eMedicine Specialties > Neurology > Neurological Infections

Viral Meningitis: Differential Diagnoses & Workup

Author: Amir Vokshoor, MD, Staff Neurosurgeon, Department of Neurosurgery, Spine Surgeon, Diagnostic and Interventional Spinal Care, St John's Health Center
Coauthor(s): Cordia Wan, MD, Staff Neurologist, Beverly Hills Pain and Neurology Institute
Contributor Information and Disclosures

Updated: Oct 28, 2009

Differential Diagnoses

Other Problems to Be Considered

Partially treated bacterial meningitis
Parameningeal infection
Coccidioides immitis infection
Cryptococcus neoformans infection
Histoplasma capsulatum infection
Candida species infection
Blastomyces dermatitidis infection
Mycoplasma infection
Listeria infection
Leptospira infection
Drugs
Heavy metals
Surgically implanted materials
Sjögren syndrome
Behçet disease
EEG in neurological infections

Workup

Laboratory Studies

• Routine chemistry and hematology tests should be performed. 
  
  • In neonatal and severe cases, arterial blood gases analysis, coagulation studies, and liver function tests should also be considered.
  • Serum WBC count is not a sensitive indicator of the severity of infection, especially in the immunocompromised, neonatal, or elderly patient. 
  • Serum sodium level may be abnormal because of dehydration or the rare occurrence of syndrome of inappropriate antidiuretic hormone secretion (SIADH).
  • Serum amylase level may be elevated in cases caused by mumps even in the absence of parotitis.
  • Recent 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; 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 viral meningitis group).
• CSF examination is the most important test in differentiating the cause of meningitis. Prior to lumbar puncture (LP), a CT scan should be performed in patients with any abnormal neurological sign, to exclude an intracranial lesion or obstructive hydrocephalus. 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. The following are some CSF characteristics used to support the diagnosis of viral meningitis:
  • Cells: Pleocytosis with WBC counts in the range of 50 to >1000 x 10⁹/L of blood has been reported in viral meningitis. Mononuclear cell predominance is the rule, but PMNs may comprise the majority of cells in the first 12-24 hours; the cell count usually is 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: CSF protein level usually is only slightly elevated, but can range from being normal to as high as 200 mg/dL.
  • Glucose: Normal in most cases, but severe hypoglycorrhachia has been reported, especially with LCMV or mumps virus. Very low glucose levels with a lymphocytic pleocytosis may be seen in tuberculous meningitis.
  • Culture, Gram stain, and acid-fast stain: These tests should be performed, as well as polymerase chain reaction (PCR) testing for the likely viral pathogens in selected cases.
  • Antigens: CSF latex antigen testing helps to rule out bacterial causes such as Haemophilus influenzae and Neisseria meningitidis. 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.
  • 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 clinical condition and suggestive facts in history and examination. For example, most cases of viral meningitis do not require PCR testing for HIV.
  • High WBC count in the CSF (especially neutrophils), high protein level, and low glucose level should suggest the diagnosis of a bacterial meningitis, although some viral pathogens may produce similar CSF profiles.
  • Real-time PCR testing for enterovirus was first cleared for marketing in 2007 by the FDA⁶ and is now available through commercial laboratories. 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 90 days of age or younger.⁷
  • 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.⁸  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 the patient has bacterial meningitis. 
    • This bacterial meningitis score may be used as an additional tool to aid in further management.
  • 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.⁹

Imaging Studies

• Imaging for suspected viral meningitis and encephalitis may include CT scan of the head with and without contrast, or MRI of the brain with gadolinium.
• CT scan with contrast helps in ruling out intracranial pathology. Contrasted scans should be obtained to evaluate for any enhancement along the meninges and to exclude cerebritis, intracranial abscess, subdural empyema, or other lesions. Alternatively, and if readily available, an MRI of the brain with gadolinium may be performed.
• MRI with contrast is the criterion standard in visualizing intracranial pathology in viral encephalitis (see Media file 1). HSV-1 commonly affects basal frontal and temporal lobes with a typical picture of diffusely enhancing bilateral lesions.
  
  

  

  T1-weighted MRI of brain demonstrates diffuse enhancement of the meninges in viral meningoencephalitis.

  [ CLOSE WINDOW ]

  

  T1-weighted MRI of brain demonstrates diffuse enhancement of the meninges in viral meningoencephalitis.

Other Tests

• All patients whose condition is not improving clinically within 24-48 hours should have more extensive work-up 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 PCR testing for HIV and CMV.
  • 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 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 case of suspected encephalitis, MRI with contrast enhancement and adequate visualization of the basal frontal and temporal areas is necessary.
• 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.

Procedures

• Lumbar puncture is the most important procedure used in 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.
• CT scan usually is 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 rarely is 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 neuro-intensivist.
• Operative brain biopsy for confirmation of herpetic encephalitis largely has been replaced by PCR testing for viral DNA. In some cases, encephalomalacia due to an unknown viral infection may be confused with vascular infarction or rarely a tumor; a biopsy may be helpful. With the use of stereotactic localization and a needle biopsy, morbidity is minimal.

Histologic Findings

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 increased number of microglial cells have been noted in specimens from patients who died of viral encephalitis.

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