Review Article

Meningitis and
Address correspondence to
Dr John E. Greenlee, Clinical
Neuroscience Center, 175 N
Medical Drive E, 5th Floor, Salt
Lake City, UT 84132,
john.greenlee@hsc.utah.edu.
Relationship Disclosure:
Encephalitis
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.

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INTRODUCTION trauma or neurosurgical procedures or

Meningitis and encephalitis are neuro-
logic emergencies. In the hospital set-
ting, the initial realization that a patient
has a CNS infectious disease is usually
made by the emergency department phy-
sician or, if the patient is already ad-
mitted, by the primary service. For this
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,
or mastoid. Bacteria may enter the sub-
arachnoid space following penetrating
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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 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 be due to
at the time of birth, and meningitis often who have undergone splenectomy) are at
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
monocytogenes.
tis, or mastoiditis may be due to strepto- capsulatum, Coccidioides immitis, or
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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 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
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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
October 2011

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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
with viral meningitis, who is not at risk
for additional complications.
Bedside Diagnosis
of Meningitis
Bacterial meningitis should be consid-
ered 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.
Continued on page 1014

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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 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 resis-
tance to passive extension of the leg at
the knee is present. Although Brudzinski
developed several tests to detect menin-
geal irritation, the maneuver most com-
monly referred to as Brudzinski sign
involves spontaneous flexion of the hips
and knees when the neck is passively
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
forehead to the knee. This test will of-
ten detect meningeal irritation at a time
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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such as neonates, may not develop fever
or nuchal rigidity. Patients with alcohol-
ism 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 proce-
dures 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 sus-
pected on the basis of the clinical
presentation and physical examination
findings, definitive diagnosis is made by
analysis of the CSF. If intracranial pres-
sure 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 sus-
pected, the most prudent course is to
begin empiric therapy and wait until
CSF pressure has been controlled be-
fore 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, cul-
ture, and PCR. Simultaneous blood glu-
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KEY POINTS
cose should also be sent to determine h The causative organisms
the CSF:blood glucose ratio. Expedi- of bacterial meningitis
tious handing of CSF by the laboratory can often be detected in
is important because cells may adhere blood cultures.
to the collecting tube over time, result- h CSF should be
ing in lower CSF cell counts, and examined for white
leukocytes may lyse in extremely puru- blood cells within 90
lent CSF.4 minutes of collection.
Typical CSF findings in bacterial h CSF glucose
meningitis include elevated opening concentrations will be
pressure, fluid that is often, but not higher in moderately to
always, turbid, elevated white blood cell severely hyperglycemic
count consisting predominantly of poly- patients. In these
morphonuclear leukocytes, elevated patients, the CSF:blood
protein concentration, and depressed glucose ratio should be
CSF:blood glucose ratio. A CSF:blood used to determine the
glucose ratio of less than 0.3 is highly true CSF glucose
correlated with bacterial meningitis. In concentration. The CSF
glucose concentration
evaluating CSF glucose concentrations,
is low when the
it is important to remember that CSF
CSF:blood glucose ratio
glucose values will be higher in moder- is less than 0.6.
ately to severely hyperglycemic patients
and that changes in CSF glucose con- h CSF bacterial PCRs are
increasingly available.
centrations may lag 30 to 120 minutes
Specific diagnosis of the
behind those in blood. Protein con- causative organism of
centrations in meningitis are a reflec- bacterial meningitis and
tion of blood-brain barrier injury but determination of
usually range between 100 mg/dL and antibiotic sensitivity
500 mg/dL.4 require bacterial culture.
Specific identification of the infect-
ing organism involves Gram stain, cul-
ture, 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 de-
colorization or reading of the slide.
A 16S ribosomal RNA conserved se-
quence broad-based bacterial PCR is
routinely available in most hospital
laboratories. Additionally, a number
of meningeal-specific PCRs detect
N. meningitidis or S. pneumoniae nu-
cleic acid in CSF, as well as a number
of other meningeal pathogens, but
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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-
fic diagnosis of the causative organism
of bacterial meningitis and determina-
tion of antibiotic sensitivity require
bacterial culture. Although this is rou-
tine in most hospitals, it may be help-
ful to alert the laboratory in advance
if anaerobic infection or other un-
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
specific once the pathogen has been
identified and the results of antimi-
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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TABLE 3-3 Antibiotics for Empiric Therapy of Bacterial Meningitis
Age and Associated
Conditions
Preterm infants
Neonates
Children and adults
Adults over the age of 55
Meningitis in the setting
of sinusitis, otitis, or known
CSF leak
Head trauma, neurosurgical
procedures, shunt infections
States of impaired cellular
immunity, including AIDS
duration of headache in enteroviral
meningitis, but the drug is not rou-
tinely 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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Probable Organism Antibiotic Therapy
Staphylococcus aureus (nosocomial) Vancomycin plus ceftazidime
Gram-negative bacilli
Group B streptococci Ampicillin plus cefotaxime
Escherichia coli
Other gram-negative bacilli
Listeria monocytogenes
Streptococcus pneumoniae Third-generation (ceftriaxone or
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
S. pneumoniae Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
Haemophilus
(cefepime) cephalosporin plus
Gram-negative bacilli vancomycin plus meropenem or
metronidazole
Anaerobic or microaerophilic streptococci
Bacteroides fragilis
S. aureus
S. aureus Vancomycin plus ceftazidime or
vancomycin plus meropenem
Staphylococcus epidermidis
Gram-negative bacilli
S. pneumoniae
L. monocytogenes Third-generation (ceftriaxone or
cefotaxime) or fourth-generation
Gram-negative bacilli
(cefepime) cephalosporin plus
S. pneumoniae vancomycin plus ampicillin
H. influenzae
Corticosteroid therapy in meningi-
tis. 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 men-
ingitis. Early studies in children with
Haemophilus influenzae meningitis
who were treated with cefotaxime plus
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 Meningitis and Encephalitis
TABLE 3-4 Antimicrobial Therapy for Tuberculous Meningitis
Drug Usual Daily Dose
Isoniazid 5 mg/kg to 10 mg/kg
Rifampin 10 mg/kg to 20 mg/kg
Pyrazinamide 15 mg/kg to 30 mg/kg
Ethambutol 15 mg/kg to 25 mg/kg
Streptomycin 15 mg/kg
a
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 re-
sponse and a decreased incidence of
deafness compared with those treated
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-
pend on its use early in the course of
infection.
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a
Maximum Dose Duration
300 mg 6 to 9 months
600 mg 6 months
2000 mg 2 months
2500 mg 2 months
1000 mg 2 months
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
October 2011

of neurologic and systemic complica-
tions, many of which may also occur in
tuberculous meningitis. Bacterial men-
ingitis 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 lora-
zepam, phenytoin (fosphenytoin), or
more aggressive therapy such as phe-
nobarbital or pentobarbital coma in
patients who fail to respond. Hypona-
tremia 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 consid-
ered a complication of bacterial men-
ingitis, has been reported in 2.3% of
patients with pneumococcal meningi-
tis.10 Bacterial sepsis and shock may be
present, as may disseminated in-
travascular coagulation, and, in the
case of N. meningitidis, Waterhouse-
Friderichsen syndrome with wide-
spread hemorrhage and adrenal failure.
Cases of meningitis associated with
S. aureus and, less often, S. pneumo-
niae 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 men-
ingitis that occurs in tuberculous menin-
gitis may produce obstructive rather than
communicating hydrocephalus.
Fungal meningitis. Recommenda-
tions for the antimicrobial therapy of
fungal meningitis are readily available,
but neurologists must be vigilant about
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KEY POINTS
the presence and development of in- h In the patient with
creased opening pressure. Opening basilar meningitis
pressure should be measured at the with basal ganglia
time of the initial lumbar puncture and ischemia or infarction,
any time a change in the neurologic ex- tuberculous meningitis
amination occurs. A time-honored prac- and cryptococcal
tice has been to perform daily lumbar meningitis should be
punctures and reduce the opening pres- considered.
sure by 50% using a manometer. In h In patients with
reality, daily lumbar punctures are often bacterial, mycobacterial,
not effective, and it is best to use a or fungal meningitis,
ventriculostomy instead. prognosis is influenced
by the level of
Prognosis consciousness at the
time of presentation
In most series, mortality has correlated
and the rapidity of
with obtundation or coma. Factors as-
antimicrobial therapy
sociated with poor prognosis include initiation.
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 Mortal-
ity 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 conscious-
ness on presentation and the rapid
institution of appropriate therapy. Viral
meningitis is usually self-limited.
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 sup-
portive care only (Case 3-3).
Etiology
The presence of fever and headache
with an altered level of consciousness
makes encephalitis more likely than
www.aan.com/continuum 1019
 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 donor’s file. Cytomegalovirus, West
1020 www.aan.com/continuum
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.
October 2011

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Varicella-zoster virus presents with focal
neurologic deficits due to ischemic and
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
in the temporal lobe on T2-weighted
images, fluid-attenuated inversion re-
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covery (FLAIR) sequences, and diffusion-
weighted imaging MR scan within 48
hours of symptom onset (Figure 3-1).
CSF analysis demonstrates a lympho-
cytic pleocytosis with a normal glucose
concentration. 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
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 de-
termine 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 demon-
strates 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 anti-
bodies should be sent.
FIGURE 3-1 T2-weighted MRI demonstrating
a hyperintensity in the left
temporal lobe in a patient with
herpes simplex virus type 1 encephalitis.
www.aan.com/continuum 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.
1022 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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
diagnose cytomegalovirus encephalitis,
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 ence-
phalitis 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 afe-
brile. 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 asso-
ciated with the antineuronal antibody.
Nonvasculitic autoimmune inflam-
matory 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 anti-
gen antibodies, antistriatal antibodies,
antinuclear antibodies, antiphospholi-
pid antibodies, and gliadin antibodies.
October 2011
NAIM is treated with 1000 mg of IV
methylprednisolone for 5 days followed
by oral prednisone therapy.
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