Review Article

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Meningitis and
Encephalitis
Karen L. Roos, MD, FAAN; John E. Greenlee, MD, FAAN
ABSTRACT
Purpose of Review: Neurologists have a vital role in the recognition of meningitis and
encephalitis, the accurate evaluation and interpretation of CSF studies, and the management and prevention of the neurologic complications of CNS infectious diseases.
Recent Findings: Although the tetravalent meningococcal glycoconjugate vaccine has
decreased the incidence of meningococcal meningitis, the vaccine does not contain serogroup B, which is responsible for one-third of cases of meningococcal disease. Thus, meningitis due to Neisseria meningitidis is still a concern in a vaccinated individual. Empiric therapy
for meningitis associated with sinusitis, otitis, or mastoiditis should include antibiotic therapy
for anaerobes. An organism that classically causes a subacute or chronic meningitis, such as
Mycobacterium tuberculosis, may on occasion present with an acute onset of symptoms.
Summary: Unlike most other diseases, the management of patients with suspected
meningitis or encephalitis begins with empiric therapy. The etiologic organism cannot
always be identified. The goal is to identify those that are treatable, provide supportive
care for those that are not, and, when possible, prevent the neurologic complications
of these infections.
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INTRODUCTION
Meningitis and encephalitis are neurologic emergencies. In the hospital setting, the initial realization that a patient
has a CNS infectious disease is usually
made by the emergency department physician or, if the patient is already admitted, by the primary service. For this
reason, neurologic consultation may be
delayed, and time is almost always of the
essence in reaching an accurate diagnosis and initiating treatment.
ACUTE MENINGITIS
Bacterial Meningitis
Bacterial meningitis is most commonly
caused by hematogenous spread of
bacteria from a remote site of infection.
Meningitis may also develop from the
spread of organisms through emissary
veins from infected sinuses, middle ear,
or mastoid. Bacteria may enter the subarachnoid space following penetrating

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trauma or neurosurgical procedures or

through congenital or acquired defects
in the skull or spinal column. Meningitis
due to entry of organisms through
congenital or acquired defects in the
skull or spinal column should be suspected in patients with recurrent episodes of meningitis. Acquired defects
are usually the result of closed head
trauma and occur at sites where the
bones of the skull are thinnest: over
the frontal, ethmoidal, or sphenoidal
sinuses or bony structures adjacent to
the middle ear or mastoid. Acquired
skull base defects may be accompanied
by CSF rhinorrhea or otorrhea if the
meninges are breached, but not all skull
base defects are associated with rhinorrhea or otorrhea. It is important to
remember that an interval of many years
may separate an episode of significant
closed head trauma and the onset of
meningitis.
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Causative agents of acute bacterial

meningitis. The agents causing bacterial meningitis vary with the age of the
patient, the route by which infection is
acquired, and the presence of associated or predisposing conditions.
The most common etiologic organism of bacterial meningitis in neonates
and infants is Streptococcus agalactiae
(group B streptococci), followed in order
of frequency by Escherichia coli, other
gram-negative bacilli, and Listeria monocytogenes. Meningitis due to S. agalactiae
occurs at two points in time: within 48
hours of the postnatal period or at 7 days
to 6 weeks of age. Cases occurring in the
immediate postnatal period are due to acquisition of the organism from the mother
at the time of birth, and meningitis often
occurs as part of a systemic infection.
Cases of S. agalactiae meningitis in older
neonates are usually not accompanied by
other evidence of systemic infection.
The most common causative organisms of bacterial meningitis in children
and adults are Streptococcus pneumoniae and Neisseria meningitidis. The
tetravalent meningococcal glycoconjugate vaccine has decreased the incidence of meningococcal meningitis.
The vaccine does not contain serogroup
B, which is responsible for one-third of
cases of meningococcal disease.1
Meningitis associated with sinusitis, otitis, or mastoiditis may be due to streptococci, anaerobes, Staphylococcus aureus,
Haemophilus, or Enterobacteriaceae.
Meningitis in the postneurosurgical
patient may be due to staphylococci,

gram-negative bacilli, or anaerobes. S.

aureus is a common causative organism in patients with penetrating head
trauma.
The organisms associated with bacterial meningitis in patients who are immunocompromised vary with the type
of immune deficiency. Individuals with
defects of cell-mediated immunity,
which includes very young infants, pregnant woman, the elderly, and patients
who are immunocompromised as a result of organ transplantation, malignancy,
AIDS, or immunosuppressive medications, have an increased prevalence of
meningitis due to L. monocytogenes or
mycobacteria. Patients with defects of humoral immune response (and patients
who have undergone splenectomy) are at
risk for fulminant meningitis with S.
pneumoniae or, less frequently, N. meningitidis. Patients with neutropenia are
susceptible to meningitis caused by Pseudomonas aeruginosa and by gramnegative enteric bacteria.
Chronic meningitis presenting
acutely. A number of etiologic organisms that typically cause a subacute or
chronic meningitis may on occasion
present with acute onset of symptoms.
This is especially true for tuberculous
meningitis but may occasionally occur
with fungal meningitides due to Cryptococcus neoformans, Histoplasma
capsulatum, Coccidioides immitis, or
other agents. The most urgent of these is
tuberculous meningitis, and presumptive
treatment should be initiated if the
condition is suspected (Case 3-1).

KEY POINTS

h The most common

causative organisms of
bacterial meningitis in
children and adults are
Streptococcus
pneumoniae and
Neisseria meningitidis.

h The tetravalent
meningococcal
glycoconjugate vaccine
does not contain
serogroup B, which
is responsible for
one-third of cases of
meningococcal disease.

h Meningitis associated
with sinusitis,
otitis, or mastoiditis
may be due to
streptococci, anaerobes,
Staphylococcus aureus,
Haemophilus, or
Enterobacteriaceae,
and empiric coverage
should include
meropenem or
metronidazole.

h Patients with defective

cell-mediated
immunity, such as
infants, the elderly,
and individuals who are
immunosuppressed,
may develop meningitis
due to Listeria
monocytogenes.

Case 3-1
A 21-year-old Laotian woman presented to the emergency department with
severe headache, fever, confusion, and difficulty with gait. Examination
revealed confusion, nuchal rigidity, bilateral Babinski signs, and ataxia. CT
scan demonstrated basilar meningeal inflammation and a mild increase in
ventricular size. CSF analysis revealed 150 white blood cells/mm3, 45%

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Meningitis and Encephalitis

KEY POINTS

h Empiric therapy for

Continued from page 1011

tuberculous meningitis
should be initiated in
patients with fever,
headache, and stiff
neck; a CSF lymphocytic
pleocytosis; and a mild
to moderate decrease in
glucose concentration
(less than 40 mg/dL but
greater than 20 mg/dL).

polymorphonuclear leukocytes and 55% mononuclear cells, a protein of

230 mg/dL, and a glucose of 30 mg/dL. No organisms were seen on Gram
stain, and both acid-fast smear and PCR for mycobacteria were negative.
The patient was treated with isoniazid (300 mg/d), rifampin (600 mg/d),
pyrazinamide (2 g/d), and ethambutol (2.5 g/d) on suspicion of tuberculous
meningitis. CSF was obtained by high cervical puncture, and 3 weeks later
Mycobacterium tuberculosis grew in culture. A chest x-ray demonstrated
innumerable small pulmonary opacities consistent with miliary tuberculosis.
Comment. Ancillary studies such as a chest radiograph are helpful in
patients with CNS infections. Skin testing with purified protein derivative
may initially be negative but then become positive as the patient improves
during the course of therapy. In patients with fungal or tuberculous
meningitis, a high cervical puncture may demonstrate the organism when
lumbar puncture does not.
Therapy for tuberculous meningitis is recommended in the patient with
fever, headache, and stiff neck, with or without cranial nerve deficits
associated with a CSF lymphocytic pleocytosis and a mild to moderately
decreased glucose concentration (less than 40 mg/dL but greater than
20 mg/dL). Evidence of basilar meningeal enhancement and hydrocephalus
on neuroimaging further supports the need for empiric therapy for
tuberculous meningitis.

h Cases of mycobacterial
or fungal meningitis
presenting acutely may
resemble bacterial
meningitis.

Viral Meningitis
Many of the viruses causing viral meningitis have a seasonal distribution
(Table 3-1). Most cases of viral meningitis are due to enteroviruses and occur
in summer or early autumn, although
occasional cases may occur throughout
the year. Meningitis associated with
West Nile virus has a similar seasonal
distribution, as does meningitis associated with other arthropodborne viruses. The exception to this rule is
Colorado tick fever, which tends to
occur in late spring or early summer.
Clinical Presentation of
Acute Meningitis
Bacterial meningitis may be preceded
by 3 to 5 days of insidiously progressive
malaise, fever, irritability, or vomiting;
develop over 1 to 2 days; or have a
fulminant presentation.2 Bacterial meningitis remains one of the few conditions in which a previously healthy

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young person may go to sleep with

mild symptoms and never awaken.
Typical symptoms are fever, headache,
photophobia, vomiting, and an altered
level of consciousness (Case 3-2). Patients may or may not complain of neck
stiffness. Seizures may occur early in
meningitis in up to 40% of affected
children and may also occur in adults.
Presentation with focal seizures or focal
neurologic symptoms, however, should
raise concern of brain abscess, cerebritis, or cerebrovascular complications.
Cases of mycobacterial or fungal meningitis presenting acutely may resemble
bacterial meningitis. Patients with viral
meningitis are usually less overtly ill,
and they never have an altered level
of consciousness or new-onset seizure
activity unless encephalitis has developed. Neurologists are critical in helping
non-neurologists distinguish between a
patient with bacterial meningitis, who
should be admitted to and observed in
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TABLE 3-1 Major Agents of Viral Meningitis

Family

Genus

Agents

Picornaviridae

Enterovirus

Coxsackieviruses
Echoviruses

Mechanism
of Spread

Peak Season

Fecal-oral
contamination

Summer to
early autumn

Enterovirus 71 and other

numbered enteroviruses
Herpesviridae

Herpesvirus

Herpes simplex virus type 2a

Human contact

No seasonal
distribution

Togaviridae

Flavivirus

West Nile virus

Mosquito

Summer to
early autumn

St. Louis virus

Bunyaviridae

Orthobunyavirus

California virus/La Crosse virus

Mosquito

Summer to
early autumn

Reoviridae

Orbivirus

Colorado tick fever

Tick

Late spring to
early summer

Arenaviridae

Arenavirus

Lymphocytic choriomeningitis
virus

Airborneb

Autumn and
winterb

HIV

Human contactc

No seasonal
distribution

Retroviridae
a

Herpes simplex virus type 2 meningitis may occur as an isolated event or may be recurrent.
Lymphocytic choriomeningitis virus is classically associated with exposure to infected wild mice and is most common during autumn or
winter when mice tend to move indoors. Infection may also occur year-round after exposure to infected pet hamsters.
c
Meningitis in HIV usually has its onset early in the course of systemic infection, at the time of seroconversion.
b

the intensive care unit, and a patient

with viral meningitis, who is not at risk
for additional complications.
Bedside Diagnosis
of Meningitis
Bacterial meningitis should be considered in any patient presenting with fever,

alteration in consciousness, and nuchal

rigidity, keeping in mind that these
findings are not present in all patients.
Presentation in coma is an ominous
prognostic sign. The classic tests for
meningeal irritation are resistance to
passive flexion of the neck (nuchal
rigidity), Kernig sign, and Brudzinski

Case 3-2
A 62-year-old woman had been in good health until 4 days prior to admission, when she reported shaking
chills, cough, and purulent sputum production to her husband. Two days prior to admission she reported
a headache. On the day of admission, her husband found her unresponsive in the early morning hours
and called an ambulance. She was brought first to an outlying facility and then transferred.
On examination, the patient was diaphoretic and unresponsive. Pulse was 108 beats/min, blood
pressure was 108/84 mm Hg, and temperature was 39.8-C (103.6-F). General physical examination was
unremarkable except for rales over the right lower lung field and nuchal rigidity with a positive
Brudzinski sign. Fundi showed flat disks but absent venous pulsations. Blood cultures were obtained,
and empiric therapy for bacterial meningitis and herpes simplex virus type 1 encephalitis was initiated
with dexamethasone, ceftriaxone, vancomycin, ampicillin, and acyclovir.

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Continued from page 1013

Complete blood count showed a white blood cell count of 15,000 2/L with 85% neutrophils and 5%
bands. CT scan was unremarkable. Lumbar puncture revealed an opening pressure of 430 mm H2O,
turbid fluid, 2290 white blood cells/mm3, 95% polymorphonuclear leukocytes, a protein of 410 mg/dL,
and a glucose of 28 mg/dL with a blood glucose of 125 mg/dL. Gram stain showed innumerable
polymorphonuclear leukocytes and occasional lancet-shaped gram-positive diplococci.
The patient was treated with dexamethasone, ceftriaxone, vancomycin, and ampicillin pending
cultures, and subsequently antimicrobial therapy was modified after Streptococcus pneumoniae was
isolated and antibiotic sensitivities demonstrated the organism was sensitive to ceftriaxone.
Comment. Empiric adjunctive and antimicrobial therapy is initiated for bacterial meningitis, herpes
simplex virus type 1 encephalitis, and tickborne bacterial infections (during the season when ticks are
biting) immediately after blood cultures are obtained and prior to CT and CSF analysis. Empiric therapy is
then modified when the results of CSF analysis and antimicrobial sensitivity testing are known.

sign. Kernig sign is present when resistance to passive extension of the leg at
the knee is present. Although Brudzinski
developed several tests to detect meningeal irritation, the maneuver most commonly referred to as Brudzinski sign
involves spontaneous flexion of the hips
and knees when the neck is passively
flexed. Brudzinski sign is the more sensitive of the two. Both signs, when present, are strongly suggestive of meningeal
irritation; however, they were developed
in the preantibiotic era when meningitis
was frequently advanced at the time of
presentation and may not be detected
early in the course of infection. In awake
patients, a more sensitive test is to ask
patients to put their chin on their chest
with the mouth closed. Keeping the
mouth closed is important, because
patients experiencing pain on flexion
may hold their neck still but touch their
chin to their chest by opening the jaw
widely. One of the most sensitive tests
of nuchal rigidity is a test that was developed during the days of the polio
epidemic and involves asking the patient to kiss his or her knee (in children,
who consider this request perfectly
reasonable) or, in adults, to touch the
forehead to the knee. This test will often detect meningeal irritation at a time

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when other tests are negative. It is important to keep in mind that elderly
patients with extensive cervical spine
disease may have neck stiffness, and
occasionally patients with influenza and
severe myalgias may also report neck
pain. In both groups of patients, pain
and resistance to movement usually occur not only upon flexion but also upon
lateral rotation. Patients with meningitis, however, can usually turn the head
even if neck stiffness to flexion is present. Particular attention should be paid
to the presence of cutaneous rashes,
petechiae, or purpura suggestive of meningococcemia; pulmonary consolidation suggestive of pneumonia due to
S. pneumoniae; or cardiac murmurs
suggestive of endocarditis.
Atypical Presentations
of Meningitis
In neonates, bacterial meningitis may
present with tachypnea, apneic spells,
changes in heart rate, atypical seizures,
or simply vague decline. Although a
feeble, high-pitched cry in an infant has
been said to suggest meningitis, this is
not a reliable sign. Similarly, a bulging
fontanelle is a late sign, indicating significantly increased intracranial pressure.
Individuals who are immunocompromised,
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such as neonates, may not develop fever

or nuchal rigidity. Patients with alcoholism presenting in the setting of severe
inebriation may have meningitis without
clearly detectable signs. Meningitis may
also be deceptively asymptomatic in the
elderly, and the only sign of meningitis
may be confusion in a previously alert
older patient or altered responsiveness in
a patient who already has dementia. In
these patients, as well as in neonates, the
threshold for CSF analysis should be low.
However, patients with alcoholism and
elderly patients are also at risk for falls and
subdural hematomas. In such patients,
it is appropriate to begin antimicrobial
therapy and obtain a head CT scan or MRI
before CSF analysis. The onset of bacterial
meningitis following neurosurgical procedures is often insidious, developing over
hours or days. Patients in this setting are
at increased risk, as an alteration of
consciousness or neck stiffness may be
attributed to the expected postoperative
course.
Laboratory Diagnosis
of Meningitis
Although bacterial meningitis is suspected on the basis of the clinical
presentation and physical examination
findings, definitive diagnosis is made by
analysis of the CSF. If intracranial pressure is greatly increased, there is a risk of
brain herniation independent of, but
also associated with, lumbar puncture,
and the likelihood of fatal herniation
cannot be reliably predicted from CT or
MRI.3 In severely ill patients in whom
very high intracranial pressure is suspected, the most prudent course is to
begin empiric therapy and wait until
CSF pressure has been controlled before performing lumbar puncture. The
organism can often be identified in
blood cultures. CSF should be sent for
cell count with differential, protein and
glucose concentration, Gram stain, culture, and PCR. Simultaneous blood gluContinuum Lifelong Learning Neurol 2011;17(5):10101023

cose should also be sent to determine

the CSF:blood glucose ratio. Expeditious handing of CSF by the laboratory
is important because cells may adhere
to the collecting tube over time, resulting in lower CSF cell counts, and
leukocytes may lyse in extremely purulent CSF.4
Typical CSF findings in bacterial
meningitis include elevated opening
pressure, fluid that is often, but not
always, turbid, elevated white blood cell
count consisting predominantly of polymorphonuclear leukocytes, elevated
protein concentration, and depressed
CSF:blood glucose ratio. A CSF:blood
glucose ratio of less than 0.3 is highly
correlated with bacterial meningitis. In
evaluating CSF glucose concentrations,
it is important to remember that CSF
glucose values will be higher in moderately to severely hyperglycemic patients
and that changes in CSF glucose concentrations may lag 30 to 120 minutes
behind those in blood. Protein concentrations in meningitis are a reflection of blood-brain barrier injury but
usually range between 100 mg/dL and
500 mg/dL.4
Specific identification of the infecting organism involves Gram stain, culture, and PCR. Gram stain provides
the most rapid initial identification of
the organism. Detection of organisms
on Gram stain requires approximately
100,000 organisms/mm3.5 Errors in
Gram stain may result from careless
handling of CSF, inadequate efforts to
resuspend bacteria if CSF has been
allowed to settle, and errors in decolorization or reading of the slide.
A 16S ribosomal RNA conserved sequence broad-based bacterial PCR is
routinely available in most hospital
laboratories. Additionally, a number
of meningeal-specific PCRs detect
N. meningitidis or S. pneumoniae nucleic acid in CSF, as well as a number
of other meningeal pathogens, but

KEY POINTS

h The causative organisms

of bacterial meningitis
can often be detected in
blood cultures.

h CSF should be
examined for white
blood cells within 90
minutes of collection.

h CSF glucose
concentrations will be
higher in moderately to
severely hyperglycemic
patients. In these
patients, the CSF:blood
glucose ratio should be
used to determine the
true CSF glucose
concentration. The CSF
glucose concentration
is low when the
CSF:blood glucose ratio
is less than 0.6.

h CSF bacterial PCRs are

increasingly available.
Specific diagnosis of the
causative organism of
bacterial meningitis and
determination of
antibiotic sensitivity
require bacterial culture.

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TABLE 3-2 CSF Abnormalities in Acute Meningitis

Type of
Meningitis

Cellsa

Protein

Glucose

Specific Diagnosis

Bacterial
meningitis

Polymorphonuclear
leukocytes

Elevated

G50% of
blood
glucose

Gram stain

Tuberculous
meningitis

Variable pleocytosis,
usually with
lymphocytes 9
polymorphonuclear
leukocytes

Elevated

Lymphocytes

Elevated

Bacterial culture
PCR

Fungal
meningitis

G50% of
blood
glucose

Acid-fast stainb
PCR
Culture

G50% of
blood
glucose

Cryptococcal polysaccharide antigen

Histoplasma polysaccharide antigen Coccidioides
immitis complement fixation antibody
India ink and culture

Viral
meningitis

Lymphocytes

Elevated

950% of
blood
glucose

Reverse transcriptase PCR for enteroviruses

PCR herpes simplex virus type 2
Immunoglobulin M (West Nile or other arboviruses)

Cell count, glucose, and protein may be minimally abnormal in patients who are severely immunocompromised.
In tuberculous meningitis, diagnosis by CSF acid-fast smear has a low sensitivity, diagnostic reliability of PCR is only 50%, and culture
requires up to 7 weeks. For this reason, tuberculous meningitis is treated as described in Case 3-1.
c
CSF during the first 24 to 48 hours of viral meningitis may exhibit a mixed pleocytosis with predominance of polymorphonuclear leukocytes.
b

these are not routinely available. Specific diagnosis of the causative organism
of bacterial meningitis and determination of antibiotic sensitivity require
bacterial culture. Although this is routine in most hospitals, it may be helpful to alert the laboratory in advance
if anaerobic infection or other unusual organisms or culture requirements are anticipated. Yield on culture
can be reduced by prior antibiotic therapy. Table 3-2 is a list of the expected
CSF results in meningitis due to bacteria, viruses, mycobacteria, and fungi.
Treatment of Acute Meningitis
Antibiotic therapy for bacterial meningitis. Antibiotic therapy for bacterial
meningitis is initially empiric and then
specific once the pathogen has been
identified and the results of antimi-

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crobial sensitivity testing are known

(Table 3-3).
Therapy of chronic meningitis presenting acutely. Specific diagnosis of
tuberculous meningitis can be difficult:
yield by PCR approaches 50%, and
sensitivity of culture (which may take
up to 6 weeks) is only 70%.4 Thus, therapy for tuberculous meningitis should
be initiated presumptively if the diagnosis
is suspected (Table 3-4). Treatment of
fungal meningitis is usually not begun
empirically unless organisms are seen
in CSF.
Treatment of viral meningitis. Most
cases of viral meningitis resolve spontaneously. The headache may persist
for months and can be managed with
amitriptyline and nonsteroidal antiinflammatory agents. Limited data suggest that pleconaril may shorten the
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TABLE 3-3 Antibiotics for Empiric Therapy of Bacterial Meningitis

Age and Associated
Conditions

Probable Organism

Antibiotic Therapy

Preterm infants

Staphylococcus aureus (nosocomial)

Vancomycin plus ceftazidime

Gram-negative bacilli
Neonates

Group B streptococci

Ampicillin plus cefotaxime

Escherichia coli
Other gram-negative bacilli
Listeria monocytogenes
Children and adults

Streptococcus pneumoniae
Neisseria meningitidis

Adults over the age of 55

S. pneumoniae
L. monocytogenes
Gram-negative bacilli

Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
(cefepime) cephalosporin plus
vancomycin
Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
(cefepime) cephalosporin plus
vancomycin plus ampicillin

Haemophilus influenzae
Meningitis in the setting
of sinusitis, otitis, or known
CSF leak

S. pneumoniae
Haemophilus
Gram-negative bacilli
Anaerobic or microaerophilic streptococci

Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
(cefepime) cephalosporin plus
vancomycin plus meropenem or
metronidazole

Bacteroides fragilis
S. aureus
Head trauma, neurosurgical
procedures, shunt infections

S. aureus
Staphylococcus epidermidis

Vancomycin plus ceftazidime or

vancomycin plus meropenem

Gram-negative bacilli
S. pneumoniae
States of impaired cellular
immunity, including AIDS

L. monocytogenes
Gram-negative bacilli
S. pneumoniae

Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
(cefepime) cephalosporin plus
vancomycin plus ampicillin

H. influenzae

duration of headache in enteroviral

meningitis, but the drug is not routinely available.5 Acyclovir is efficacious
in treating herpes simplex virus type 2
(HSV-2) meningitis, and prophylactic
therapy with acyclovir, valacyclovir, or
famciclovir is efficacious in preventing
recurrent meningitis due to HSV-2.
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Corticosteroid therapy in meningitis. The realization that neurologic injury

in bacterial meningitis is due to the host
inflammatory response has led to a focus
on controlling this aspect of meningitis. Early studies in children with
Haemophilus influenzae meningitis
who were treated with cefotaxime plus
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a
TABLE 3-4 Antimicrobial Therapy for Tuberculous Meningitis

Drug

Usual Daily Dose

Maximum Dose

Duration

Isoniazid

5 mg/kg to 10 mg/kg

300 mg

6 to 9 months

Rifampin

10 mg/kg to 20 mg/kg

600 mg

6 months

Pyrazinamide

15 mg/kg to 30 mg/kg

2000 mg

2 months

Ethambutol

15 mg/kg to 25 mg/kg

2500 mg

2 months

Streptomycin

15 mg/kg

1000 mg

2 months

Multiple drug regimens (four or more) should be used when a high probability of drug resistance exists.

dexamethasone demonstrated an
effect on the CSF inflammatory response and a decreased incidence of
deafness compared with those treated
with cefotaxime alone.6 More recently,
studies from EuropeVincluding a nationwide prospective study from the
Netherlands in which dexamethasone
was used in all patients above 16 years
of age with pneumococcal meningitisV
demonstrated reduced mortality rates
and neurologic sequelae in patients
with pneumococcal meningitis treated
with dexamethasone begun at the initiation of antibiotic therapy (class III
evidence).7,8 Dexamethasone is given
as 10 mg intravenously, beginning immediately prior to or with the initial
dose of antibiotics, followed by 10 mg
intravenously every 6 hours for 4 days.
Early institution of dexamethasone and
antibiotic therapy appears to be crucial, and dexamethasone has not been
shown to be effective in less-developed
countries where patients tend to present later in the course of their disease.8 The role of dexamethasone in
tuberculous or fungal meningitides is
less well established. In tuberculous
meningitis, dexamethasone has been reported to decrease mortality but not
neurologic sequelae in survivors.9 As
with bacterial meningitis, however,
the utility of dexamethasone may depend on its use early in the course of
infection.

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Other measures to treat cerebral

edema. Patients presenting with papilledema or signs of impending brain
herniation warrant emergent treatment
for increased intracranial pressure. Elevation of the head of the bed to 30
degrees will often reduce pressure
somewhat. Hyperventilation to a PCO2
of 27 mm Hg to 30 mm Hg will cause
intracranial vasoconstriction and may be
lifesaving over the short term. This
usually requires intubation and paralysis, and in some cases the patient will
already be hyperventilating to that level.
In children, 0.5 g/kg to 2.0 g/kg of
mannitol is given intravenously over 30
minutes and repeated as needed. The
adult dosage is a 1.0 g/kg bolus repeated as needed every 3 to 4 hours or
0.25 g/kg every 2 to 3 hours. Pentobarbital coma has been used in extreme
cases, but no controlled data exist for
its use in meningitis. Decompressive
craniectomy is not normally used in
meningitis because the cerebral involvement is diffuse rather than focal. Surgery
may be required, however, to drain an
accompanying brain abscess or parameningeal focus of infection. For more
information, refer to the article Evaluation and Management of Increased
Intracranial Pressure in this issue of
.
Other complications of meningitis
requiring treatment. Bacterial meningitis may be accompanied by a variety
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of neurologic and systemic complications, many of which may also occur in

tuberculous meningitis. Bacterial meningitis arising from sinusitis or otitis may
be complicated by epidural abscess,
subdural empyema, brain abscess, or
venous sinus thrombosis, any of which
may require emergent surgery. Seizures
require emergent treatment with lorazepam, phenytoin (fosphenytoin), or
more aggressive therapy such as phenobarbital or pentobarbital coma in
patients who fail to respond. Hyponatremia may be caused by cerebral salt
wasting, the syndrome of inappropriate
secretion of antidiuretic hormone, or IV
fluids. Subdural effusions are common
in children with meningitis; these do
not usually require drainage and may be
followed by CT or MRI. Patients may
develop cerebral vasculitis, stroke, or
spontaneous intracranial hemorrhage.10
Myelitis, although not usually considered a complication of bacterial meningitis, has been reported in 2.3% of
patients with pneumococcal meningitis.10 Bacterial sepsis and shock may be
present, as may disseminated intravascular coagulation, and, in the
case of N. meningitidis, WaterhouseFriderichsen syndrome with widespread hemorrhage and adrenal failure.
Cases of meningitis associated with
S. aureus and, less often, S. pneumoniae may be a complication of bacterial
endocarditis. Meningitis in the presence
of S. pneumoniae endocarditis is often
accompanied by rapid destruction of
the aortic valve. Basilar meningitis with
basal ganglia ischemia or infarction can
occur in both tuberculous meningitis and
cryptococcal meningitis. The basilar meningitis that occurs in tuberculous meningitis may produce obstructive rather than
communicating hydrocephalus.
Fungal meningitis. Recommendations for the antimicrobial therapy of
fungal meningitis are readily available,
but neurologists must be vigilant about
Continuum Lifelong Learning Neurol 2011;17(5):10101023

the presence and development of increased opening pressure. Opening

pressure should be measured at the
time of the initial lumbar puncture and
any time a change in the neurologic examination occurs. A time-honored practice has been to perform daily lumbar
punctures and reduce the opening pressure by 50% using a manometer. In
reality, daily lumbar punctures are often
not effective, and it is best to use a
ventriculostomy instead.
Prognosis
In most series, mortality has correlated
with obtundation or coma. Factors associated with poor prognosis include
age older than 60 years, concomitant
debilitating diseases, low Glasgow
Coma Scale score on admission, focal
neurologic deficits, and low CSF cell
count.10Y12 Seizures have predicted a
worse outcome in some studies, as has
low CSF:serum glucose ratio.11 Mortality in tuberculous meningitis is in the
range of 25%, with good recovery in
only 50% of patients.13 As in bacterial
meningitis, prognosis is significantly
influenced by the level of consciousness on presentation and the rapid
institution of appropriate therapy. Viral
meningitis is usually self-limited.

KEY POINTS

h In the patient with

basilar meningitis
with basal ganglia
ischemia or infarction,
tuberculous meningitis
and cryptococcal
meningitis should be
considered.

h In patients with
bacterial, mycobacterial,
or fungal meningitis,
prognosis is influenced
by the level of
consciousness at the
time of presentation
and the rapidity of
antimicrobial therapy
initiation.

ENCEPHALITIS
In patients with an altered level of
consciousness or an acute confusional
state, the first question to ask is
whether the patient has encephalitis
or an encephalopathy. If the patient has
encephalitis, the next question to ask is
whether he or she has encephalitis that
can be treated with antimicrobial agents
or encephalitis that is treated with supportive care only (Case 3-3).
Etiology
The presence of fever and headache
with an altered level of consciousness
makes encephalitis more likely than
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1019

Meningitis and Encephalitis

KEY POINTS

Case 3-3

h The most common

identifiable etiologic
organisms of
encephalitis are
herpesviruses
(eg, herpes simplex
virus type 1 or
varicella-zoster virus),
a tickborne bacterial
infection, or an
arthropodborne virus.

A 20-year-old college junior was brought to the emergency department by

her boyfriend because of a 3-day history of fever, headache, and
intermittent confusion. On examination, she had a temperature of 38-C
(100.4-F), was oriented to self but not to date or place, and had difficulty
following commands. The boyfriend denied alcohol or illicit drug use.
Complete blood count with differential was normal. Noncontrast cranial
CT scan was normal. CSF analysis demonstrated 100 white blood cells/mm3,
lymphocytic predominance, 700 red blood cells/mm3, a glucose
concentration of 47 mg/dL, and a protein concentration of 56 mg/dL.
The patient was treated empirically with acyclovir for herpes simplex virus
(HSV) encephalitis based on her clinical presentation and CSF analysis. CSF
PCR for HSV-1 DNA was obtained as well as serum and CSF immunoglobulin G
(IgG) antibodies to determine a serum:CSF antibody ratio.
Comment. The CSF PCR should be positive, as she is 3 days into her illness,
but it is likely too early to detect the intrathecal synthesis of antibodies.
Antibodies do not appear in CSF until 8 days after symptom onset but may
be detectable for up to 3 months. HSV IgG on serum and CSF should be
obtained. A serum:CSF ratio of less than 20:1 is diagnostic of HSV encephalitis.
Fluid-attenuated inversion recovery (FLAIR) sequences and diffusion-weighted
imaging (DWI) magnetic resonance scans are indicated and would be
expected to demonstrate an area of increased signal intensity in the temporal
lobe. In 90% of adults with HSV encephalitis, an area of increased signal
intensity is seen in the temporal lobe on T2-weighted images, FLAIR
sequences, and DWI within 48 hours of symptom onset.

h Neuroinvasive disease
due to West Nile virus,
St. Louis encephalitis
virus, or Japanese
encephalitis virus
may present with
encephalitis, a flaccid,
weak limb (a
poliomyelitis syndrome),
or parkinsonian
features.

encephalopathy. The etiologic organism of the encephalitis can be predicted

based on the following: (1) the time of
year, (2) prodromal symptoms (eg,
flulike illness in West Nile virus infection), (3) area of residence, (4) travel
and occupational and recreational activities, (5) rash (eg, varicella, meningococcemia, Rocky Mountain spotted
fever), (6) contact with animals, and
(7) immunosuppression from medications, malignancy, chronic corticosteroid use, or organ transplantation.14
The most common identifiable etiologic organisms of encephalitis are
the reactivation of a latent herpesvirus
infection (eg, HSV-1 or varicella-zoster
virus), a tickborne bacterial infection, or
an arthropodborne virus.
In the organ transplant recipient, it is
critical to obtain the donor history from
the donors file. Cytomegalovirus, West

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Nile virus, and rabies have been transmitted from organ donor to recipient.
Clinical Presentation
Patients with encephalitis have fever
and headache and one or more of the
following: confusion, behavioral abnormalities, depressed level of consciousness, focal neurologic deficits,
and new-onset seizure activity.
Certain features, or a combination
of features, suggest a specific etiology.
Patients with West Nile virus may have a
tremor, a history of diarrhea, or a maculopapular rash. The three most clinically significant flaviviruses (West Nile
virus, St. Louis encephalitis virus, and
Japanese encephalitis virus) may present
with a flaccid, weak limb (a poliomyelitis
syndrome) or parkinsonian features.
Confusion and word-finding difficulty
are common in HSV-1 encephalitis.
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Varicella-zoster virus presents with focal

neurologic deficits due to ischemic and
hemorrhagic infarctions. Although varicella-zoster virus encephalitis may follow
shingles, encephalitis due to varicellazoster virus may occur in the absence of
a history of shingles. The rash of Rocky
Mountain spotted fever typically begins
on the wrists and ankles and then
spreads centrally to the face, chest, and
abdomen. This is in contrast to the rash
of an enterovirus, which begins on the
face and chest and then spreads to the
limbs. Borrelia burgdorferi, the causative spirochete of Lyme disease in North
America, does not cause encephalitis.
Thus, the appearance of a single erythematous lesion on the trunk or extremities is not a clue to the etiologic agent.
Diagnosis
Although the specific tests for encephalitis are magnetic resonance (MR) scan,
CSF analysis, blood cultures, and complete blood count with differential and
serologies, routine tests for encephalopathy should be sent as well, including
serum electrolytes, glucose, creatinine,
liver function test, ammonia, and serum
and urine toxicology screens. An MR
scan is more sensitive than a CT scan for
encephalitis.
The importance of serologies (acute
phase immunoglobulin M [IgM] and
acute and convalescent immunoglobulin G [IgG] titers) cannot be overstated.
One of the biggest impacts that PCR has
had on the diagnosis of neurologic infectious diseases has been the increased
awareness of other serum and CSF tests
that have been available for years but
were often overlooked because of the
emphasis on neuroimaging abnormalities in diagnosing encephalitis.
Herpes simplex virus type 1. In 90%
of adults with HSV encephalitis, an area
of increased signal intensity is seen
in the temporal lobe on T2-weighted
images, fluid-attenuated inversion reContinuum Lifelong Learning Neurol 2011;17(5):10101023

covery (FLAIR) sequences, and diffusionweighted imaging MR scan within 48

hours of symptom onset (Figure 3-1).
CSF analysis demonstrates a lymphocytic pleocytosis with a normal glucose
concentration. Red blood cells or xanthochromia may be seen in the CSF as
this is hemorrhagic, necrotic encephalitis. The CSF PCR may be falsely
negative in the first 72 hours of HSV
encephalitis symptoms, and detection
rates decrease 10 days after the onset
of symptoms. Serum and CSF HSV IgG
antibodies should be obtained to determine whether intrathecal synthesis
of antibodies is present. A serum:CSF
ratio of less than 20:1 is diagnostic of
HSV encephalitis. It takes at least 8
days for antibodies to be detected in
CSF, and antibodies may be detectable
for up to 3 months. The EEG demonstrates periodic sharp-and-slow wave
complexes occurring at regular 1- to
3-second intervals. These abnormalities
are most typically seen between the
second and fifteenth days of illness.
For HSV-1 encephalitis, CSF PCR
for HSV-1 and CSF and serum antibodies should be sent.

T2-weighted MRI demonstrating

a hyperintensity in the left
temporal lobe in a patient with
herpes simplex virus type 1 encephalitis.

FIGURE 3-1

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1021

Meningitis and Encephalitis

KEY POINTS

h To diagnose herpes
simplex virus type 1
encephalitis, CSF PCR
for herpes simplex virus
type 1 and CSF and
serum antibodies should
be obtained.

h The best diagnostic

test for varicella-zoster
virus encephalitis
is the detection of
varicella-zoster virus
immunoglobulin M
in CSF.

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Varicella-zoster virus. The best diagnostic test for varicella-zoster virus encephalitis is the detection of varicellazoster virus IgM in CSF.
Mosquitoborne viruses. In encephalitis due to any of the flaviviruses, hyperintense lesions may be seen in the
thalami, substantia nigra, and basal ganglia on T2-weighted and FLAIR sequences. The best test for West Nile virus
encephalitis is the detection of CSF IgM
antibodies specific for the virus. Serum
IgM and IgG antibodies cannot be used
to diagnose neuroinvasive disease.
For the other mosquitoborne viral encephalitides, acute and convalescent serology remain the mainstay of diagnosis.
Epstein-Barr virus. Diagnosis of
Epstein-Barr virus (EBV) depends on a
combination of serology and CSF PCR.
If serology demonstrates a positive virus capsid antigen (VCA) and negative
Epstein-Barr nuclear antigen (EBNA) and
the CSF PCR for EBV DNA is positive,
a diagnosis of EBV encephalitis can be
made. If serology demonstrates a negative VCA IgM and a positive EBNA and
the CSF PCR is positive, a diagnosis of
EBV encephalitis cannot be made, as the
CSF PCR may be positive for EBV nucleic
acid in an immunocompetent individual
in any inflammatory CNS disorder.
Rocky Mountain spotted fever. The
serologic tests for the rickettsial infections have a low sensitivity early in the
disease. It is important to biopsy any skin
lesions that are present and to repeatedly
send serology. A number of different
serologic tests are available, including the
indirect fluorescent antibody test, ELISA,
and flow immunoassays.
Progressive multifocal leukoencephalopathy. The CSF should be noninflammatory. To diagnose progressive
multifocal leukoencephalopathy, CSF
PCR should be sent for JC virus DNA;
sensitivity may only be around 60%.
Cytomegalovirus encephalitis. To
diagnose cytomegalovirus encephalitis,

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CSF PCR for cytomegalovirus nucleic

acid should be sent.
Therapy
HSV-1 encephalitis is treated with
10 mg/kg of IV acyclovir every 8 hours
for 3 weeks. Varicella-zoster virus encephalitis is treated with 10 mg/kg of IV
acyclovir every 8 hours for 10 to 14 days.
Acyclovir is not recommended for EBV
encephalitis, as it is felt to provide
little or no benefit.15 Rocky Mountain
spotted fever is treated with 100 mg of
doxycycline twice daily for at least
3 days after the patient becomes afebrile. Cytomegalovirus encephalitis is
treated with a combination of 60 mg/kg
of IV foscarnet every 8 hours and 5 mg/kg
of IV ganciclovir every 12 hours.
Noninfectious Encephalitis
Patients with noninfectious encephalitis
have headache, confusion, behavioral
abnormalities, gait abnormalities, and
involuntary movements. CSF analysis
demonstrates a lymphocytic pleocytosis
with an increased protein concentration
and a normal glucose concentration.
The hyperintensity in the temporal lobe
on T2-weighted and FLAIR MR images
of paraneoplastic limbic encephalitis has
a similar appearance to that of HSV-1
encephalitis. Serology and CSF should
be sent for antineuronal antibodies, and,
when positive, diagnostic studies should
be performed for the malignancy associated with the antineuronal antibody.
Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM)
steroid-responsive encephalopathy
(previously referred to as Hashimoto
encephalopathy) has been associated
with a number of antibodies, including
thyroperoxidase antibodies, thyroid
microsomal antibodies, thyroglobulin
antibodies, extractable nuclear antigen antibodies, antistriatal antibodies,
antinuclear antibodies, antiphospholipid antibodies, and gliadin antibodies.
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NAIM is treated with 1000 mg of IV

methylprednisolone for 5 days followed
by oral prednisone therapy.
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