
ocytes but
differenti • Pleocytosis (lymphocytes, mon • Pleocytosis (lympho
al also granulocytes and mononuclea
onuclear cells) cytes)
r cells)

Opening
• ↑↑ • ↑↑ • ↑↑
pressure

Lactate • ↑ • Variable • ↑

Protein • ↑ • Normal or ↑ • ↑

Glucose • ↓ • Normal or ↓ • ↓

Additional microbiological testing

• Special microbiological stains
o Acid-fast staining: if there is suspicion for tuberculous meningitis
o India ink preparation: if there is suspicion for cryptococcus
o Wright or Giemsa stain: if there is suspicion for toxoplasmosis
• Special cultures
o Viral culture
▪ Not typically recommended
▪ May confirm enterovirus, herpes simplex virus infection
o M. tuberculosis cultures: Results can take up to 6 weeks.
o Fungal cultures: for the identification of Candida spp., Cryptococcus spp.
o For patients with CSF shunts or drains: Extend CSF cultures for at least 10 days.
• PCR for viral meningitis and specific bacterial subtypes
o Indications
▪ Confirmation of viral meningitis/encephalitis (e.g., HSV)
▪ Detection of intracellular bacteria (e.g., TB, rickettsial infections)
o Disadvantages
▪ No antibiotic sensitivity data for bacterial infections
▪ Not readily available for unusual pathogens (especially bacteria)
• Latex agglutination test
o Bacterial antigen detection
▪ Not routinely used because of variable accuracy
▪ Consider in patients in whom there is strong suspicion for bacterial meningitis despite
negative Gram stain or culture after 48 hours
o Fungal latex agglutinations: especially relevant for cryptococcal antigen testing

Treatment
Approach
• Apply appropriate isolation precautions.
• Stabilize the patient as needed.
• Administer empiric antibiotics as soon as possible, preferably within 1 hour .
o If LP can be performed rapidly, administer antibiotics and adjuvant
therapy (e.g., dexamethasone) after obtaining CSF.
o If LP is delayed (e.g., because neuroimaging is required),
administer antibiotics and adjuvant therapy (e.g., dexamethasone) immediately.
o Add other antimicrobial therapy (e.g., antivirals, antifungals) as needed .
• Tailor antimicrobial therapy once the pathogen is identified.
• Provide postexposure prophylaxis for close contacts if indicated .
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
• Airway management: Secure the airway (e.g., intubate) if GCS < 8, the patient has
intractable seizures, or there are signs of cerebral herniation.
• Provide hemodynamic support with fluids and/or vasopressors.
• Identify and reverse any coagulopathy .
• Identify and treat elevated ICP .

Antimicrobial therapy
Empiric antibiotic therapy
• 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:
o Epidemiological factors (e.g., local flora, resistance patterns)
o Bioavailability: Antimicrobial agents should cross the blood-brain barrier and higher doses
may be needed.
o Individual patient risk factors and comorbidities

• Empiric regimen – The empiric regimen should include coverage for meningococcus and
penicillin-resistant pneumococcus, the two most common causes of bacterial meningitis
in infants and children.
✓ For most patients, we suggest vancomycin plus high doses of a third-generation
cephalosporin (eg, ceftriaxone, cefotaxime) :
Vancomycin 60 mg/kg/day IV (maximum dose 4 g/day) in four divided doses, plus
Ceftriaxone 100 mg/kg/day IV (maximum dose 4 g/day) in two divided doses, or
cefotaxime (where available) 300 mg/kg/day IV (maximum dose 12 g/day) in three or
four divided doses.
✓ Duration of empiric therapy – The duration of empiric therapy depends upon the culture
results, CSF parameters, and clinical concern for bacterial meningitis:

Positive culture – Once culture results are available, treatment should be

modified based on the specific pathogen isolated in CSF and/or blood culture.
Negative culture with normal CSF profile – For children who have a normal CSF
profile and negative blood and CSF cultures, we usually discontinue antimicrobial
therapy if cultures remain sterile after 48 to 72 hours of incubation.

Negative culture with CSF pleocytosis – For children with CSF pleocytosis whose
blood and CSF cultures remain negative after 48 to 72 hours, the decision to
 continue or discontinue empiric antibiotic therapy is individualized based upon
the clinical status of the child and level of clinical concern for bacterial
meningitis. Consultation with a pediatric infectious diseases specialist is advised
if the clinician is uncertain how to manage such children. Important
considerations include:

➢ CSF cultures may be negative in children who received antibiotic therapy before
CSF examination
➢ Negative CSF culture does not preclude the development of meningitis hours or
days after the LP; if clinical signs suggest meningitis, repeat LP may be warranted
➢ Molecular tests can help to identify the specific pathogen in some cases
Nonbacterial causes of CSF pleocytosis should also be considered.

Empiric antibiotic therapy for bacterial meningitis

Patient characteristics Recommended regimen

• Ampicillin

• PLUS an aminoglycoside (e.g., gentamicin)

• AND/OR a third-generation cephalosporin

o Cefotaxime
Age < 1 month
o If cefotaxime is unavailable: ceftazidime

o Ceftriaxone is contraindicated in patients aged < 1

month because of a higher risk of biliary sludging

and kernicterus.

• Vancomycin

• PLUS one of the following third-

Age > 1 month to 50 years generation cephalosporins:

o Cefotaxime

o Ceftriaxone

Age > 50 years • Vancomycin

 Empiric antibiotic therapy for bacterial meningitis

Patient characteristics Recommended regimen

• PLUS ampicillin

• PLUS one of the following third-

generation cephalosporins:

o Cefotaxime

o Ceftriaxone

• Vancomycin
Immunocompromised
• PLUS ampicillin
(E.g., as a result of HIV, AIDS, use
• PLUS one of the following:
of immunosuppressants, or

following transplantation) o Cefepime

o Meropenem

✓ Ampicillin is added if patients are at risk of Listeria spp. infection (e.g., newborns,
pregnant women, adults > 50 years of age, 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.

Empiric therapy for viral meningitis

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
o 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)
o Concern for other herpesviruses, e.g., VZV, EBV
• Recommended empiric antiviral agent: acyclovir
o 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

Pathogen Examples of antimicrobial agents

S. pneumoniae (penicillin-
resistant strains)
• Vancomycin
MRSA

S. epidermidis

H. influenzae • Third-

generation cephalosporin (e.g., cefotaxime OR ceftria

N. meningitidis
xone)

L. monocytogenes

• Ampicillin
S. agalactiae

• Third

E. coli generation cephalosporin (e.g., cefotaxime OR ceftria

xone)

Enterococcus spp. • Gentamicin

 Pathogen-specific therapy in meningitis

Pathogen Examples of antimicrobial agents

• PLUS either ampicillin OR vancomycin

P. aeruginosa • Cefepime

R. rickettsii • Doxycycline

Herpesviruses • Acyclovir

✓ N. meningitidis – The preferred agents for meningococcal meningitis arethird-

generation cephalosporins (eg, ceftriaxone 100 mg/kg/day IV in two divided doses
[maximum 4 g/day] or cefotaxime [where available] 225 to 300 mg/kg/day IV [maximum
dose 12 g/day] in three or four divided doses). High-dose penicillin G (300,000
units/kg/day in four divided doses) is an alternative low-cost option.
✓ H. influenzae – Meningitis due to H. influenzae is usually treated with a third-generation
cephalosporin such as ceftriaxone (100 mg/kg/day IV in two divided doses [maximum dose 4
g/day]) or cefotaxime (where available; 200 mg/kg/day IV in three or four divided doses
[maximum dose 12 g/day]). Treatment duration is 7 to 10 days. Ampicillin is appropriate only if
the infecting pathogen has been shown to be beta-lactamase negative
✓ Listeria monocytogenes – The preferred regimen for treatment of meningitis due to L.
monocytogenes in infants and children consists of ampicillin (300 mg/kg/day IV in four divided
doses [maximum dose 12 g/day]) plus gentamicin (7.5 mg/kg/day IV in three divided doses) .
The usual treatment duration is 21 to 28 days .
✓ Group B streptococcus (GBS) – The preferred agents for treatment of GBS (Streptococcus
agalactiae) meningitis are penicillin G (450,000 to 500,000 units/kg/day IV in four divided
doses) or ampicillin (300 mg/kg/day IV in three divided doses). The usual treatment duration is
14 to 21 days
 ✓ Staphylococcus aureus – The standard therapy for methicillin-susceptible S.
aureus (MSSA) meningitis is nafcillin or oxacillin (both are dosed at 150 to 200
mg/kg/day IV in four doses [maximum 12 g/day]) [11,14]. Treatment duration is typically
14 days.The preferred therapy for methicillin-resistant S. aureus (MRSA) meningitis
is vancomycin (60 mg/kg/day IV in four divided doses [maximum dose 4 g/day]) .
Treatment duration is at least 14 days
✓ Treatment duration — The duration of antimicrobial therapy depends upon the
causative organism and clinical course. We suggest the following durations of therapy
for uncomplicated meningitis caused by the following organisms :
S. pneumoniae – 10 to 14 days
N. meningitidis – 5 to 7 days
H. influenzae – 7 to 10 days
L. monocytogenes – 21 to 28 days
S. aureus – At least two weeks
Gram-negative bacilli – Three weeks or a minimum of two weeks beyond the first sterile
CSF culture, whichever is longer.

Corticosteroids
• Indication: suspected or proven meningitis due to S. pneumoniae or H. influenzae in adults
and children
• Mechanism: reduces the local and systemic inflammation seen in bacterial meningitis and
improves outcome
• the local and systemic inflammation seen in bacterial meningitis and improves outcomes
• Recommended agent: dexamethasone
o Should be administered before or concomitant to antibiotics for optimal results
o Discontinue if a pathogen other than S. pneumoniae or H. influenzae is identified.
• Disadvantages: side effects, e.g., hyperglycemia, GI bleeding
✓ Do not delay antibiotics to administer adjuvant therapy. If dexamethasone is not readily
available, start antibiotics immediately.

Subtypes and variants

Tuberculous meningitis
• Pathogen: Mycobacterium tuberculosis
• Incubation period: approximately 2–8 weeks
• Risk factors: immunocompromise (e.g., HIV infection)
• Clinical course
o Subacute course over several weeks or months
o Gradual manifestation with intermittent fever
• Clinical features
o Typical symptoms of meningitis, including fever, headache, neck stiffness, and altered
mental status .
o Focal neurological deficits (e.g., hemiparesis) due to hematogenous dissemination
of cranial arteritis
o Cranial nerve deficits are most commonly seen in basal meningitis and predominantly
involve the abducens nerve
• Diagnostics
o CSF fluid
▪ Presence of acid-fast bacilli on CSF Gram stain
▪ Culture is the gold standard for diagnosis, but results may take weeks.
▪ Analysis of adenosine deaminase (ADA) activity
▪ ↑↑ Activity in CSF of individuals with tuberculous meningitis compared to CSF of
individuals with other types of meningitis (e.g., cryptococcal or bacterial meningitis)
▪ For the differentiation of tuberculous from other types of meningitis, combining
serum and CSF ADA activity can increase sensitivity and specificity.
▪ However, reported sensitivity and specificity vary greatly in the
literature; confounding factors include the CSF ADA cut-offs, assay types, and
comorbidities (especially HIV).
o CT/MRI: possible hydrocephalus, basilar meningeal
thickening, tuberculomas, edema, infarcts
• Complications
o Communicating (malabsorptive) hydrocephalus
o Pituitary gland insufficiency
• Treatment
o Adjunctive glucocorticoid therapy with dexamethasone or prednisolone tapered over 6–8
weeks

Cryptococcal meningitis
• Pathogen: Cryptococcus neoformans (a type of encapsulated yeast)
• Risk factors
 o AIDS
o Exposure to pigeon droppings
• Clinical course: subacute onset with (low) fever, fatigue, and headaches
• Clinical features
o Meningeal symptoms are often absent
• Diagnostics
o Cryptococcal antigen testing of CSF and serum
▪ Highly specific and sensitive
▪ Typically performed via latex agglutination or enzyme immunoassay
o CSF culture (Sabouraud agar)
o CSF gram staining: India Ink (clear halo), mucicarmine (red inner capsule)
MRI: gelatinous pseudocysts (soap bubble appearance)
o
• Treatment
o Induction: Intravenous amphotericin B PLUS flucytosine for at least 2 weeks
o Consolidation: fluconazole for at least 8 weeks
o Maintenance: fluconazole for at least 1 year
o Important consideration: Delay initiation of cART for 4–6 weeks after
starting antifungal therapy to reduce the risk of immune reconstitution syndrome.

Tick-borne diseases
North America
• Lyme meningitis: See Lyme disease.
• See Rocky Mountain spotted fever (RMSF).
• See Ehrlichiosis.
Eurasia: Tick-borne meningoencephalitis
• Pathogen: tick-borne encephalitis virus (TBEV)
o TBEVs are part of the Flaviviridae family and occur predominantly in parts of Europe,
Russia, and Asia.
o 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
o Ixodid tick acts as a vector; therefore, transmission is predominantly in June/July and
September/October.
 o Occasional transmission via unpasteurized dairy products from infected livestock
• Incubation period: usually 7–14 days
• Clinical features:
o Nearly 90% of cases are asymptomatic.
o 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:
o Full recovery is common (particularly in children and adolescents).
o In symptomatic disease, residual symptoms may occur.
• Prevention: A vaccine is not available in the US.
o Active immunization with an inactivated TBEV (inactivated vaccination): Large-
scale implementation of this vaccination is not generally recommended.
o 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 amebic meningoencephalitis

• 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
o CSF analysis
▪ Findings similar to those of bacterial meningitis (e.g.,
neutrophilic pleocytosis, hypoglycorrhachia, increased CSF protein)
▪CSF erythrocytosis (due to hemorrhagic necrosis)
▪ Microscopy shows trophozoites
• Treatment: amphotericin B, miltefosine
• Prognosis: nearly always fatal
 Complications
Neurologic
• Most common: sensorineural hearing loss (transient or permanent)
• Focal neurological deficits
• 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
o Dangerous complication of a number of diseases but most commonly associated
with meningococcal meningitis
o 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
o Fever
o Myalgia
o Nonblanching, petechial rash (mostly on trunk and legs); in severe cases, even purpura
fulminans with extensive necrosis of the skin
o Severe malaise
o Hypotension or even shock
o Findings of disseminated intravascular coagulation
o Findings of acute adrenal gland failure
o Respiratory failure
• Treatment
o Treatment of the underlying cause
o Parenteral fluid therapy and management of disorders of sodium balance
 o Coagulopathy treatment
• Prognosis: fatal without treatment and often fatal even with treatment, particularly if
associated with meningococcal infection (> 40% mortality rate)

Prognosis
• Bacterial meningitis
o Fatal if left untreated
o Prognosis in treated patients depends on age, overall condition, immune status and
the pathogen(s) involved.
• Viral meningitis
o Resolves spontaneously in the majority of cases
o Residual symptoms such as sensorineural hearing loss, epilepsy, and cognitive deficits are
rare.
• Fungal meningitis
o Associated with neurological sequelae and a high mortality rate
oTreatment adherence is very important to avoid relapse.
Prevention
• Pre-exposure prophylaxis
o Meningococcal vaccination (a polysaccharide conjugate vaccine)
o Hib vaccination
Droplet prophylaxis
o
o See immunization schedule.
• Postexposure measures in bacterial meningitis
o Postexposure vaccination: may be considered if the particular serogroup is known and
available as a vaccine
o Postexposure chemoprophylaxis: For meningococcal infections, this should ideally be
administered within 24 hours of the index patient's symptom onset.

Postexposure chemoprophylaxis for bacterial meningitis

Pathogen Indications Recommended regimen

 Postexposure chemoprophylaxis for bacterial meningitis

Pathogen Indications Recommended regimen

• Close contact with

the index patient in

the 7 days before the

onset of symptoms

o All household

and/or day-

care members • Rifampicin

o Anyone exposed to • OR ceftriaxone

N. secretions, o Preferred chemoprophylaxis during pregnancy.

meningitidis including: • OR ciprofloxacin

▪ Healthcare o Avoid during pregnancy and for patients < 18 years of

providers age.

▪ Travelers: either

direct or ≥ 8

hours of contact

with people

from endemic ar

eas
 Postexposure chemoprophylaxis for bacterial meningitis

Pathogen Indications Recommended regimen

• Household contacts (≥

4 hours of

contact/day): If any of

the contacts are

unvaccinated children ≤

4 years of age

or immunocompromise

d, administer

prophylaxis to all

members of the

household except

pregnant women.
H.
• Day-care facility (if • Rifampicin
influenzae
attended 5–7

days before the onset

of symptoms): If there

are children ≤ 2

years of age,

unvaccinated children,

or ≥ 2 cases within 60

days, administer

prophylaxis for all

children and personnel

PLUS vaccines when

indicated.
For N. meningitidis, ceftriaxone is the chemoprophylaxis of choice during pregnancy.