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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.
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%
Continued on page 1012
KEY POINTS
h Empiric therapy for
tuberculous meningitis
Continued from page 1011
should be initiated in
polymorphonuclear leukocytes and 55% mononuclear cells, a protein of
patients with fever,
230 mg/dL, and a glucose of 30 mg/dL. No organisms were seen on Gram
headache, and stiff
stain, and both acid-fast smear and PCR for mycobacteria were negative.
neck; a CSF lymphocytic
The patient was treated with isoniazid (300 mg/d), rifampin (600 mg/d),
pleocytosis; and a mild
pyrazinamide (2 g/d), and ethambutol (2.5 g/d) on suspicion of tuberculous
to moderate decrease in
meningitis. CSF was obtained by high cervical puncture, and 3 weeks later
glucose concentration
Mycobacterium tuberculosis grew in culture. A chest x-ray demonstrated
(less than 40 mg/dL but
innumerable small pulmonary opacities consistent with miliary tuberculosis.
greater than 20 mg/dL).
Comment. Ancillary studies such as a chest radiograph are helpful in
h Cases of mycobacterial patients with CNS infections. Skin testing with purified protein derivative
or fungal meningitis may initially be negative but then become positive as the patient improves
presenting acutely may during the course of therapy. In patients with fungal or tuberculous
resemble bacterial meningitis, a high cervical puncture may demonstrate the organism when
meningitis. 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.
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.
Continued on page 1014
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- when other tests are negative. It is im-
tance to passive extension of the leg at portant to keep in mind that elderly
the knee is present. Although Brudzinski patients with extensive cervical spine
developed several tests to detect menin- disease may have neck stiffness, and
geal irritation, the maneuver most com- occasionally patients with influenza and
monly referred to as Brudzinski sign severe myalgias may also report neck
involves spontaneous flexion of the hips pain. In both groups of patients, pain
and knees when the neck is passively and resistance to movement usually oc-
flexed. Brudzinski sign is the more sen- cur not only upon flexion but also upon
sitive of the two. Both signs, when pres- lateral rotation. Patients with meningi-
ent, are strongly suggestive of meningeal tis, however, can usually turn the head
irritation; however, they were developed even if neck stiffness to flexion is pres-
in the preantibiotic era when meningitis ent. Particular attention should be paid
was frequently advanced at the time of to the presence of cutaneous rashes,
presentation and may not be detected petechiae, or purpura suggestive of me-
early in the course of infection. In awake ningococcemia; pulmonary consolida-
patients, a more sensitive test is to ask tion suggestive of pneumonia due to
patients to put their chin on their chest S. pneumoniae; or cardiac murmurs
with the mouth closed. Keeping the suggestive of endocarditis.
mouth closed is important, because
patients experiencing pain on flexion Atypical Presentations
may hold their neck still but touch their of Meningitis
chin to their chest by opening the jaw In neonates, bacterial meningitis may
widely. One of the most sensitive tests present with tachypnea, apneic spells,
of nuchal rigidity is a test that was de- changes in heart rate, atypical seizures,
veloped during the days of the polio or simply vague decline. Although a
epidemic and involves asking the pa- feeble, high-pitched cry in an infant has
tient to kiss his or her knee (in children, been said to suggest meningitis, this is
who consider this request perfectly not a reliable sign. Similarly, a bulging
reasonable) or, in adults, to touch the fontanelle is a late sign, indicating sig-
forehead to the knee. This test will of- nificantly increased intracranial pressure.
ten detect meningeal irritation at a time Individuals who are immunocompromised,
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- crobial sensitivity testing are known
fic diagnosis of the causative organism (Table 3-3).
of bacterial meningitis and determina- Therapy of chronic meningitis pre-
tion of antibiotic sensitivity require senting acutely. Specific diagnosis of
bacterial culture. Although this is rou- tuberculous meningitis can be difficult:
tine in most hospitals, it may be help- yield by PCR approaches 50%, and
ful to alert the laboratory in advance sensitivity of culture (which may take
if anaerobic infection or other un- up to 6 weeks) is only 70%.4 Thus, ther-
usual organisms or culture require- apy for tuberculous meningitis should
ments are anticipated. Yield on culture be initiated presumptively if the diagnosis
can be reduced by prior antibiotic ther- is suspected (Table 3-4). Treatment of
apy. Table 3-2 is a list of the expected fungal meningitis is usually not begun
CSF results in meningitis due to bac- empirically unless organisms are seen
teria, viruses, mycobacteria, and fungi. in CSF.
Treatment of viral meningitis. Most
Treatment of Acute Meningitis cases of viral meningitis resolve spon-
Antibiotic therapy for bacterial men- taneously. The headache may persist
ingitis. Antibiotic therapy for bacterial for months and can be managed with
meningitis is initially empiric and then amitriptyline and nonsteroidal anti-
specific once the pathogen has been inflammatory agents. Limited data sug-
identified and the results of antimi- gest that pleconaril may shorten the
a
TABLE 3-4 Antimicrobial Therapy for Tuberculous Meningitis
KEY POINTS
h The most common
identifiable etiologic
Case 3-3
A 20-year-old college junior was brought to the emergency department by
organisms of
her boyfriend because of a 3-day history of fever, headache, and
encephalitis are
intermittent confusion. On examination, she had a temperature of 38-C
herpesviruses
(100.4-F), was oriented to self but not to date or place, and had difficulty
(eg, herpes simplex
following commands. The boyfriend denied alcohol or illicit drug use.
virus type 1 or
Complete blood count with differential was normal. Noncontrast cranial
varicella-zoster virus),
CT scan was normal. CSF analysis demonstrated 100 white blood cells/mm3,
a tickborne bacterial
lymphocytic predominance, 700 red blood cells/mm3, a glucose
infection, or an
concentration of 47 mg/dL, and a protein concentration of 56 mg/dL.
arthropodborne virus.
The patient was treated empirically with acyclovir for herpes simplex virus
h Neuroinvasive disease (HSV) encephalitis based on her clinical presentation and CSF analysis. CSF
due to West Nile virus, PCR for HSV-1 DNA was obtained as well as serum and CSF immunoglobulin G
St. Louis encephalitis (IgG) antibodies to determine a serum:CSF antibody ratio.
virus, or Japanese Comment. The CSF PCR should be positive, as she is 3 days into her illness,
encephalitis virus but it is likely too early to detect the intrathecal synthesis of antibodies.
may present with Antibodies do not appear in CSF until 8 days after symptom onset but may
encephalitis, a flaccid, be detectable for up to 3 months. HSV IgG on serum and CSF should be
weak limb (a obtained. A serum:CSF ratio of less than 20:1 is diagnostic of HSV encephalitis.
poliomyelitis syndrome), Fluid-attenuated inversion recovery (FLAIR) sequences and diffusion-weighted
or parkinsonian imaging (DWI) magnetic resonance scans are indicated and would be
features. 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- Nile virus, and rabies have been trans-
ism of the encephalitis can be predicted mitted from organ donor to recipient.
based on the following: (1) the time of
year, (2) prodromal symptoms (eg, Clinical Presentation
flulike illness in West Nile virus infec- Patients with encephalitis have fever
tion), (3) area of residence, (4) travel and headache and one or more of the
and occupational and recreational activ- following: confusion, behavioral ab-
ities, (5) rash (eg, varicella, meningo- normalities, depressed level of con-
coccemia, Rocky Mountain spotted sciousness, focal neurologic deficits,
fever), (6) contact with animals, and and new-onset seizure activity.
(7) immunosuppression from medica- Certain features, or a combination
tions, malignancy, chronic corticoste- of features, suggest a specific etiology.
roid use, or organ transplantation.14 Patients with West Nile virus may have a
The most common identifiable etio- tremor, a history of diarrhea, or a macu-
logic organisms of encephalitis are lopapular rash. The three most clini-
the reactivation of a latent herpesvirus cally significant flaviviruses (West Nile
infection (eg, HSV-1 or varicella-zoster virus, St. Louis encephalitis virus, and
virus), a tickborne bacterial infection, or Japanese encephalitis virus) may present
an arthropodborne virus. with a flaccid, weak limb (a poliomyelitis
In the organ transplant recipient, it is syndrome) or parkinsonian features.
critical to obtain the donor history from Confusion and word-finding difficulty
the donor’s file. Cytomegalovirus, West are common in HSV-1 encephalitis.
1020 www.aan.com/continuum October 2011
KEY POINTS
h To diagnose herpes Varicella-zoster virus. The best diag- CSF PCR for cytomegalovirus nucleic
simplex virus type 1 nostic test for varicella-zoster virus en- acid should be sent.
encephalitis, CSF PCR cephalitis is the detection of varicella-
for herpes simplex virus zoster virus IgM in CSF. Therapy
type 1 and CSF and Mosquitoborne viruses. In encepha- HSV-1 encephalitis is treated with
serum antibodies should litis due to any of the flaviviruses, hy- 10 mg/kg of IV acyclovir every 8 hours
be obtained. perintense lesions may be seen in the for 3 weeks. Varicella-zoster virus ence-
h The best diagnostic thalami, substantia nigra, and basal gan- phalitis is treated with 10 mg/kg of IV
test for varicella-zoster glia on T2-weighted and FLAIR sequen- acyclovir every 8 hours for 10 to 14 days.
virus encephalitis ces. The best test for West Nile virus Acyclovir is not recommended for EBV
is the detection of encephalitis is the detection of CSF IgM encephalitis, as it is felt to provide
varicella-zoster virus antibodies specific for the virus. Serum little or no benefit.15 Rocky Mountain
immunoglobulin M IgM and IgG antibodies cannot be used spotted fever is treated with 100 mg of
in CSF. to diagnose neuroinvasive disease. doxycycline twice daily for at least
For the other mosquitoborne viral en- 3 days after the patient becomes afe-
cephalitides, acute and convalescent serol- brile. Cytomegalovirus encephalitis is
ogy remain the mainstay of diagnosis. treated with a combination of 60 mg/kg
Epstein-Barr virus. Diagnosis of of IV foscarnet every 8 hours and 5 mg/kg
Epstein-Barr virus (EBV) depends on a of IV ganciclovir every 12 hours.
combination of serology and CSF PCR.
If serology demonstrates a positive vi- Noninfectious Encephalitis
rus capsid antigen (VCA) and negative Patients with noninfectious encephalitis
Epstein-Barr nuclear antigen (EBNA) and have headache, confusion, behavioral
the CSF PCR for EBV DNA is positive, abnormalities, gait abnormalities, and
a diagnosis of EBV encephalitis can be involuntary movements. CSF analysis
made. If serology demonstrates a neg- demonstrates a lymphocytic pleocytosis
ative VCA IgM and a positive EBNA and with an increased protein concentration
the CSF PCR is positive, a diagnosis of and a normal glucose concentration.
EBV encephalitis cannot be made, as the The hyperintensity in the temporal lobe
CSF PCR may be positive for EBV nucleic on T2-weighted and FLAIR MR images
acid in an immunocompetent individual of paraneoplastic limbic encephalitis has
in any inflammatory CNS disorder. a similar appearance to that of HSV-1
Rocky Mountain spotted fever. The encephalitis. Serology and CSF should
serologic tests for the rickettsial infec- be sent for antineuronal antibodies, and,
tions have a low sensitivity early in the when positive, diagnostic studies should
disease. It is important to biopsy any skin be performed for the malignancy asso-
lesions that are present and to repeatedly ciated with the antineuronal antibody.
send serology. A number of different Nonvasculitic autoimmune inflam-
serologic tests are available, including the matory meningoencephalitis (NAIM)
indirect fluorescent antibody test, ELISA, steroid-responsive encephalopathy
and flow immunoassays. (previously referred to as Hashimoto
Progressive multifocal leukoence- encephalopathy) has been associated
phalopathy. The CSF should be non- with a number of antibodies, including
inflammatory. To diagnose progressive thyroperoxidase antibodies, thyroid
multifocal leukoencephalopathy, CSF microsomal antibodies, thyroglobulin
PCR should be sent for JC virus DNA; antibodies, extractable nuclear anti-
sensitivity may only be around 60%. gen antibodies, antistriatal antibodies,
Cytomegalovirus encephalitis. To antinuclear antibodies, antiphospholi-
diagnose cytomegalovirus encephalitis, pid antibodies, and gliadin antibodies.
1022 www.aan.com/continuum October 2011