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Aseptic meningitis

Handbook of Clinical Neurology, Vol. 112 (3rd series)
Pediatric Neurology Part II
O. Dulac, M. Lassonde, and H.B. Sarnat, Editors
© 2013 Elsevier B.V. All rights reserved
Chapter 119
Aseptic meningitis
Department of Medicine, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA
Meningitis refers to inflammation of the cerebrospinal
fluid (CSF) and the meninges that surround the brain
and spinal cord (Fig.119.1). Aseptic meningitis or viral
meningitis cases occur at any age but are most common
in infants and young children. Most cases of aseptic
meningitis have a benign, self-limited course with
maximal symptom duration of 1–2 weeks. The youngest
patients, particularly neonates within the first few weeks
of life, typically have the most severe symptoms. Meningoencephalitis occurs when infection involves the brain
parenchyma as well as the meninges.
Young children and infants with meningitis may present
with nonspecific signs: fever, irritability, lethargy, poor
feeding, or vomiting (Rittichier et al., 2005). Older children with meningitis may present with fever, photophobia, headache, or stiff neck. Seizures are most common
with herpes meningoencephalitis. Physical examination
findings such as the Brudzinski sign (active flexion of
the neck results in passive flexion of the patient’s hip)
and Kernig sign (pain with knee extension when the
hip is flexed), although rare, are highly suggestive of
A lumbar puncture is diagnostic of meningitis and should
be performed as soon as the patient’s clinical stability
allows. Head computed tomography prior to lumbar
puncture need not be performed routinely, but should
be considered when the child has evidence of increased
intracranial pressure or a fucal neurologic exon because
of the risk of subsequent cerebral herniation. Signs of
increased intracranial pressure include a bulging fontanel,
blurred optic disk margins, or any focal neurological
deficit. Antibiotic pretreatment prior to diagnostic evaluation for possible meningitis should lower the clinical
threshold to perform a diagnostic lumbar puncture due
to the potential of partially treated bacterial meningitis.
A case of aseptic meningitis is defined by the presence
of CSF pleocytosis (CSF white blood cell (WBC) 10
cells/mm3) with a negative CSF bacterial culture in a
patient who has not received prior antibiotics. Bleeding
due to traumatic insertion of the lumbar puncture needle
complicates the interpretation of the CSF analysis due to
the introduction of both red blood cells (RBCs) and
WBCs. Although several methods of correcting CSF
WBCs for the presence of RBCs have been developed,
none of these methods can accurately identify all cases
of meningitis (Bonadio et al., 1990). Use of local anesthetic and removal of the catheter stylet after the lumbar
puncture needle pierces the skin are modifiable procedural factors that have been shown to reduce the rate
of traumatic lumbar puncture (Nigrovic et al., 2007b).
In the era of widespread vaccinations against bacterial
pathogens, most cases of meningitis are caused by viral
not bacterial infection. Enteroviruses are picornaviruses
which are responsible for the vast majority of aseptic
meningitis cases (85–95% of cases in which a pathogen
is identified; Lee et al., 2006). The picornavirus family
includes echovirus, Coxsackie A and B viruses, as well
as the polioviruses. Poliovirus, although exceedingly rare
due to effective widespread vaccination, results in selective destruction of the motor neurons leading to flaccid
paralysis. Enterovirus 71 has been linked to several
recent outbreaks of encephalitis with high associated
mortality. Although these infections occur year round,
peak yearly incidence in temperate climates occurs
*Correspondence to: Lise E. Nigrovic, M.D., M.P.H., Assistant Professor of Pediatrics, Department of Medicine, Children’s
Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: þ1-617-355-6363,
Fax: þ1-617-730-0335, E-mail: [email protected]
Fig.119.1. Cross-sectional anatomy. Meningitis is caused by inflammation of cerebrospinal fluid (CSF) and the meninges that
surround the brain and spinal cord. Reprinted with permission from Torpy et al., 2007. Copyright 2007 American Medical
during the summer and fall months (June through
October). Transmission of the enteroviruses occurs via
the fecal–oral route, although inhalation of infected
droplets has also been reported. The incubation period
is usually 3–6 days.
Other less common viral causes include the following:
Epstein–Barr virus, herpes simplex, human paraechovirus, mumps, and varicella-zoster virus. Aseptic meningitis may also be caused by nonviral infections
(Bartonella henselae (cat scratch disease), Borrelia
burgdorferi (Lyme disease), Cryptococcus, Mycobacterium tuberculosis (Mollaret’s meningitis), Rickettsia
species, Mycoplasma pneumoniae) or noninfectious
entities (drugs, autoimmune/collagen vascular diseases,
Kawasaki disease).
Definitive discrimination between aseptic and bacterial
meningitis depends on the results of the CSF culture;
it takes 2–3 days to exclude bacterial growth reliably.
Meningeal signs (defined by the presence of neck stiffness, Kernig’s or Brudinski’s sign, or bulging fontanelle
in an infant) are associated with the presence of bacterial
meningitis but also aseptic meningitis, pneumonia, deep
neck-space infections, as well as other self-limiting diseases such as myalgias or torticollis.
Clinicians use CSF results to distinguish bacterial
from aseptic meningitis. CSF Gram stain is the best
single predictor with a sensitivity of approximately
65% depending on the bacterial pathogen and the colony
count. Other CSF parameters such as WBC count, glucose, or protein have a wide zone of overlap between
bacterial and aseptic meningitis. Biomarkers such as
C-reactive protein or CSF lactate may not show elevation
early in bacterial disease and may also be elevated in
patients with viral infections. Recent studies suggest that
procalcitonin (which is in widespread clinical usage in
Europe but not the USA) may have a role in discriminating
between aseptic and bacterial meningitis, although further
investigations are needed (Dubos et al., 2006a). Enteroviral polymerase chain reaction (EV-PCR), however,
provides a means to identify positively cases of viral meningitis. A new commercially available PCR testing platform can provide clinicians with EV-PCR results within
a few hours, having the potential to affect management
decisions about antibiotic administration and disposition
(Ramers et al., 2000; Archimbaud et al., 2009).
Multivariate clinical prediction rules combine readily
available clinical and laboratory parameters to distinguish cases of bacterial from aseptic meningitis. One
meningitis prediction rule (the Bacterial Meningitis
Score) was validated on a large multicenter cohort in
the era of widespread conjugate pneumococcal vaccination. This prediction rule identifies a group of patients at
very low risk of bacterial meningitis if they lack all of the
high-risk criteria (Table 119.1; Nigrovic et al., 2002,
2007a) and has now been validated in eight published
studies (Nigrovic et al., 2012). Application of a validated
meningitis decision rule has the potential to help clinicians improve the care of children with CSF pleocytosis
Table 119.1
Bacterial Meningitis Score: five high-risk criteria
Positive CSF Gram stain
CSF absolute neutrophil count (ANC) 1000 cells/mm3
CSF protein 80 mg/dL
Peripheral blood ANC 10 000 cells/mm3
Presence of a seizure at or prior to presentation
From Nigrovic et al. (2007a).
by identifying a subset of patients at very low risk of bacterial meningitis who could, in the appropriate clinical
context, be managed as outpatients after strong consideration of administration of a long-acting parenteral
antibiotic (Dubos et al., 2006b, 2008). Meningitis clinical
prediction rules should be applied cautiously to the youngest infants ( 2 months of age), who are most likely to
be misclassified and who are the most difficult to evaluate clinically. Clinicians also need to be aware that these
prediction models do not identify patients at risk of other
treatable types of central nervous system infections such
as Lyme meningitis or herpes encephalitis.
Administration of antibiotics prior to lumbar puncture
may render CSF culture results falsely negative, making
the determination of the appropriate duration of antibiotics more difficult (Kanegaye et al., 2001). When bacterial meningitis is clinically suspected, however, empirical
antibiotics should be started without delay even if
the diagnostic lumbar puncture is to be deferred. Antibiotic pretreatment has also been shown to affect CSF
profiles by decreasing CSF protein and increasing CSF
glucose without significant effects on CSF cell counts
(Nigrovic et al., 2008). Therefore, clinical prediction
rules for bacterial meningitis should not be applied to
patients pretreated with antibiotics. CSF latex agglutination tests detect the presence of bacterial antigens in the
CSF but have low sensitivity and limited clinical utility.
Viral meningitis is treated with supportive measures
alone. Inpatient care is required only for intravenous
hydration and pain control. No currently available antiviral agents have activity against enteroviruses. Definitive exclusion of bacterial infections depends on
bacterial culture results, which take several days to reliably exclude bacterial growth. Empirical antibiotics
should be initiated early for all patients with a clinical
concern for bacterial meningitis. For these patients, antibiotics should be selected to have a broad antimicrobial
spectrum that covers the likely bacterial pathogens and
known resistance patterns. The duration of antibiotics
should be determined by a combination of clinical presentation, viral diagnostics, and bacterial culture results.
Children with meningoencephalitis present with acute
onset of altered mental status, focal neurological deficits, ataxia, aphasia, or focal seizures. Most children will
also have an associated fever. Examination of the CSF
typically reveals a mild pleocytosis with a lymphocytic
Herpes simplex virus (HSV) is the most commonly
identified cause of encephalitis and occurs in patients
of all ages. Neonates are particularly susceptible to
HSV infection, with most cases transmitted peripartum
(although in utero and postnatal transmission are also
reported). Neonatal HSV meningitis often occurs without
cutaneous findings and typically presents within the first 2
weeks of life. If HSV infection is suspected, CSF should
be obtained for PCR detection as well as routine studies.
Abnormalities in the temporal lobe region on neuroimaging suggest HSV encephalitis, although the viral tropism is
not specific enough to enable definite identification of the
infecting virus. Aciclovir therapy should be initiated pending diagnostic test results. Children with proven HSV
encephalitis should be treated with intravenous aciclovir
for 21 days as well as long-term suppressive therapy
(Kimberlin et al., 2011). Even after appropriate diagnosis
and treatment, children with HSV encephalitis can have
significant associated morbidity and mortality.
Arthropod-borne viruses cause epidemic encephalitis. Because the mosquito is the most common vector,
most cases occur during the summer months when insect
activity is the highest. West Nile encephalitis was first
reported in the West Nile district of Uganda in the
1930s. Now, West Nile virus has been detected in 46
of the states (concentrated in the East and South) as
well as throughout Europe. Other causes of arborviral
encephalitis in the USA include: eastern equine,
La Crosse, St. Louis, and western equine viruses. Therapy for arborvirus infection is largely supportive,
although empirical acyclovir should be considered until
HSV infection can be definitely excluded. Most patients
make a complete recovery, although some patients with
arborviral encephalitis are left with seizure disorder or
persistent neurological deficits.
Influenza virus infection (particularly type A)
has also been rarely associated with encephalitis. The
incidence of neurological complications is highest in
children under 5 years of age. Viral transmission occurs
person to person through respiratory secretions with a
peak incidence during the winter months (January
through February).
Aseptic meningitis can result from noninfectious causes
such as medications. Drugs that have been implicated as
possible causes of aseptic meningitis include nonsteroidal anti-inflammatory drugs (NSAIDs), sulfa drugs, and
intravenous immunoglobulin (IVIG). Medicationinduced aseptic meningitis must remain a diagnosis of
exclusion after other more common infectious causes
have been effectively excluded.
Recurrent or Mollaret meningitis is an extremely rare
clinical entity defined as three or more episodes of aseptic meningitis. Patients present with fever and meningismus lasting several days followed by spontaneous
resolution. There is considerable patient-to-patient variability in the time between episodes (weeks to years). The
CSF reveals a mild pleocytosis with a lymphocytic predominance. Most commonly, these episodes are caused
by HSV (type 1 or 2) infection identified by PCR testing
of the CSF. Patients often do not have a history of genital
lesions. Noninfectious causes of Mollaret meningitis,
such as an epidermoid cyst, must also be considered.
Aseptic meningitis is a common but typically benign childhood infection. The incidence is highest in infants and during the summer months. Affected children typically make a
complete recovery with supportive care alone. Because of
the overlap between the clinical and laboratory features of
patients with aseptic and bacterial meningitis, many
patients with aseptic meningitis are treated with empirical
antibiotics while awaiting bacterial culture results. Viral
diagnostics allow for more rapid exclusion of bacterial
infection as well as initiation of specific therapy when available. Meningoencephalitis may cause more severe neurological symptoms, but clinical care is largely supportive.
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