Viral Meningitis Workup

Routine chemistry and hematology tests should be performed.

In neonatal and severe cases of viral meningitis, arterial blood gas analysis, coagulation studies, and liver function tests should also be considered.

The serum white blood cell (WBC) count is not a sensitive indicator of the severity of infection, especially in the immunocompromised, neonatal, or elderly patient.

The serum sodium level may be abnormal because of dehydration or the rare occurrence of syndrome of inappropriate antidiuretic hormone secretion (SIADH).

The serum amylase level may be elevated in cases of viral meningitis that are caused by mumps, even in the absence of parotitis.

Reports have shown high C-reactive protein (CRP) levels in the serum of children with bacterial meningitis whose CSF Gram stain findings were negative for bacteria. However, a comparable group of children with viral meningitis did not have similar elevations in serum CRP (ie, 50-150 in bacterial meningitis group vs < 20 in the viral meningitis group).

All patients whose condition is not improving clinically within 24-48 hours should have a more extensive workup to discern the cause of meningitis.

Blood, feces, and throat swabs may be sent for viral serology and cultures.

Acid-fast staining of CSF should be performed, and the remaining fluid should be sent for testing, using the polymerase chain reaction (PCR), for HIV and CMV. ^[8]

Serum titers of antibodies against HIV and toxoplasma should be obtained.

Additional serum collection 10-21 days later may aid in discerning rising titers in the antibodies against specific viral pathogens; a 4-fold increase in viral antibodies confirms the diagnosis. This is particularly useful for arboviral and LCMV cases, but it also is helpful in ruling out toxoplasmosis, leptospirosis, borreliosis, and rickettsial infections. Although some of these studies do not yield an immediate result for clinical decision making, they may be useful for prognostication.

In patients in whom encephalitis is suspected, MRI with contrast enhancement and adequate visualization of the basal frontal and temporal areas is necessary

Electroencephalography (EEG) may be performed if encephalitis or subclinical seizures are suspected in the altered patient. Periodic lateralized epileptiform discharges (PLEDs) are often seen in herpetic encephalitis.

CSF examination is the most important test in differentiating the cause of meningitis. Prior to lumbar puncture (LP), a computed tomography (CT) scan should be performed in patients with any abnormal neurologic sign, to exclude an intracranial lesion or obstructive hydrocephalus. ^[20] CSF culture remains the criterion standard in discerning bacterial or pyogenic from aseptic meningitis. Again, a partially-treated bacterial meningitis may present with a negative Gram stain result and thus appear aseptic.

Consider saving CSF for less common tests (ie, PCR for HIV and CMV) if the cause of meningitis is not certain after initial tests.

The exact sequence of testing for these agents depends on the patient’s clinical condition and on suggestive facts in his or her history and examination. For example, most cases of viral meningitis do not require PCR testing for HIV.

A high WBC count in the CSF (especially neutrophils), a high protein level, and a low glucose level should suggest a diagnosis of a bacterial meningitis, although some viral pathogens may produce similar CSF profiles.

PCR testing

Real-time PCR testing for enterovirus was first cleared for marketing in 2007 by the US Food and Drug Administration (FDA) and is now available through commercial laboratories. ^[9] Results are available in approximately 3 hours, as opposed to days to weeks in traditional PCR studies.

In clearing the test, the FDA cited a multicenter study in which 96% of patients who tested positive did have viral meningitis, and 97% of patients who tested negative did not have viral meningitis.

In a retrospective study of routine PCR testing of CSF for enterovirus—using a test with turnaround time of 23 hours—confirmation of enteroviral meningitis by PCR decreased the length of hospitalization and the duration of antibiotic use among infants aged 90 days or younger. ^[10]

Pleocytosis

A retrospective multicenter study found that neither the presence nor quantity of immature neutrophils (bands) in CSF independently predicted bacterial meningitis among children with CSF pleocytosis. ^[11]

Pleocytosis with WBC counts in the range of 50 to more than 1000 x 10⁹/L of blood has been reported in viral meningitis. Mononuclear cell predominance is the rule, but PMNs may make up most cells in the first 12-24 hours; the cell count is usually then dominated by lymphocytes in the classic CSF pattern of viral meningitis. This helps to distinguish viral from bacterial meningitis, which has a much higher cell count and a predominance of PMNs in the cell differential; this is by no means an absolute rule, however.

Protein levels

The CSF protein level usually is only slightly elevated, but it can range from normal to as high as 200 mg/dL.

Glucose levels

The glucose level is normal in most cases, but severe hypoglycorrhachia has been reported, especially with LCMV or the mumps virus. Very low glucose levels with a lymphocytic pleocytosis may be seen in tuberculous meningitis.

Antigens

CSF latex antigen testing helps to rule out bacterial causes of meningitis, such as Haemophilus influenzae and Neisseria meningitidis. The addition of a drop of CSF sediment to an India ink preparation may aid in the diagnosis of cryptococcal meningitis, although antigen assay testing for cryptococci is the preferred test.

Other tests

Culture, Gram stain, and acid-fast stain tests should be performed.

Tests in the absence of clinical improvement

If the CSF Gram stain result is negative but moderate-to-severe pleocytosis is noted (WBC >1000 x 10⁹/L), a repeat LP should be considered in 12-18 hours if the patient has not improved clinically. All patients with suspected bacterial meningitis should be treated empirically with appropriate antibiotics.

After the bacterial Gram stain, latex antigen tests, and cultures return negative, antibacterial therapy can be discontinued. If the results of PCR testing of the CSF and the viral culture for herpes simplex are negative, acyclovir can be discontinued; otherwise, a 10-day course is recommended.

If no clinical improvement in the patient is noted and all the common bacterial and viral pathogens have been ruled out, the following tests should be performed and the therapy modified depending on their results:

• CSF - Venereal Disease Research Laboratories test (VDRL), PCR for CMV, acid-fast stain

• Skin - Purified protein derivative (PPD) to help exclude tuberculosis

Blood - HIV antibody and PCR, rapid plasma reagent (RPR), Lyme antibody (in areas of endemic disease or if history suggests), toxoplasmosis antibody (especially in infants and newborns)

Imaging for suspected viral meningitis and encephalitis may include CT scanning of the head, with and without contrast, or MRI of the brain, with gadolinium.

CT scanning with contrast helps to rule out intracranial pathology. Contrasted scans should be obtained to evaluate for any enhancement along the meninges and to exclude cerebritis, intracranial abscess, subdural empyema, and other lesions.

MRI with contrast is the criterion standard in visualizing intracranial pathology in viral encephalitis. HSV-1 commonly affects the basal frontal and temporal lobes with a typical picture of diffusely enhancing bilateral lesions. An MRI scan of a patient with meningoencephalitis is seen below.

LP is the most important procedure used in the diagnosis of viral meningitis. Other potential procedures, depending on individual indications and disease severity, include intracranial pressure monitoring, brain biopsy, and ventricular drainage or shunting. ^[12]

CT scanning is usually performed prior to LP to rule out intracranial hematoma, mass effect, or obstructive hydrocephalus. The LP itself may provide significant symptomatic relief, presumably due to the decrease in intracranial pressure. LP should be performed in the standard sterile fashion, and the CSF opening pressure should be measured. Coagulopathy due to intrinsic or extrinsic factors (eg, warfarin) is a relative contraindication to LP. The clinician should exercise caution and, as for all medical procedures, weigh the risks and benefits associated with each individual case.

Intracranial pressure monitoring is rarely needed in patients with meningoencephalitis complicated by cerebral edema. The risks of intracranial hemorrhage in cases with coagulopathy often outweigh the diagnostic benefit of the monitor. The monitor should be placed under strictly sterile conditions by a neurosurgeon or neurointensivist.

Operative brain biopsy for confirmation of herpetic encephalitis largely has been replaced by PCR testing for viral DNA. In some cases, however, encephalomalacia due to an unknown viral infection may be confused with vascular infarction or, rarely, a tumor; in these cases, a biopsy may be helpful. With the use of stereotactic localization and a needle biopsy, morbidity is minimal.

Because of the low mortality rate associated with acute viral meningitis, pathologic features other than lymphocytic response within the CSF are generally not in evidence. The leptomeninges undergo inflammation with PMNs and later mononuclear cells in the acute phase of the disease. Perivascular cuffing, neuronophagia, and an increased number of microglial cells have been noted in specimens from patients who died of viral encephalitis.

In 2007, the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics published a Bacterial Meningitis Score that clinically predicts whether patients are at high or low risk for having bacterial meningitis versus aseptic meningitis. ^[13] According to the score, patients have a very low risk for bacterial meningitis if all of the following are absent:

• Positive CSF Gram stain

• CSF absolute neutrophil count (ANC) of ≥1000

• CSF protein of ≥80 mg/dL

• Peripheral ANC of ≥10,000 cells/mcL

• Seizure before or at time of presentation

The higher number of criteria present, the higher the chance is that the patient has bacterial meningitis.