Aseptic Meningitis in Adults

2016. 10. 14.
Aseptic meningitis in adults - UpToDate
Official reprint from UpToDate

www.uptodate.com 2016 UpToDate
Aseptic meningitis in adults
Author: R Paul Johnson, MD

Section Editor: Martin S Hirsch, MD
Deputy Editor: Jennifer Mitty, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: Sep 28, 2012.
INTRODUCTION The term aseptic meningitis refers to patients who have clinical and laboratory
evidence for meningeal inflammation with negative routine bacterial cultures. The most common cause is
enterovirus [1]. Additional etiologies include other infections, (mycobacteria, fungi, spirochetes),
parameningeal infections, medications, and malignancy (table 1) [2].
Aseptic meningitis often has a similar presentation to bacterial meningitis (eg, fever, headache, altered
mental status, stiff neck, photophobia), which can be a life-threatening illness. However, in contrast to
bacterial meningitis, the majority of patients with aseptic meningitis have a self-limited course that will
resolve without specific therapy.
The assessment of patients with probable aseptic meningitis is complicated by the large number of
potential etiologic agents and the relatively limited diagnostic tools for identifying specific pathogens. (See
"Clinical features and diagnosis of acute bacterial meningitis in adults" and "Herpes simplex virus type 1
encephalitis".)
The symptoms, signs, and cerebrospinal fluid (CSF) findings for various etiologies of aseptic meningitis
will be reviewed here. Each diagnostic entity is discussed in detail separately on the appropriate topic
reviews.
MENINGITIS VERSUS ENCEPHALITIS The presence or absence of normal brain function is the
important distinguishing feature between encephalitis and meningitis. Patients with meningitis may be
uncomfortable, lethargic, or distracted by headache, but their cerebral function remains normal. In
encephalitis, however, abnormalities in brain function are common, including altered mental status, motor
or sensory deficits, altered behavior and personality changes, and speech or movement disorders.
Seizures and postictal states can be seen with meningitis alone and should not be construed as definitive
evidence of encephalitis. Other neurologic manifestations include hemiparesis, flaccid paralysis, and
paresthesias.
However, the distinction between the two entities is frequently blurred since some patients may have both
a parenchymal and meningeal process with clinical features of both. The patient is usually labeled as
having meningitis or encephalitis based upon which features predominate in the illness although
meningoencephalitis is also a common term that recognizes the overlap. (See "Viral encephalitis in
adults".)
VIRAL MENINGITIS A number of viruses produce aseptic meningitis including enteroviruses, herpes
simplex virus (HSV), human immunodeficiency virus (HIV), West Nile virus (WNV), varicella-zoster virus
(VZV), mumps, and lymphocytic choriomeningitis virus (LCM) (table 2) [3]. (See "Viral encephalitis in
adults".)
Enteroviruses Aseptic meningitis occurring during the summer or fall is most likely to be caused by
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2016. 10. 14. Aseptic meningitis in adults - UpToDate
enteroviruses (eg, Coxsackie, echovirus, other non-poliovirus enteroviruses), the most common cause of
viral meningitis [3]. However, seasonal variation of certain CNS viral infections is relative and not absolute.
Enteroviruses continue to cause 6 to 10 percent of cases of viral meningitis in the winter and spring
despite their predilection for inciting illness in the late summer and fall [4].
The presenting signs and symptoms of enteroviral meningitis are not distinctive. The onset of symptoms is
characteristically abrupt and typically includes headache, fever, nausea or vomiting, malaise,
photophobia, and meningismus. Rash, diarrhea, and upper respiratory symptoms may also be present.
Cerebrospinal fluid (CSF) findings are typical of other viral meningitides and include a white blood cell
(WBC) count that is generally less than 250 cells/microL, a modest elevation in CSF protein concentration
(generally less than 150 mg/dL), and a normal glucose concentration (table 3). (See "Cerebrospinal fluid:
Physiology and utility of an examination in disease states".)
Up to two-thirds of patients with enteroviral meningitis have a polymorphonuclear predominance in the

CSF when examined early in the course of the illness. Repeat lumbar puncture after 12 to 24 hours, if
performed, generally shows an evolution to a lymphocytic predominance. PCR for enteroviruses can be
considered if a definitive diagnosis is desired, or in the setting of an outbreak situation, but is not
necessary in all patients. CSF PCR for enteroviruses yields a diagnosis in up to 75 percent of patients
with culture-negative aseptic meningitis [5]. Among patients with CNS manifestations and a negative CSF
PCR, upper respiratory tract and gastrointestinal tract specimens for enterovirus PCR may be useful to
establish a diagnosis of enterovirus infection [6].
(See "Clinical manifestations and diagnosis of enterovirus and parechovirus infections" and
"Epidemiology, pathogenesis, treatment, and prevention of enterovirus and parechovirus infections".)
HIV infection Primary infection with HIV frequently presents as a mononucleosis-like syndrome
manifested by fever, malaise, lymphadenopathy, rash, and pharyngitis. A subset of these patients will
develop meningitis or meningoencephalitis, manifested by headache, confusion, seizures or cranial nerve
palsies. (See "Acute and early HIV infection: Pathogenesis and epidemiology".)
In most patients with HIV-1 meningitis, the clinical findings resolve without treatment, and patients may be
erroneously assumed to have a benign cause of viral meningitis. Thus, clinicians should have a high index
of suspicion for primary HIV infection in patients at increased risk for acquisition of this virus and all
patients should be questioned about possible risk factors. The identification of the patient with acute HIV
infection is also important from a public health viewpoint since the risk of transmission is facilitated by high
levels of viremia.
The CSF profile characteristically has a lymphocytic pleocytosis, an elevated protein concentration, and
normal glucose concentration (table 3). Documentation of primary HIV infection is accomplished by
demonstration of seroconversion or detection of HIV-1 viremia in the absence of HIV antibody. (See
"Techniques and interpretation of HIV-1 RNA quantitation" and "Screening and diagnostic testing for HIV
infection".)
Herpes simplex meningitis Primary HSV has been increasingly recognized as a cause of viral
meningitis in adults. In contrast to HSV encephalitis, which is almost exclusively due to HSV-1, viral
meningitis in immunocompetent adults is generally caused by HSV-2 [3]. (See "Epidemiology, clinical
manifestations, and diagnosis of genital herpes simplex virus infection".)
Between 13 and 36 percent of patients presenting with primary genital herpes have clinical findings
consistent with meningeal involvement, including headache, photophobia and meningismus. On the other
hand, genital lesions are present in approximately 85 percent of patients with primary HSV-2 meningitis
and generally precede the onset of CNS symptoms by seven days. The CSF profile includes a pleocytosis
with a predominance of lymphocytes, and a normal CSF glucose concentration (table 3). HSV meningitis
can also occur without evidence of genital lesions, although this is less common [3,7]. Thus, the absence
of genital lesions should not deter the clinician from testing for HSV-2 infection in a patient with aseptic
meningitis. (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or
meningitis".)
There is no standard approach to the treatment of HSV meningitis [8]. For hospitalized patients, we prefer
intravenous acyclovir at 10 mg/kg administered every eight hours. Patients can be switched to an oral
agent on discharge for a total of 10 to 14 days of treatment.
Recurrent (Mollaret's) meningitis Mollaret's meningitis is a form of recurrent benign lymphocytic

meningitis (RBLM), an uncommon illness characterized by greater than three episodes of fever and
meningismus lasting two to five days, followed by spontaneous resolution [9]. There is a large patient-to-
patient variation in the time course to recurrence that can vary from weeks to years. One-half of patients
can also exhibit transient neurological manifestations, including seizures, hallucinations, diplopia, cranial
nerve palsies, or altered consciousness.
The most common etiologic agent in Mollaret's meningitis is HSV-2, although some patients do not have
evidence of genital lesions at the time of presentation [10]. Studies suggest that recurrent meningitis
occurs in approximately 20 percent of patients who present with primary HSV-2 infection with meningitis
[11,12]. The diagnosis can be made by PCR testing for HSV DNA in the CSF.
A randomized controlled trial evaluated whether suppressive therapy with valacyclovir (500 mg twice daily)
was more effective than placebo in preventing recurrent HSV-2-related recurrent meningitis [13]. Study
participants had been diagnosed with meningitis related to primary HSV-2 infection or had a history of
recurrent meningitis in the past. Although genital HSV-2 recurrences were lower in the treatment arm
during the first year of follow-up, valacyclovir did not have an effect on the number of episodes of
meningitis over the two-year follow-up. The trial was limited by a) inclusion of patients without a clear
etiologic diagnosis at study entry, b) use of symptoms alone for the diagnosis of recurrent meningitis, c)
possible low rates of adherence in year two when genital recurrences were similar in the treatment and
placebo groups, and d) small sample size.
Patients who are troubled by recurrent HSV-2-related genital lesions may benefit from antiviral
suppressive therapy or episodic therapy. However, the role of antiviral therapy for the prevention of HSV-
2-related recurrent meningitis remains unclear. (See "Treatment of genital herpes simplex virus infection".)
Noninfectious etiologies for Mollaret's meningitis have also been proposed. As an example, patients with
an intracranial epidermoid cyst or other cystic abnormalities in the brain can develop meningeal irritation
due to intermittent leakage of irritating squamous material into the CSF [14,15]. This may be detected
acutely by polarizing microscopy of CSF. Imaging studies should be performed subsequently when the
patient is asymptomatic, since the epidermoid cyst is often collapsed immediately after leaking its
contents.
Lymphocytic choriomeningitis virus Lymphocytic choriomeningitis virus (LCMV) is a human

zoonosis caused by a rodent-borne arenavirus. LCMV is excreted in the urine and feces of rodents,
including mice, rats, and hamsters, and is transmitted to humans by exposure to secretions or excretions
(by direct contact or aerosol) of infected animals or contaminated environmental surfaces [16-18].
Infection is more common during winter months.
Affected patients generally present with an influenza-like systemic illness accompanied by headache and
meningismus. A minority of patients develop orchitis, parotitis, myopericarditis, or arthritis.
CSF findings are typical of other causes of viral meningitis except that low glucose concentrations are
observed in 20 to 30 percent of patients with LCMV meningitis and CSF WBC counts of greater than
1000/microL are not unusual [19]. The diagnosis is established by documentation of seroconversion to
the virus in paired serum samples. There is no specific antiviral therapy for LCMV.
Mumps Aseptic meningitis is the most frequent extrasalivary complication of mumps virus infection.
Prior to the introduction of the mumps vaccine in 1967, this paramyxovirus was a relatively common cause
of viral meningitis, accounting for between 10 and 20 percent of all cases [4,19].
The most frequent manifestations are headache, low-grade fever, and mild nuchal rigidity. The onset of
meningitis is variable and can occur before, during, or after an episode of mumps parotitis. (See
"Epidemiology, clinical manifestations, diagnosis, and management of mumps".)
The CSF profile typically reveals fewer than 500 WBC/microL with a lymphocytic predominance, but more
than 1000 WBC/microL and an early neutrophil predominance can occasionally be seen. The CSF total
protein is generally normal or mildly elevated and the CSF glucose levels may be mildly depressed.
Miscellaneous viruses A number of other viruses can infrequently be associated with viral
meningitis. In certain areas of the United States, arthropod-borne viruses can cause aseptic meningitis.
West Nile virus, St. Louis encephalitis virus, and California encephalitis virus all can cause aseptic
meningitis but more frequently are associated with encephalitis. (See "Epidemiology and pathogenesis of
West Nile virus infection" and "St. Louis encephalitis" and "Viral encephalitis in adults".)
Aseptic meningitis can also be associated with either primary varicella zoster infection [20] or outbreaks of
herpes zoster, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, and adenoviruses. (See
appropriate topic reviews).
OTHER INFECTIONS
Spirochetes The two major spirochetes that need to be considered in the differential diagnosis of
aseptic meningitis are Treponema pallidum, the causative agent of syphilis, and Borrelia burgdorferi, the
spirochete that leads to Lyme disease.
Syphilis Treponema pallidum, the causative agent of syphilis, disseminates to the central nervous
system during early infection. Syphilitic meningitis can present in the setting of secondary syphilis with
headache, malaise, and disseminated rash.
CSF findings include a lymphocytic pleocytosis with an elevated protein concentration; occasionally a
depressed glucose concentration may also be seen. Serum and CSF VDRL are nearly always positive.
(See "Neurosyphilis", section on 'Symptomatic meningitis' and "Syphilis: Epidemiology, pathophysiology,
and clinical manifestations in HIV-uninfected patients", section on 'Clinical manifestations'.)
Lyme disease Lyme meningitis typically occurs in the late summer and early fall, the same time as
the peak incidence of enteroviral meningitis. During the acute primary infection, some patients develop
headache, neck stiffness, and photophobia. Fever is usually mild; Kernig and Brudzinski signs are usually
absent on physical examination, and neurologic features can include cranial nerve palsies, especially
involving the facial nerve, which may be bilateral.
The diagnosis of aseptic meningitis due to Lyme disease is facilitated when other characteristic findings
are present, such as erythema chronicum migrans. When Lyme meningitis occurs alone, the diagnosis
can be missed unless the clinician considers other risk factors, such as potential exposure to tick bites or
travel history. (See "Epidemiology of Lyme disease" and "Diagnosis of Lyme disease".)
Tick-borne diseases Tick-borne diseases that can be considered in the differential diagnosis of
aseptic meningitis include Rocky Mountain spotted fever and ehrlichiosis.
Rocky Mountain spotted fever In the early phase of illness, patients with RMSF can present with
fever, a severe headache, malaise, myalgias, arthralgias, and nausea with or without vomiting. If a lumbar
puncture is performed to evaluate the headache, CSF findings can include a mild lymphocytic pleocytosis
that can be confused with viral meningitis. Less than one-half of patients develop a rash in the first 72
hours of illness. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)
Ehrlichiosis Patients with ehrlichiosis present in a similar manner as those with RMSF, eg, with
fever and nonspecific symptoms such as malaise, myalgia, headache, and chills. Rash, which can be
macular, maculopapular, or petechial, occurs in a minority of patients. (See "Human ehrlichiosis and
anaplasmosis".)
Neurologic symptoms, including mental status changes, stiff neck, and clonus occur in some cases. CSF
findings include a lymphocytic pleocytosis with elevated protein. In one case report, characteristic
inclusions within mononuclear cells were seen, compatible with Ehrlichia morulae. (See "Human
ehrlichiosis and anaplasmosis".)
Fungal infections The two major fungal infections that should be considered in the differential
diagnosis of aseptic meningitis include cryptococcus and coccidioidomycosis.
Cryptococcal infection Cryptococcus neoformans produces infection following inhalation through

the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the
CNS, particularly in patients with advanced AIDS. (See "Clinical manifestations and diagnosis of
Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Epidemiology, clinical
manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients".)
Symptoms typically begin in an indolent fashion, usually over a period of one to two weeks. The three
most common symptoms are fever, malaise, and headache. Stiff neck, photophobia, and vomiting are
seen in one-fourth to one-third of patients.
The CSF WBC count is typically low (<50/microL) with a mononuclear predominance and the protein and
glucose concentrations are usually only slightly abnormal.
Coccidioidal infection Coccidioides immitis is endemic in desert regions of the southwestern

United States and Central and South America. This infection has protean manifestations, and primary
infection is frequently unrecognized. Meningitis is the most lethal complication of coccidioidomycosis and is
therefore crucial to recognize.
Symptoms of meningitis, including persistent and severe headache, usually develop within several months
of the initial infection. Abnormal neurologic findings on physical examination are frequently absent early in
the course of coccidioidal meningitis.
The CSF WBC counts ranges from one to several hundred cells. A significant numbers of eosinophils may
be present, but this finding is not specific for coccidioidal meningitis. The CSF glucose concentration may
be depressed and is occasionally profoundly low in association with an elevation of the CSF protein
concentration. (See "Coccidioidal meningitis".)
Tuberculous meningitis Patients with tuberculous meningitis frequently have protracted headache,
vomiting, confusion, and varying degrees of cranial nerve signs. Mental status changes can occur, leading
to coma, seizures, and at times hemiparesis. Signs of disseminated TB are of diagnostic importance, but
are often absent.
CSF analysis typically shows elevated protein and lowered glucose concentrations with a mononuclear
pleocytosis. (See "Central nervous system tuberculosis".)
Bacterial infections There are a variety of ways in which bacterial infections can lead to a clinical
picture of aseptic meningitis with a CSF pleocytosis:
Parameningeal sources, such as an epidural or subdural abscess, sinus, or ear infection, can
occasionally extend to involve the central nervous system. A thorough history and physical
examination can lead to appropriate imaging and the correct diagnosis. (See "Spinal epidural
abscess" and "Intracranial epidural abscess" and "Acute sinusitis and rhinosinusitis in adults: Clinical
manifestations and diagnosis" and "Acute otitis media in children: Epidemiology, microbiology, clinical
manifestations, and complications", section on 'Complications and sequelae'.)
Bacterial endocarditis can lead to brain microabscesses and seeding of the cerebrospinal fluid via
hematogenous seeding. (See "Complications and outcome of infective endocarditis", section on
'Neurologic complications'.)
A lymphocytic CSF profile and sterile cultures may be seen in partially treated bacterial meningitis.
(See "Clinical features and diagnosis of acute bacterial meningitis in adults".)
Angiostrongylus infection Angiostrongylus cantonensis, the rat lungworm, is a parasite that is

endemic in Southeast Asia and Pacific that can also cause an aseptic meningitis. Symptoms include
severe headache, stiff neck, paresthesias, and uncommonly facial nerve palsy [21,22].
The diagnosis of cerebral angiostrongyliasis is generally based upon the clinical presentation, CSF
eosinophilia, and an epidemiologic history of known or possible exposure to infective A. cantonensis
larvae. The CSF protein concentration is usually elevated, but the glucose concentration is normal or only
minimally reduced. Peripheral blood and CSF eosinophilia frequently occur. (See "Eosinophilic
meningitis".)
NEOPLASMS OF THE LEPTOMENINGES Hematologic malignancies, have a particular propensity to

seed the CNS, especially large cell lymphomas and acute leukemias. Solid tumors frequently causing
carcinomatous meningitis include breast cancer, lung cancer, melanoma, gastrointestinal malignancies,
and cancers of unknown primary origin. (See "Treatment of leptomeningeal metastases (carcinomatous
meningitis)".)
Meningeal signs caused by tumor invasion of the leptomeninges and secondary inflammation are
common. Headache, nausea, and vomiting may be presenting symptoms of increased intracranial
pressure.
The diagnosis of neoplastic meningitis is the cytologic identification of malignant cells within the CSF. The
CSF profile may include an elevated protein concentration and a lymphocytic pleocytosis; a very high
protein concentration suggests a CSF block. CSF eosinophilia can be seen in Hodgkin lymphoma.
DRUG-INDUCED MENINGITIS Drug-induced meningitis is an unusual adverse reaction that is usually

a diagnosis of exclusion [23-25]. A number of drugs can induce symptoms and signs of aseptic meningitis
including nonsteroidal antiinflammatory drugs (NSAIDs) [23-27], certain antibiotics (eg, trimethoprim-
sulfamethoxazole) [28], intravenous immune globulin [23,24,29], rofecoxib, cetuximab [30], antiepileptic
drugs [31,32] and OKT3 antibodies.
Two mechanisms have been proposed for drug-induced meningitis: a delayed hypersensitivity type
reaction and direct meningeal irritation [25].
The CSF profile typically has a neutrophilic pleocytosis. Symptoms often resolve a few days after drug
discontinuation [23,29,30].
There are also multiple reports of drug-induced meningitis in patients with autoimmune disease [26,28,33].
Many of these reports implicate use of NSAIDs. It is unclear whether these patients are inherently at
increased risk or whether the incidence is greater as a result of the prevalent usage of nonsteroidal
antiinflammatory drugs [34]. (See "Neurologic manifestations of systemic lupus erythematosus", section on
'Meningitis'.)
APPROACH TO THE PATIENT The clinical presentation of aseptic meningitis is generally nonspecific,
with fever, headache, nausea and vomiting, occasionally accompanied by photophobia and a stiff neck.
Physical examination typically reveals signs of nuchal rigidity.
As noted above, the approach to patients with aseptic meningitis is complicated by the diverse range of
etiologic agents and relatively limited available diagnostic tools.
Historical clues Clinicians should bear in mind the following points:
Obtain a comprehensive travel and exposure history, including exposure to rodents (LCM), ticks
(Lyme), and tuberculosis, sexual activity (HSV-2, HIV, syphilis), and contact with other individuals with
similar symptoms or viral exanthems (enteroviruses).
Carefully consider potential nonviral etiologies. Patients should be specifically questioned about
preceding use of drugs associated with meningitis (eg, NSAIDs, intravenous immune globulin,
trimethoprim-sulfamethoxazole).
Clues on physical examination Physical examination may reveal findings suggestive of a specific
agent:
A diffuse maculopapular exanthem in a mildly ill patient may be consistent with enteroviral infection,
primary HIV, or syphilis. The clinician should also be aware that a maculopapular rash can
occasionally be seen in meningococcal infection and Rocky Mountain spotted fever as well.
Parotitis suggests mumps meningitis in an unvaccinated patient.
Severe vesicular and ulcerative genital lesions suggests a primary episode of HSV-2 infection.
Oropharyngeal thrush and cervical lymphadenopathy is consistent with primary HIV infection.
Asymmetric flaccid paralysis strongly suggests the possibility of West Nile virus meningitis [25]. (See
"Clinical manifestations and diagnosis of West Nile virus infection".)
Management Based upon the history, physical examination, and CSF findings, patients can be
classified as having probable bacterial meningitis, probable viral meningitis, or indeterminant (table 3).
(See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)
For patients with suspected bacterial meningitis (eg, positive Gram stain, WBC count >1000/microL,
glucose concentration <40 mg/dL [2.2 mmol/L]), antibiotics should be initiated promptly. (See "Initial
therapy and prognosis of bacterial meningitis in adults".)
Patients with probable viral meningitis include those with CSF findings of cell count <500/microL, >50
percent CSF lymphocytes, protein concentration less than 80 to 100 mg/dL, normal glucose
concentration, and negative Gram stain. Patients who are elderly, immunocompromised, or have
received antibiotics prior to presentation should be given antibiotics even if viral meningitis is the
suspected diagnosis. Otherwise, the clinician can consider observing the patient without antibiotic
therapy.
When it is not clear whether the patient has a viral or bacterial process, the treating physician can
choose empiric antibiotics after obtaining blood and CSF cultures or observation with repeat lumbar
puncture (LP) in 6 to 24 hours. The majority of clinicians opt for empiric antibiotics until culture results
are available in 24 to 48 hours. If the patient is symptomatically improved and culture results are
negative, then antibiotics can generally be stopped without a repeat LP. However, repeat LP may be
indicated in patients with persistent symptoms who do not have a clear diagnosis.
Many patients fall into the indeterminate category because of the lack of specificity of presenting
symptoms and signs and because each CSF finding taken in isolation often displays significant overlap
among patients with viral and bacterial meningitis. (See "Clinical features and diagnosis of acute bacterial
meningitis in adults", section on 'CSF analysis'.)
Examination of multiple parameters with the use of a nomogram may be helpful in deciding which patients
should be treated empirically [35]. However, the 2004 Infectious Diseases Society of America guidelines
on bacterial meningitis suggested that these prediction rules should not be used to make clinical decisions
in individual patients [36]. These guidelines can be accessed through the Infectious Diseases Society of
America's website [37].
Thus, in view of the serious consequences if treatment of bacterial meningitis is delayed, the threshold to
initiate empiric antibiotic therapy pending the results of cultures should be relatively low. (See "Initial
therapy and prognosis of bacterial meningitis in adults".)
For patients with suspected viral meningitis or indeterminate CSF results, the CSF should be sent for virus
detection assay (e.g., PCR for HSV) or virus culture, as well as for bacterial culture (in addition to the
routine CSF studies). In patients with cutaneous clues as to the etiology (eg, genital herpes or herpes
zoster), PCR testing is preferred. Other tests to consider in selected patients include: serum and CSF
VDRL, HIV antibody or RNA testing, Lyme serology, and acute/convalescent serologic testing for specific
viruses (LCMV, mumps, measles). (See "Syphilis: Screening and diagnostic testing" and "Diagnosis of
Lyme disease".)
The differential diagnosis should be broadened for the patient with lymphocytic predominance in the CSF
and negative bacterial cultures if symptoms worsen or persist. Evaluation should include a repeat CSF
analysis with removal of large volume of fluid (3 to 5 mL, if possible) for fungal and mycobacterial cultures,
and imaging of the CNS and sinuses with magnetic resonance imaging (MRI) or computed tomography
(CT). Potential noninfectious etiologies should also be considered (table 1).
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Basics topics (see "Patient education: Aseptic meningitis (The Basics)" and "Patient education: Viral
meningitis (The Basics)")
SUMMARY AND RECOMMENDATIONS The diagnosis of a patient with aseptic meningitis may be
difficult because of the large variety of potential etiologic agents and the overlap between self-limited viral
illnesses and potentially fatal bacterial infections.
Management A careful history should include travel and exposure history, including exposure to
rodents (LCMV), ticks (Lyme borrelia, RMSF, ehrlichia), mosquitoes (West Nile virus, St. Louis encephalitis
virus) and patients with tuberculosis, sexual activity (HSV-2, HIV, syphilis), travel (C. immitis, A.
cantonensis) and contact with other individuals with similar symptoms or viral exanthems (enteroviruses).
The patient should also be questioned about medications and other comorbidities.
The opening CSF pressure should be noted and CSF should be sent for cell count, glucose, protein and
culture or specific antigen or nucleic acid tests for viruses, as well as culture for bacteria. Whether
additional studies (eg, culture for fungi and mycobacteria) should be performed will depend on the clinical
presentation (see discussion above and individual topic cards).
Based upon the history, physical examination and CSF findings, patients can often be classified as having
probable bacterial or viral meningitis, although overlap can be frequent, particularly if bacterial meningitis
has been partially treated with previous antibiotics.
Suspected bacterial meningitis For patients with suspected bacterial meningitis, antibiotics
should be initiated promptly. (See "Initial therapy and prognosis of bacterial meningitis in adults".)
Suspected viral meningitis The approach to empiric therapy in the patient with viral meningitis will
depend upon the clinical appearance of the patient and underlying host factors. Patients who are elderly,
immunocompromised, or have received antibiotics prior to presentation may be considered for empiric
therapy for 48 hours, even if viral meningitis is the suspected diagnosis. Otherwise, the clinician can
consider observing the patient without antibiotic therapy.
If HIV is a diagnostic consideration, then blood testing for HIV RNA and HIV antibody should be performed.
(See "Techniques and interpretation of HIV-1 RNA quantitation" and "Screening and diagnostic testing for
HIV infection".)
If aseptic meningitis due to HSV is suspected (eg, concomitant genital lesions), empiric therapy with
acyclovir (10 mg/kg intravenously every eight hours) can be administered. (See "Acyclovir: An overview".)
Unclear etiology When it is not clear whether the patient has a viral or bacterial process, we
recommend empiric antibiotics after obtaining blood and CSF cultures or observation with repeat lumbar
puncture in 6 to 24 hours. If the patient is symptomatically improved and culture results are negative, then
antibiotics can generally be stopped without a repeat LP. However, repeat LPs may be indicated in
patients with persistent symptoms who do not have a clear diagnosis.
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Topic 1296 Version 13.0
GRAPHICS
Differential diagnosis of aseptic meningitis
Common Uncommon Rare
Viral Echoviruses C ytomegalovirus Rotavirus

C oxsackieviruses types A and B Epstein Barr virus Encephalomyocarditis
Herpes simplex type 2 Varicella zoster virus
Human immunodeficiency virus virus Vaccinia
Lymphocytic choriomeningitis virus Herpes simplex type Influenza A and B

I Parainfluenza
Arboviruses
Adenovirus
Mumps
Measles
Poliovirus
Rubella
Bacterial Parameningeal bacterial infection Treponema pallidum Borrelia recurrentis

(epidural, subdural abscess) (syphilis) (relapsing fever)
Partially treated bacterial meningitis Mycoplasma Spirillum minor (rat bite
Leptospira spp. pneumoniae fever)
Borrelia burgdorferi (Lyme disease) Rickettsia spp. Listeria monocytogenes
Mycobacterium tuberculosis Ehrlichia spp. Mycoplasma hominis
Bacterial endocarditis Brucella spp. Nocardia spp.

C hlamydia spp. Actinomyces spp.
Fungal C ryptococcus C andida spp.

neoformans Aspergillus spp.
C occidioides immitis Blastomyces
Histoplasma dermatitidis
capsulatum Sporothrix schenckii
Parasitic Angiostrongylus Taenia solium

cantonensis (cysticercosis)
Toxoplasma gondii Trichenella spiralis
Drug lbuprofen Trimethoprim-

sulfamethoxazole
Other NSAIDs
Pyridium
(phenazopyridine)
anti-C D3
monoclonal antibody
Azathioprine
Malignancy Lymphoma
Leukemia
Metatstatic carcinomas and
adenocarcinomas
Autoimmune Sarcoid Vogt-Koyanagi-Harada

Behcet's disease syndrome
Systemic lupus
erythematosus
Other Epidermoid cyst

Postvaccination
Etiologies are classified according to their relative frequency among all causes of aseptic meningitis.
Modified from Connolly, KJ, Hammer, SM. Infect Dis Clin North Am 1990; 4:599.
Graphic 79745 Version 1.0
Viral infections of the central nervous system (CNS)
Meningitis Encephalitis
Enteroviruses
C oxsackie A and B viruses C ommon Rare
Echoviruses C ommon Rare
Polioviruses C ommon Rare
Arthropod-borne viruses (arboviruses)
West Nile virus Infrequent C ommon
St. Louis encephalitis virus C ommon C ommon
C alifornia encephalitis virus C ommon C ommon
Eastern encephalitis virus Rare C ommon
Western encephalitis virus C ommon C ommon
Venezuelan equine encephalitis virus - Infrequent
C olorado tick fever - Infrequent
Powassan encephalitis - Rare
Herpesviruses
Herpes simplex type I Rare C ommon
Herpes simplex type 2 C ommon Rare
C ytomegalovirus Infrequent C ommon
Varicella zoster virus Infrequent Infrequent
Epstein Barr virus Infrequent C ommon
Simian herpes B virus Rare C ommon
Other viruses
Human immunodeficiency virus C ommon C ommon
Rabies virus Rare C ommon
Lymphocytic choriomeningitis virus C ommon Infrequent
Influenza virus Rare C ommon
Mumps virus C ommon Infrequent
Measles C ommon Rare
* The terms common, infrequent, and rare refer to the propensity of a viral C NS infection to result in either
meningitis or encephalitis and not to how commonly a specific virus causes C NS infection.
Typical cerebrospinal fluid findings in central nervous system infections*
Total white blood cell count

Glucose (mg/dL) Protein (mg/dL)
(cells/microL)
100 to 100 to
<10 10 to 40 50 to 300 >1000 5 to 100
500 1000
More Bacterial Bacterial Bacterial Viral meningitis Bacterial Bacterial or Early

common meningitis meningitis meningitis Nervous system meningitis viral bacterial
Lyme disease meningitis meningitis
(neuroborreliosis) TB Viral
Neurosyphilis meningitis meningitis
TB meningitis Neurosyphilis
TB
meningitis
Less TB Neurosyphilis Some Encephalitis Encephalitis

common meningitis Some viral cases of
Fungal infections mumps
meningitis (such as and LC MV
mumps and
LC MV)
TB: tuberculosis; LC MV: lymphocytic choriomeningitis virus.

* It is important to note that the spectrum of cerebrospinal fluid values in bacterial meningitis is so wide that
the absence of one or more of these findings is of little value. Refer to the UpToDate topic reviews on bacterial
meningitis for additional details.
<0.6 mmol/L.
0.6 to 2.2 mmol/L.
1 to 5 g/L.
0.5 to 3 g/L.
C erebrospinal fluid protein concentrations may be higher in some patients with tuberculous meningitis;
concentrations >500 mg/dL are an indication of blood-brain barrier disruption or increased intracerebral
production of immunoglobulins, and extremely high concentrations, in the range of 2 to 6 g/dL, may be found
in association with subarachnoid block.
Contributor Disclosures
R Paul Johnson, MD Nothing to disclose Martin S Hirsch, MD Nothing to disclose Jennifer Mitty,
MD, MPH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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2016. 10. 14.

Aseptic meningitis in adults - UpToDate

Official reprint from UpToDate

Author: R Paul Johnson, MD

Up to two-thirds of patients with enteroviral meningitis have a polymorphonuclear predominance in the

Recurrent (Mollaret's) meningitis Mollaret's meningitis is a form of recurrent benign lymphocytic

Lymphocytic choriomeningitis virus Lymphocytic choriomeningitis virus (LCMV) is a human

Cryptococcal infection Cryptococcus neoformans produces infection following inhalation through

Coccidioidal infection Coccidioides immitis is endemic in desert regions of the southwestern

Angiostrongylus infection Angiostrongylus cantonensis, the rat lungworm, is a parasite that is

NEOPLASMS OF THE LEPTOMENINGES Hematologic malignancies, have a particular propensity to

DRUG-INDUCED MENINGITIS Drug-induced meningitis is an unusual adverse reaction that is usually

Historical clues Clinicians should bear in mind the following points:

Parotitis suggests mumps meningitis in an unvaccinated patient.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 1296 Version 13.0

Differential diagnosis of aseptic meningitis

Common Uncommon Rare

Viral Echoviruses C ytomegalovirus Rotavirus

Human immunodeficiency virus virus Vaccinia

Lymphocytic choriomeningitis virus Herpes simplex type Influenza A and B

Bacterial Parameningeal bacterial infection Treponema pallidum Borrelia recurrentis

Borrelia burgdorferi (Lyme disease) Rickettsia spp. Listeria monocytogenes

Mycobacterium tuberculosis Ehrlichia spp. Mycoplasma hominis

Bacterial endocarditis Brucella spp. Nocardia spp.

Fungal C ryptococcus C andida spp.

Parasitic Angiostrongylus Taenia solium

Drug lbuprofen Trimethoprim-

Autoimmune Sarcoid Vogt-Koyanagi-Harada

Other Epidermoid cyst

Graphic 79745 Version 1.0

Viral infections of the central nervous system (CNS)

C oxsackie A and B viruses C ommon Rare

Echoviruses C ommon Rare

Polioviruses C ommon Rare

Arthropod-borne viruses (arboviruses)

West Nile virus Infrequent C ommon

St. Louis encephalitis virus C ommon C ommon

C alifornia encephalitis virus C ommon C ommon

Eastern encephalitis virus Rare C ommon

Western encephalitis virus C ommon C ommon

Venezuelan equine encephalitis virus - Infrequent

C olorado tick fever - Infrequent

Powassan encephalitis - Rare

Herpes simplex type I Rare C ommon

Herpes simplex type 2 C ommon Rare

C ytomegalovirus Infrequent C ommon

Varicella zoster virus Infrequent Infrequent

Epstein Barr virus Infrequent C ommon

Simian herpes B virus Rare C ommon

Human immunodeficiency virus C ommon C ommon

Rabies virus Rare C ommon

Lymphocytic choriomeningitis virus C ommon Infrequent

Influenza virus Rare C ommon

Mumps virus C ommon Infrequent

Measles C ommon Rare

Graphic 53862 Version 3.0

Typical cerebrospinal fluid findings in central nervous system infections*

Total white blood cell count

More Bacterial Bacterial Bacterial Viral meningitis Bacterial Bacterial or Early

Less TB Neurosyphilis Some Encephalitis Encephalitis

TB: tuberculosis; LC MV: lymphocytic choriomeningitis virus.

Graphic 76324 Version 9.0