OVERVIEW: What every practitioner needs to know

Are you sure your patient has aseptic meningitis? What should you expect to find?

The general term meningitis refers to the nonspecific inflammation of the meninges.
Meningitis is distinct from encephalitis, which is inflammation of the brain parenchyma and is strongly associated with altered mental status.
Meningitis and encephalitis are entities along a spectrum and it may be difficult to exactly distinguish one from the other. In some cases, a combination of the two, called meningoencephalitis, can occur. This is important because it has implications for diagnosis and treatment (see below).
Patients with aseptic meningitis often present with classic meningeal symptoms, including fever, neck pain or stiffness, photophobia, headache, nausea or vomiting and perhaps altered mental status although this is NOT a prominent feature of viral meningitis, the most common cause of aseptic meningitis. If altered mental status is pronounced, it is likely that the patient may have acute purulent meningitis, fungal or mycobacterial meningitis or encephalitis.
In contrast to bacterial meningitis, in viral aseptic meningitis these symptoms are often self-limited without specific treatment.
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For most causes of aseptic meningitis, the history is usually indolent progression of these symptoms, but in some cases, the presentation may be sudden and severe, making it initially difficult to distinguish from bacterial meningitis or encephalitis based on the history and physical findings alone.
A history of travel is important to elicit as this may prove clues to possible fungal causes (Coccidioides if the patient has been in the Southwest US.) or parasitic causes (Angiostrongylus).
The key physical exam findings of aseptic meningitis may include fever, nuchal rigidity (neck stiffness) and photophobia.
Altered mental status is rare and if present should increase suspicion for acute purulent meningitis or encephalitis. However, there is also a spectrum of physical exam findings and some of these may be minimal or absent.
Some classic signs of bacterial meningitis may be present: Kernig’s sign is neck pain elicited when the patient lies on his/her back and the leg is straight and raised to 90 degrees. Brudzinski’s sign is involuntary bending or raising of the legs when the patient is lying on his/her back and the head and neck are lifted by the examiner. Both are a result of meningeal irritation.
In certain cases, there may be other helpful physical findings. For example, a diffuse rash may be seen in syphilis or HIV infection, and an expanding circular rash (erythema migrans) is seen in early Lyme disease.

How did the patient develop aseptic meningitis? What was the primary source from which the infection spread?

Aseptic meningitis can be caused by infectious and non-infectious causes. The non-infectious causes include drugs (including NSAIDs, trimethoprim/sulfamethoxazole, intravenous immune globulin (IVIG), vasculitis (including those caused by autoimmune diseases such as lupus or Sjogren’s Disease), sarcoidosis, and malignancy, including metastases to the meninges.
Infectious causes can be further grouped into the following:

Viral: enteroviruses are by far the most common identified cause of aseptic meningitis (85-90%), but others include arboviruses, herpesviruses (including HSV-2, HSV-1, VZV, EBV, CMV), influenza, measles, lymphocytic choriomeningitis virus, mumps, HIV. Molleret’s syndrome is defined as recurrent aseptic meningitis, which has been linked to HSV-2.

Partially treated bacterial meningitis (routine organisms such as S. pneumoniae, N. meningitidis and others) or a bacterial infection next to the meninges (parameningeal focus of infection such as an epidural abscess or mastoiditis) can also present with an aseptic meningitis picture. Other causes can include mycobacterium tuberculosis, brucella, leptospira and syphilis.

Rarely, fungal (Cryptococcus neoformans or Coccidioides species) or parasitic meningitis (Angiostrongylus) can occur. There are more likely to have a chronic course.

Viral causes of aseptic meningitis show seasonal patterns in colder climates but may also occur year-round in tropical regions. For viral aseptic meningitis due to enteroviruses, which is spread by oral fecal contamination or respiratory droplets, there are annual peaks in the summer and early fall in temperate climates. There is also a higher incidence in young children than in adults, and the serotypes in all ages vary from year to year with some being more neurotropic than others. West Nile virus (WNV) can also cause aseptic meningitis, and is transmitted by Culex mosquitoes. These infections are most common in the warmer months. Prior to an effective vaccine, mumps meningitis, which is transmitted by respiratory secretions, was most common in the winter months.

Which individuals are at greater risk of developing aseptic meningitis?

For viral aseptic meningitis, risk factors include those for the specific agents. Enteroviruses can be transmitted by exposure to an infected individual’s secretions entering the oral cavity through sneezing or oral fecal contact. Proper hand hygiene and covering sneezes and coughs can therefore decrease the risk of transmission. For arboviruses such as WNV, avoiding mosquito exposure is the key through minimizing outdoor activities in the summer, by wearing long sleeves and long pants, and using repellant. Areas with plentiful mosquito breeding areas of still water place nearby residents at higher risk. Individuals who have not been fully immunized with MMR vaccine are at continued risk for mumps meningitis. Patients with known HSV-2 (more commonly) or HSV-1 can develop meningitis. Meningitis can occur in a patient with positive HSV-2 serology even if they have never had a recognized outbreak of genital herpes.
For partially treated acute purulent meningitis or parameningeal foci of bacterial infections that lead to an aseptic meningitis picture, the history of these infections is the key risk factor. Clinicians should also elicit a thorough medication history to review for recent antibiotics that may have resulted in a partially treated infection. Individuals with risk factors for bacteremia would also be at risk as well as those who have undergone surgical procedures at parameningeal sites.
AIDS patients with CD4 below 100 are at risk for cryptococcal meningitis. Travel to the Southwestern United States, an area endemic for Coccidioides species, is a risk factor for meningitis due to this fungus. The risk is increased in immunocompromised, pregnant women and those of African or Filipino descent. For more information, follow the links above to their respective chapters.
Patients with underlying connective tissue diseases or sarcoid are at risk for developing aseptic meningitis related to these conditions.
Patients who have recently taken NSAIDs, trimenthoprim/sulfamethoxazole, or IVIG are at risk for drug induced aseptic meningitis.
Patients from endemic areas for Mycobacterium tuberculosis may be at risk for developing tuberculous meningitis (any other than United States, Western Europe, Australia, Japan, Canada).

Beware: there are other diseases that can mimic aseptic meningitis:

It is important to exclude a bacterial infection in close proximity to the meninges (a parameningeal focus) that may cause sterile inflammation of the meninges. Examples can include epidural abscess, mastoiditis or otitis. In these cases, the underlying bacterial infection must be identified and treated.
Also, keep in mind that a bacterial meningitis that is partially treated with a course of oral antibiotics may present with meningitis but with no microorganisms identified in the CSF, mimicking aseptic meningitis, therefore always get a thorough history of recent antibiotic use in patients presenting with meningitis.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

The peripheral blood counts may show a slightly elevated white blood cell (WBC) count but may also be completely normal. In the rare case of parasitic meningitis, there may be a peripheral blood and CSF eosinophilia. A lumbar puncture must be performed on all patients presenting with signs and symptoms of meningitis to obtain CSF for glucose, protein, cell count, gram stain and culture (please see Table I). Most often, for viral meningitis (the most common cause of aseptic meningitis) the following values are expected:

glucose: normal

protein: normal or slightly increased,

CSF cell count:100-1000 cells/mm3 (usually with a lymphocytic or monocytic predominance)

gram stain and culture: negative.
It is important to remember that it may be impossible based on laboratory findings alone to distinguish a partially treated bacterial meningitis from viral meningitis, so a complete assessment of the patient’s history, physical exam and laboratory findings are needed in order to determine the best treatment.
If a patient has genital ulcers as well as meningitis, HSV PCR may help suggest the diagnosis if other causes are excluded.
If syphilis is suspected, serum RPR as well as CSF VDRL should be ordered. The CSF VDRL is relatively insensitive (sensitivity 40-70%), so negative results do not rule out neurosyphilis.
HIV antibody testing and HIV RNA should be done in sexually active patients as HIV can lead to an aseptic meningitis.
ELISA and Western blot for Lyme disease if patient lives in, or has traveled to, an endemic area and may have been exposed to infected ticks.
Patients from endemic areas for Mycobacterium tuberculosis may be at risk for developing tuberculous meningitis (any other than US, Western Europe, Australia, Japan, Canada). These individuals should be screened for infection with tuberculin skin testing (TST) or interferon gamma release assays (IGRAs). However, in cases where there is high suspicion for TB meningitis based on the patient’s epidemiology and CSF analysis, a large volume (10mL) of CSF should be sent on 2-3 consecutive days for mycobacterial culture for optimum yield. Infectious disease consultation is often helpful in these cases. M. tuberculosis PCR is available for use on CSF in some laboratories, but has variable sensitivity, so a negative result does not exclude the diagnosis.

CSF analysis results for several types of meningitis.

Results that confirm the diagnosis

Blood cultures are negative except in rare cases (e.g. brucellosis).
Routine CSF cultures are generally negative.
In patients in whom there is high suspicion for M. tuberculosis (see section on “which patients are at higher risk for developing aseptic meningitis” above), large volumes (10mL) of CSF should be submitted for mycobacterial cultures on several consecutive days for highest yield.
In select laboratories, PCR testing for viral agents, such as enteroviruses or HSV is available.

What imaging studies will be helpful in making or excluding the diagnosis of aseptic meningitis?

Plain radiographs are not recommended in meningitis. Other imaging studies, such as computed tomography (CT) or magnetic resonance imaging (MRI), are generally not helpful except to exclude other conditions in the differential diagnosis, such as a parameningeal focus of infection, or if the patient has a history or physical exam which would indicate a focal imaging study.
CT or MRI of the brain is most useful if the patients present with a more complex illness than classic aseptic meningitis and are instead on the clinical spectrum toward encephalitis or vasculitis.
Average costs: limited brain CT – $$-$$$, brain MRI with and without contrast – $$$-$$$$ ($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000).

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has aseptic meningitis, what therapies should you initiate immediately?

Since it is not possible to accurately distinguish whether acute meningitis is viral or bacterial, in individuals at high risk for morbidity (the elderly, immunocompromised, those that present with severe illness) it is important to cover empirically for common bacterial organisms, including Streptococcus pneumonia and Neisseria meningitidiswhile awaiting CSF laboratory results. These can either be stopped immediately once the CSF cell counts are known to be consistent with aseptic meningitis if the patient is stable or may be stopped in 48-72 hours once CSF gram stain and culture is negative. For elderly, immunocompromised or nonverbal patients, empiric antibiotics should be continued until the CSF cultures are negative. Please see the chapter on bacterial meningitis for full details. Consult the infectious disease physicians for unusual cases, or for patients that fail to improve within 24-48 hours.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

If the patient is elderly, immunocompromised or appears very ill on presentation, follow the empiric antibiotic regimens recommended for bacterial meningitis. These can be stopped in 24-48 hours once CSF gram stain and culture is negative (Table I).

2. Next, list other key therapeutic modalities

In general, supportive measures such as rehydration (oral or IV), pain control and observation are the key management interventions for aseptic meningitis, however, other conditions must be ruled out at presentation, including drug side effects, connective tissue diseases, and presentations of systemic infections such as Lyme disease, syphilis, tuberculosis, and HIV. In these cases, treatment should be directed toward the underlying systemic infection, or non-infectious cause.
In HSV encephalitis (in contrast to meningitis, discussed here) there is benefit to treatment with IV acyclovir.
If tuberculous meningitis is suspected, obtain infectious diseases consultation. The patient should be placed in a negative pressure room under respiratory isolation until a full evaluation for pulmonary tuberculosis is completed and negative. Four drug RIPE (rifampin, isoniazid, pyrazinamide, and ethambutol) therapy with corticosteroids may be required.
There are limited data for the use of immune serum globulin for enteroviruses.

What complications could arise as a consequence of aseptic meningitis?

What should you tell the family about the patient's prognosis?

Generally aseptic meningitis is a self-limited condition that primarily requires supportive treatment. If there is an underlying, non-infectious cause such as connective tissues disease, it must be identified and treated. For drug associated aseptic meningitis, stop the offending agent. In cases of systemic infection that leads to aseptic meningitis such as HIV, syphilis, Lyme disease, tuberculosis, and others mentioned above, treatment should be directed toward the underlying systemic infection, or non-infectious cause.

Add what-if scenarios here:

If the CSF profile and peripheral serologies or other diagnostic tests suggest M. tuberculosis, the patient should be placed into a negative pressure room under respiratory isolation and the full work-up for M. tuberculosis infection should be done (please see the M. tuberculosis chapter for full details).
If the clinical presentation is atypical and the work-up does not reveal a causative organism, but the patient is not improving clinically, seek consultation with infectious diseases.

What pathogens are responsible for this aseptic meningitis?

A partially treated bacterial meningitis may have a clinical presentation indistinguishable from aseptic meningitis. Similarly, a bacterial parameningeal focus of infection (e.g. epidural abscess, mastoiditis) can present as an aseptic meningitis. These can be distinguished by a careful history – has the patient recently taken any antibiotics that may partially mask a bacterial meningitis? Do they have any localized pain that might suggest a bacterial infection? A thorough physical exam should also be performed if a parameningeal source is suspected. Follow up imaging with CT or MRI to the identified area can then be performed.

Suspect possible tuberculous meningitis in patients from endemic areas (any other than US, Western Europe, Australia, Japan, Canada). It is possible that the tuberculin skin test (TST) or IGRAs may be negative in patients who do have the disease. The history usually also suggests a more indolent course. Culture remains the mainstay of diagnosis and often requires submitting several high volumes of CSF from consecutive days. In some centers, CSF PCR for M. tuberculosis is also available, but sensitivity is variable and a negative result does not rule out disease.

Angiostrongylus cantonensis is the most common cause of eosinophilic aseptic meningitis. It is a neurotropic parasite that is endemic in Southeast Asia and the Pacific rim. Humans can become infected by eating an infected slug or snail, or freshwater crustacean. Vegetables may also contain a small snail that may be unknowingly ingested. Review the history for the patient’s country of origin or travel to an endemic area. Patients very commonly have a peripheral eosinophilia as well as a CSF eosinophilis – there are only a few organisms in the differential diagnosis, and Angiostrongylus is the most common.

How do these pathogens cause aseptic meningitis?

Enteroviruses, the most commonly identified viral cause of aseptic meningitis, is transmitted by a fecal-oral route. They are non-enveloped capsids, and have single-strand RNA genome. The virus enters through the oropharynx and infects tonsillar tissue, where it replicates and may lead to a ‘minor viremia’ and local shedding. It is acid resistant and as it is shed from the pharynx into the alimentary tract, it passes to the distal small intestine where it replicates greatly in Peyer’s patches. This can then lead to a “major viremia” from which infection of end organs, including the central nervous system, can occur.

For full details, please see the chapter on enteroviruses, including poliovirus, echovirus, coxsackievirus.

What other additional laboratory findings may be ordered?

CSF lactate is being investigated as a method to distinguish bacterial from aseptic meningitis. However, data to date are mixed, so it is not appropriate to use to guide clinical decision making currently.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Epidemiology

Kupila, L, Vuorinen, T, Vainionpää, R, Hukkanen, V, Marttila, RJ, Kotilainen, P. “Etiology of aseptic meningitis and encephalitis in an adult population”. Neurology. vol. 66. 2006. pp. 75(Finnish study – 66% of cases of aseptic meningitis had etiologic agent identified, and enteroviruses most common at 26%.)

Clinical overview

Irani, DN. “Aseptic meningitis and viral myelitis”. Neurol Clin. vol. 26. 2008. pp. 635-55. (Good general overview of epidemiology, clinical features and management.)

Diagnostic

Sakushima, K, Hayashino, Y, Kawaguchi, T, Jackson, JL, Fukuhara, S. “Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis”. J Infect. vol. 62. 2011. pp. 255-62. (CSF lactate has a high negative likelihood ratio, but pre-test treatment may distort accuracy.)

Lee, BE, Davies, HD. “Aseptic meningitis”. Curr Opin Infect Dis. vol. 20. 2007. pp. 272-7. (Discusses possible advantages of using PCR and other nucleic acid amplification tests in patients with aseptic meningitis.)

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