Review Article

Address correspondence to Dr
John E. Greenlee, Clinical
Neuroscience Center, 175 N
Medical Drive E, 5th Floor, Salt
Meningitis and
Lake City, UT 84132,
john.greenlee@hsc.utah.edu. Encephalitis
Relationship Disclosure:
Dr Roos is the editor-in-chief Karen L. Roos, MD, FAAN; John E. Greenlee, MD, FAAN
of Seminars in Neurology and
has received compensation
for legal work. Dr Greenlee
has received personal ABSTRACT
compensation for activities
with Perseid Therapeutics Purpose of Review: Neurologists have a vital role in the recognition of meningitis and
as a consultant and has encephalitis, the accurate evaluation and interpretation of CSF studies, and the man-
served in an editorial capacity agement and prevention of the neurologic complications of CNS infectious diseases.
for Medlink.
Unlabeled Use of
Recent Findings: Although the tetravalent meningococcal glycoconjugate vaccine has
Products/Investigational decreased the incidence of meningococcal meningitis, the vaccine does not contain sero-
Use Disclosure: Dr Roos group B, which is responsible for one-third of cases of meningococcal disease. Thus, menin-
and Dr Greenlee report no
disclosure.
gitis due to Neisseria meningitidis is still a concern in a vaccinated individual. Empiric therapy
Copyright * 2011, for meningitis associated with sinusitis, otitis, or mastoiditis should include antibiotic therapy
American Academy of for anaerobes. An organism that classically causes a subacute or chronic meningitis, such as
Neurology. All rights Mycobacterium tuberculosis, may on occasion present with an acute onset of symptoms.
reserved.
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.

Continuum Lifelong Learning Neurol 2011;17(5):10101023.

INTRODUCTION or mastoid.
Meningitis and encephalitis are neuro- Bacteria may
logic emergencies. In the hospital set- enter the
ting, the initial realization that a patient sub-
has a CNS infectious disease is usually arachnoid
made by the emergency department phy- space
sician or, if the patient is already ad- following
mitted, by the primary service. For this penetrating
reason, neurologic consultation may be
delayed, and time is almost always of the
essence in reaching an accurate diagno-
sis 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,

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 Review Article
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 sus- pected in patients with
recurrent epi- sodes 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 rhino- rrhea 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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 Review Article

KEY POINTS
Causative agents of acute bacterial gram-negative bacilli, or anaerobes. S. h The most common
meningitis. The agents causing bacte- aureus is a common causative organ- causative organisms of
rial meningitis vary with the age of the ism in patients with penetrating head bacterial meningitis in
patient, the route by which infection is trauma. children and adults are
acquired, and the presence of associ- The organisms associated with bacte- Streptococcus
ated or predisposing conditions. rial meningitis in patients who are im- pneumoniae and
The most common etiologic organ- munocompromised vary with the type Neisseria meningitidis.
ism of bacterial meningitis in neonates of immune deficiency. Individuals with h The tetravalent
and infants is Streptococcus agalactiae defects of cell-mediated immunity, meningococcal
(group B streptococci), followed in order which includes very young infants, preg- glycoconjugate vaccine
of frequency by Escherichia coli, other nant woman, the elderly, and patients does not contain
gram-negative bacilli, and Listeria mono- who are immunocompromised as a re- serogroup B, which
cytogenes. Meningitis due to S. agalactiae sult of organ transplantation, malignancy, is responsible for
occurs at two points in time: within 48 AIDS, or immunosuppressive medica- one-third of cases of
meningococcal disease.
hours of the postnatal period or at 7 days tions, have an increased prevalence of
to 6 weeks of age. Cases occurring in the meningitis due to L. monocytogenes or h Meningitis associated
immediate postnatal period are due to ac- mycobacteria. Patients with defects of hu- with sinusitis,
quisition of the organism from the mother moral immune response (and patients otitis, or mastoiditis may
at the time of birth, and meningitis often who have undergone splenectomy) are at be due to streptococci,
anaerobes,
occurs as part of a systemic infection. risk for fulminant meningitis with S.
Staphylococcus aureus,
Cases of S. agalactiae meningitis in older pneumoniae or, less frequently, N. men- Haemophilus, or
neonates are usually not accompanied by ingitidis. Patients with neutropenia are Enterobacteriaceae,
other evidence of systemic infection. susceptible to meningitis caused by Pseu- and empiric coverage
The most common causative organ- domonas aeruginosa and by gram- should include
isms of bacterial meningitis in children negative enteric bacteria. meropenem or
and adults are Streptococcus pneumo- Chronic meningitis presenting metronidazole.
niae and Neisseria meningitidis. The acutely. A number of etiologic organ- h Patients with defective
tetravalent meningococcal glycocon- isms that typically cause a subacute or cell-mediated
jugate vaccine has decreased the inci- chronic meningitis may on occasion immunity, such as
dence of meningococcal meningitis. present with acute onset of symptoms. infants, the elderly,
The vaccine does not contain serogroup This is especially true for tuberculous and individuals who are
B, which is responsible for one-third of meningitis but may occasionally occur immunosuppressed,
cases of meningococcal disease.1 with fungal meningitides due to Cryp- may develop meningitis
Meningitis associated with sinusitis, oti- tococcus neoformans, Histoplasma due to Listeria
tis, or mastoiditis may be due to strepto- capsulatum, Coccidioides immitis, or monocytogenes.
cocci, anaerobes, Staphylococcus aureus, other agents. The most urgent of these is
Haemophilus, or Enterobacteriaceae. tuberculous meningitis, and presumptive
Meningitis in the postneurosurgical treatment should be initiated if the
patient may be due to staphylococci, condition is suspected (Case 3-1).

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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 Review Article
Continued on page 1012

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 Meningitis and Encephalitis

KEY POINTS
h Empiric therapy for
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).
h Cases of mycobacterial
or fungal meningitis
presenting acutely may
resemble bacterial
meningitis.
Continued from page 1011
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.

Viral Meningitis young person may go to sleep with

Many of the viruses causing viral men-
ingitis have a seasonal distribution
(Table 3-1). Most cases of viral menin-
gitis 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 asso-
ciated with other arthropodborne vi-
ruses. 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 men-
ingitis remains one of the few condi-
tions in which a previously healthy
mild symptoms and never awaken.
Typical symptoms are fever, headache,
photophobia, vomiting, and an altered
level of consciousness (Case 3-2). Pa-
tients 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, cere-
britis, or cerebrovascular complications.
Cases of mycobacterial or fungal men-
ingitis 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 devel-
oped. 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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 Meningitis and Encephalitis

TABLE 3-1 Major Agents of Viral Meningitis

Mechanism
Family Genus Agents of Spread Peak Season
Picornaviridae Enterovirus Coxsackieviruses Fecal-oral Summer to
contamination early autumn
Echoviruses
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 Airborneb Autumn and
virus winterb
Retroviridae HIV Human contactc No seasonal
distribution
a
Herpes simplex virus type 2 meningitis may occur as an isolated event or may be recurrent.
b
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.

the intensive care unit, and a patient alteration in consciousness, and nuchal
with viral meningitis, who is not at risk rigidity, keeping in mind that these
for additional complications. findings are not present in all patients.
Presentation in coma is an ominous
Bedside Diagnosis prognostic sign. The classic tests for
of Meningitis meningeal irritation are resistance to
Bacterial meningitis should be consid- passive flexion of the neck (nuchal
ered in any patient presenting with fever, 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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 Meningitis and Encephalitis
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 Meningitis and Encephalitis

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 H2 O,
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 resis- forehead to

tance to passive extension of the leg at the knee.
the knee is present. Although Brudzinski This test
developed several tests to detect menin- will of- ten
geal irritation, the maneuver most com- detect
monly referred to as Brudzinski sign meningeal
involves spontaneous flexion of the hips irritation at a
and knees when the neck is passively time
flexed. Brudzinski sign is the more sen-
sitive of the two. Both signs, when pres-
ent, 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 de-
veloped during the days of the polio
epidemic and involves asking the pa-
tient to kiss his or her knee (in children,
who consider this request perfectly
reasonable) or, in adults, to touch the

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 Meningitis and Encephalitis
when other tests are negative. It is im- portant 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 oc- cur not only upon flexion but also
upon lateral rotation. Patients with meningi- tis, however, can
usually turn the head even if neck stiffness to flexion is pres- ent.
Particular attention should be paid to the presence of cutaneous
rashes, petechiae, or purpura suggestive of me- ningococcemia;
pulmonary consolida- tion 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 sig- nificantly increased
intracranial pressure. Individuals who are immunocompromised,

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 Meningitis and Encephalitis

glucose concentration, Gram

such as neonates, may not develop fever cose should also be sent to
stain, cul- ture, and PCR.
or nuchal rigidity. Patients with alcohol- determine the CSF:blood glucose
Simultaneous blood glu-
ism presenting in the setting of severe ratio. Expedi- tious handing of
inebriation may have meningitis without CSF by the laboratory is
clearly detectable signs. Meningitis may important because cells may
also be deceptively asymptomatic in the adhere to the collecting tube over
elderly, and the only sign of meningitis time, result- ing in lower CSF
may be confusion in a previously alert cell counts, and leukocytes may
older patient or altered responsiveness in lyse in extremely puru- lent CSF.4
a patient who already has dementia. In Typical CSF findings in
these patients, as well as in neonates, the bacterial meningitis include
threshold for CSF analysis should be low. elevated opening pressure, fluid
However, patients with alcoholism and that is often, but not always,
elderly patients are also at risk for falls and turbid, elevated white blood cell
subdural hematomas. In such patients, count consisting predominantly
it is appropriate to begin antimicrobial of poly- morphonuclear
therapy and obtain a head CT scan or MRI leukocytes, elevated protein
before CSF analysis. The onset of bacterial concentration, and depressed
meningitis following neurosurgical proce- CSF:blood glucose ratio. A
dures is often insidious, developing over CSF:blood glucose ratio of less
hours or days. Patients in this setting are than 0.3 is highly correlated with
at increased risk, as an alteration of bacterial meningitis. In
consciousness or neck stiffness may be evaluating CSF glucose
attributed to the expected postoperative concentrations, it is important to
course. remember that CSF glucose
values will be higher in moder-
Laboratory Diagnosis ately to severely hyperglycemic
of Meningitis patients and that changes in
Although bacterial meningitis is sus- CSF glucose con- centrations
pected on the basis of the clinical may lag 30 to 120 minutes
presentation and physical examination behind those in blood. Protein
findings, definitive diagnosis is made by con- centrations in meningitis
analysis of the CSF. If intracranial pres- are a reflec- tion of blood-brain
sure is greatly increased, there is a risk of barrier injury but usually range
brain herniation independent of, but between 100 mg/dL and
also associated with, lumbar puncture, 500
and the likelihood of fatal herniation mg/d
cannot be reliably predicted from CT or L.4
MRI.3 In severely ill patients in whom Specific identification of the
very high intracranial pressure is sus- infect- ing organism involves
pected, the most prudent course is to Gram stain, cul- ture, and PCR.
begin empiric therapy and wait until Gram stain provides the most
CSF pressure has been controlled be- rapid initial identification of the
fore performing lumbar puncture. The organism. Detection of
organism can often be identified in organisms on Gram stain
blood cultures. CSF should be sent for requires approximately
cell count with differential, protein and 100,000 organisms/mm3.5
Errors in

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 Meningitis and Encephalitis
Gram stain may result from careless handling of KEY POINTS
CSF, inadequate efforts to resuspend bacteria if h The causative organisms of
CSF has been allowed to settle, and errors in de- bacterial meningitis can often be
detected in blood cultures.
colorization or reading of the slide. A 16S
ribosomal RNA conserved se- quence broad-based h CSF should be examined for
bacterial PCR is routinely available in most white blood cells within 90
hospital laboratories. Additionally, a number of minutes of collection.
meningeal-specific PCRs detect N. h CSF glucose concentrations will
meningitidis or S. pneumoniae nu- cleic acid in be higher in moderately to
CSF, as well as a number of other meningeal severely hyperglycemic patients.
pathogens, but 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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 Meningitis and Encephalitis

TABLE 3-2 CSF Abnormalities in Acute Meningitis

Type of
Meningitis Cellsa Protein Glucose Specific Diagnosis
Bacterial Polymorphonuclear Elevated G50% of Gram stain
meningitis leukocytes blood
Bacterial culture
glucose
PCR
Tuberculous Variable pleocytosis, Elevated G50% of Acid-fast stainb
meningitis usually with blood
PCR
lymphocytes 9 glucose
polymorphonuclear Culture
leukocytes
Fungal Lymphocytes Elevated G50% of Cryptococcal polysaccharide antigen
meningitis blood
Histoplasma polysaccharide antigen Coccidioides
glucose
immitis complement fixation antibody
India ink and culture
c
Viral Lymphocytes Elevated 950% of Reverse transcriptase PCR for enteroviruses
meningitis blood
PCR herpes simplex virus type 2
glucose
Immunoglobulin M (West Nile or other arboviruses)
a
Cell count, glucose, and protein may be minimally abnormal in patients who are severely immunocompromised.
b
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.

these are not routinely available. Speci- specific

fic diagnosis of the causative organism once the
of bacterial meningitis and determina- pathogen
tion of antibiotic sensitivity require has been
bacterial culture. Although this is rou- identified
tine in most hospitals, it may be help- and the
ful to alert the laboratory in advance results of
if anaerobic infection or other un- antimi-
usual organisms or culture require-
ments are anticipated. Yield on culture
can be reduced by prior antibiotic ther-
apy. Table 3-2 is a list of the expected
CSF results in meningitis due to bac-
teria, viruses, mycobacteria, and fungi.

Treatment of Acute Meningitis

Antibiotic therapy for bacterial men-
ingitis. Antibiotic therapy for bacterial
meningitis is initially empiric and then

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 Meningitis and Encephalitis
crobial sensitivity testing are known
(Table 3-3).
Therapy of chronic meningitis pre- senting 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, ther- apy 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 spon- taneously. The headache may persist for months
and can be managed with amitriptyline and nonsteroidal anti-
inflammatory agents. Limited data sug- gest that pleconaril may
shorten the

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 Meningitis and Encephalitis

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 Third-generation (ceftriaxone or

Adults over the age of 55
cefotaxime) or fourth-generation
Neisseria meningitidis
(cefepime) cephalosporin plus
vancomycin
S. pneumoniae Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
L. monocytogenes (cefepime) cephalosporin plus
Gram-negative bacilli vancomycin plus ampicillin
Haemophilus influenzae

Meningitis in the setting S. pneumoniae Third-generation (ceftriaxone or

of sinusitis, otitis, or known cefotaxime) or fourth-generation

CSF leak Haemophilus (cefepime) cephalosporin plus

Gram-negative bacilli vancomycin plus meropenem or
metronidazole
Anaerobic or microaerophilic streptococci
Bacteroides fragilis
S. aureus

Head trauma, neurosurgical S. aureus Vancomycin plus ceftazidime or

procedures, shunt infections vancomycin plus meropenem

Staphylococcus epidermidis
Gram-negative bacilli
S. pneumoniae

States of impaired cellular L. monocytogenes Third-generation (ceftriaxone or

immunity, including AIDS cefotaxime) or fourth-generation

Gram-negative bacilli (cefepime) cephalosporin plus

S. pneumoniae vancomycin plus ampicillin
H. influenzae

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 Meningitis and Encephalitis
duration of headache in enteroviral Corticosteroid therapy in meningi-
meningitis, but the drug is not rou- tis. The realization that neurologic injury
tinely available.5 Acyclovir is efficacious in bacterial meningitis is due to the host
in treating herpes simplex virus type 2 inflammatory response has led to a focus
(HSV-2) meningitis, and prophylactic on controlling this aspect of men-
therapy with acyclovir, valacyclovir, or ingitis. Early studies in children with
famciclovir is efficacious in preventing Haemophilus influenzae meningitis
recurrent meningitis due to HSV-2. who were treated with cefotaxime plus

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 Meningitis and Encephalitis

TABLE 3-4 Antimicrobial Therapy for Tuberculous Meningitisa

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

dexamethasone demonstrated an pend on its

effect on the CSF inflammatory re- use early in
sponse and a decreased incidence of the course
deafness compared with those treated of infection.
with cefotaxime alone.6 More recently,
studies from EuropeVincluding a na-
tionwide 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 ini-
tiation of antibiotic therapy (class III
evidence).7,8 Dexamethasone is given
as 10 mg intravenously, beginning im-
mediately 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 cru-
cial, and dexamethasone has not been
shown to be effective in less-developed
countries where patients tend to pres-
ent later in the course of their dis-
ease.8 The role of dexamethasone in
tuberculous or fungal meningitides is
less well established. In tuberculous
meningitis, dexamethasone has been re-
ported to decrease mortality but not
neurologic sequelae in survivors.9 As
with bacterial meningitis, however,
the utility of dexamethasone may de-

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 Meningitis and Encephalitis
Other measures to treat cerebral edema. Patients presenting
with papil- ledema or signs of impending brain herniation warrant
emergent treatment for increased intracranial pressure. Ele- vation
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 paraly- sis, 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 re- peated as needed every 3 to 4 hours or
0.25 g/kg every 2 to 3 hours. Pentobar- bital 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 involve- ment is diffuse rather than
focal. Surgery may be required, however, to drain an accompanying
brain abscess or para- meningeal focus of infection. For more
information, refer to the article Eval- uation and Management of
Increased Intracranial Pressure in this issue of .
Other complications of meningitis
requiring treatment. Bacterial menin- gitis may be accompanied
by a variety

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 Meningitis and Encephalitis

fungal meningitis are readily

of neurologic and systemic complica- the presence and development
available, but neurologists
tions, many of which may also occur in of in- creased opening pressure.
must be vigilant about
tuberculous meningitis. Bacterial men- Opening pressure should be
ingitis arising from sinusitis or otitis may measured at the time of the
be complicated by epidural abscess, initial lumbar puncture and any
subdural empyema, brain abscess, or time a change in the neurologic
venous sinus thrombosis, any of which ex- amination occurs. A time-
may require emergent surgery. Seizures honored prac- tice has been to
require emergent treatment with lora- perform daily lumbar punctures
zepam, phenytoin (fosphenytoin), or and reduce the opening pres- sure
more aggressive therapy such as phe- by 50% using a manometer. In
nobarbital or pentobarbital coma in reality, daily lumbar punctures are
patients who fail to respond. Hypona- often not effective, and it is best
tremia may be caused by cerebral salt to use a ventriculostomy instead.
wasting, the syndrome of inappropriate
secretion of antidiuretic hormone, or IV Pro
fluids. Subdural effusions are common gno
in children with meningitis; these do sis
not usually require drainage and may be In most series, mortality has
followed by CT or MRI. Patients may correlated with obtundation or
develop cerebral vasculitis, stroke, or coma. Factors as- sociated with
spontaneous intracranial hemorrhage.10 poor prognosis include age
Myelitis, although not usually consid- older than 60 years,
ered a complication of bacterial men- concomitant debilitating
ingitis, has been reported in 2.3% of diseases, low Glasgow Coma
patients with pneumococcal meningi- Scale score on admission, focal
tis.10 Bacterial sepsis and shock may be neurologic deficits, and low
present, as may disseminated in- CSF cell count.10Y12 Seizures
travascular coagulation, and, in the have predicted a worse outcome
case of N. meningitidis, Waterhouse- in some studies, as has low
Friderichsen syndrome with wide- CSF:serum glucose ratio.11
spread hemorrhage and adrenal failure. Mortal- ity in tuberculous
Cases of meningitis associated with meningitis is in the range of
S. aureus and, less often, S. pneumo- 25%, with good recovery in only
niae may be a complication of bacterial 50% of patients.13 As in
endocarditis. Meningitis in the presence bacterial meningitis, prognosis is
of S. pneumoniae endocarditis is often significantly influenced by the
accompanied by rapid destruction of level of conscious- ness on
the aortic valve. Basilar meningitis with presentation and the rapid
basal ganglia ischemia or infarction can institution of appropriate
occur in both tuberculous meningitis and therapy. Viral meningitis is
cryptococcal meningitis. The basilar men- usually self-limited.
ingitis that occurs in tuberculous menin-
gitis may produce obstructive rather than ENCEPH
communicating hydrocephalus. ALITIS
Fungal meningitis. Recommenda- In patients with an altered level
tions for the antimicrobial therapy of of consciousness or an acute
confusional state, the first

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 Meningitis and Encephalitis
question to ask is whether the patient has KEY POINTS
encephalitis or an encephalopathy. If the patient h In the patient with basilar
has encephalitis, the next question to ask is whether meningitis with basal
ganglia
he or she has encephalitis that can be treated with
ischemia or infarction,
antimicrobial agents or encephalitis that is treated tuberculous meningitis and
with sup- portive care only (Case 3-3). cryptococcal meningitis should
be considered.
Etiology
h In patients with bacterial,
The presence of fever and headache with an
mycobacterial, or fungal
altered level of consciousness makes encephalitis meningitis, prognosis is
more likely than influenced by the level of
consciousness at the time of
presentation
and the rapidity of
antimicrobial therapy
initiation.

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 Meningitis and Encephalitis

KEY POINTS
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.
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.
Case 3-3
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.

encephalopathy. The etiologic organ-
ism 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 infec-
tion), (3) area of residence, (4) travel
and occupational and recreational activ-
ities, (5) rash (eg, varicella, meningo-
coccemia, Rocky Mountain spotted
fever), (6) contact with animals, and
(7) immunosuppression from medica-
tions, malignancy, chronic corticoste-
roid use, or organ transplantation.14
The most common identifiable etio-
logic 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
Nile virus, and rabies have been trans-
mitted from organ donor to recipient.
Clinical Presentation
Patients with encephalitis have fever
and headache and one or more of the
following: confusion, behavioral ab-
normalities, depressed level of con-
sciousness, 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 macu-
lopapular rash. The three most clini-
cally 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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 Meningitis and Encephalitis

Varicella-zoster virus presents with focal in the temporal lobe on T2-weighted images, fluid-attenuated
neurologic deficits due to ischemic and inversion re-
hemorrhagic infarctions. Although vari-
cella-zoster virus encephalitis may follow
shingles, encephalitis due to varicella-
zoster 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 causa-
tive spirochete of Lyme disease in North
America, does not cause encephalitis.
Thus, the appearance of a single erythe-
matous lesion on the trunk or extrem-
ities is not a clue to the etiologic agent.

Diagnosis
Although the specific tests for encepha-
litis are magnetic resonance (MR) scan,
CSF analysis, blood cultures, and com-
plete blood count with differential and
serologies, routine tests for encephal-
opathy 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 immunoglobu-
lin G [IgG] titers) cannot be overstated.
One of the biggest impacts that PCR has
had on the diagnosis of neurologic in-
fectious 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 abnormali-
ties in diagnosing encephalitis.
Herpes simplex virus type 1. In 90%
of adults with HSV encephalitis, an area
of increased signal intensity is seen

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 Meningitis and Encephalitis
covery should be obtained to de- termine
(FLAIR) whether intrathecal synthesis of
sequences, antibodies is present. A serum:CSF ratio
and diffusion- of less than 20:1 is diagnostic of HSV
weighted encephalitis. It takes at least 8 days
imaging MR for antibodies to be detected in CSF,
scan within and antibodies may be detectable for up
48 hours of to 3 months. The EEG demon- strates
symptom periodic sharp-and-slow wave
onset complexes occurring at regular 1- to
(Figure 3-1). 3-second intervals. These abnormalities
CSF analysis are most typically seen between the
demonstrate second and fifteenth days of illness.
s a lympho- For HSV-1 encephalitis, CSF PCR
cytic for HSV-1 and CSF and serum anti-
pleocytosis bodies should be sent.
with a
normal
glucose
concentratio
n. Red blood
cells or xan-
thochromia
may be seen
in the CSF
as this is
hemorrhagic,
necrotic
encepha-
litis. The
CSF PCR
may be
falsely FIGURE 3-1 T2-weighted MRI demonstrating
negative in a hyperintensity in the left
temporal lobe in a patient with
the first 72 herpes simplex virus type 1 encephalitis.
hours of
HSV
encephalitis
symptoms,
and
detection
rates
decrease 10
days after
the onset of
symptoms.
Serum and
CSF HSV
IgG
antibodies

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 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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diagnose cytomegalovirus encephalitis,
Varicella-zoster virus. The best diag-
nostic test for varicella-zoster virus en-
cephalitis is the detection of varicella-
zoster virus IgM in CSF.
Mosquitoborne viruses. In encepha-
litis due to any of the flaviviruses, hy-
perintense lesions may be seen in the
thalami, substantia nigra, and basal gan-
glia on T2-weighted and FLAIR sequen-
ces. 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 en-
cephalitides, acute and convalescent serol-
ogy 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 vi-
rus 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 neg-
ative 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 infec-
tions 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 leukoence-
phalopathy. The CSF should be non-
inflammatory. To diagnose progressive
multifocal leukoencephalopathy, CSF
PCR should be sent for JC virus DNA;
sensitivity may only be around 60%.
Cytomegalovirus encephalitis. To
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 Meningitis and Encephalitis
headache, confusion,
CSF PCR for
cytomegalovirus behavioral
nucleic acid should be abnormalities, gait
abnormalities, and
sent. involuntary movements.
CSF analysis demonstrates a
T
h lymphocytic pleocytosis with
e an increased protein
r concentration and a normal
a glucose concentration. The
p hyperintensity in the temporal
y lobe on T2-weighted and
FLAIR MR images of
HSV-1 encephalitis
paraneoplastic limbic
is treated with
encephalitis has a similar
10 mg/kg of IV
appearance to that of HSV-1
acyclovir every 8
hours for 3 weeks. encephalitis. Serology and
Varicella-zoster virus CSF should be sent for
ence- phalitis is treated antineuronal antibodies, and,
with 10 mg/kg of IV when positive, diagnostic
acyclovir every 8 hours studies should be performed
for 10 to 14 days. for the malignancy asso-
Acyclovir is not ciated with the antineuronal
recommended for antibody.
EBV encephalitis, as Nonvasculitic
it is felt to provide autoimmune inflam- matory
little or no benefit.15 meningoencephalitis
Rocky Mountain (NAIM) steroid-responsive
spotted fever is treated encephalopathy (previously
with 100 mg of referred to as Hashimoto
doxycycline twice encephalopathy) has been
daily for at least associated with a number of
3 days after the antibodies, including
patient becomes afe- thyroperoxidase antibodies,
brile. Cytomegalovirus thyroid microsomal
encephalitis is treated antibodies, thyroglobulin
with a combination of antibodies, extractable
60 mg/kg of IV nuclear anti- gen antibodies,
foscarnet every 8 hours antistriatal antibodies,
and 5 mg/kg of IV antinuclear antibodies,
ganciclovir every 12 antiphospholi- pid
hours. antibodies, and gliadin
antibodies.
Noninfectious
Encephalitis
Patients with
noninfectious
encephalitis have

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 Meningitis and Encephalitis
NAIM is treated with 1000 mg of IV
methylprednisolone for 5 days followed
by oral prednisone therapy.
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