Encephalitis Workup

Updated: Aug 07, 2018
  • Author: David S Howes, MD; Chief Editor: Barry E Brenner, MD, PhD, FACEP  more...
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Approach Considerations

Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are viral in origin. Accordingly, in addition to standard blood and urine tests, studies may be performed to identify the infectious agent causing the encephalitis. [5] It is important, when possible, to distinguish acute arboviral encephalitides from potentially treatable acute viral encephalitides, especially herpes simplex encephalitis (HSE) and varicella-zoster encephalitis, as a high suspicion for these disorders and prompt treatment can reduce the severity of neurological sequelae and can be lifesaving.


Blood and Urine Tests

A complete blood count (CBC) with differential should be performed, although findings are often within the normal range.

Serum electrolyte levels are usually normal unless dehydration is present; the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs in 25% of patients with St Louis encephalitis.

The serum glucose level should be determined to rule out confusion due to treatable hypoglycemia and to compare with the cerebrospinal fluid (CSF) glucose value. Low serum results are found in nutritionally deprived patients, while diabetic patients may present with elevated glucose levels compatible with complicating hyperosmolar state or diabetic ketoacidosis.

Blood urea nitrogen (BUN) and creatinine levels are helpful to assess hydration status, and liver function tests should be performed to assess for end-organ dysfunction or the need to adjust antimicrobial therapy dosing regimens.

A lumbar puncture (LP) should be performed on all patients suspected of having a viral encephalitis. A platelet count and coagulation profile are indicated in patients who are chronic alcohol users, have liver disease, and those in whom disseminated intravascular coagulation (DIC) is suspected. The patient may require platelets or fresh frozen plasma (FFP) before LP.

A urinary electrolyte test should be performed if SIADH is suspected. Urine or serum toxicology screening may be indicated in selected patients presenting with a toxic delirium or confusional state.


Studies to Identify Infectious Agent

Herpes simplex virus (HSV) cultures of suspicious lesions and a Tzanck smear should be obtained. Viral cultures of CSF, including HSV, should be performed, although the incidence of the latter being positive is rare. Blood cultures for bacterial pathogens should be obtained.

Complement fixation antibodies are useful in identifying arbovirus. Cross-reactivity exists among a subgroup of arboviruses, the flaviviruses (eg, viruses that cause St Louis encephalitis, Japanese virus encephalitis [JE], and West Nile encephalitis [WNE]), and the antibodies found in persons inoculated with yellow fever vaccine.

Heterophile antibody and cold agglutinin testing for Epstein-Barr virus (EBV) may be helpful.

Serologic tests for toxoplasmosis can be helpful in light of an abnormal computed tomography (CT) scan, particularly in the case of single lesions. However, the overlap in titer levels between exposed but currently uninfected and reactivated groups may complicate interpretation.


Computed Tomography, Magnetic Resonance Imaging, and Electroencephalography

Performance of a head CT scan with and without contrast agent should be performed in virtually all patients with encephalitis. This should be done prior to LP if there are focal complaints or findings, signs to search for evidence of elevated intracranial pressure (ICP), obstructive hydrocephalus, or mass effect due to focal brain infection. Head CT scanning also helps exclude brain hemorrhage or infarction as a cause of an encephalopathic state. Magnetic resonance imaging (MRI) is more sensitive than CT scanning in demonstrating brain abnormalities earlier in the disease course.

In HSE, MRI may show several foci of increased T2 signal intensity in medial temporal lobes and inferior frontal gray matter. Head CT commonly shows areas of edema or petechial hemorrhage in the same areas. EEE and tick-borne encephalitis may show similar increased MRI signal intensity in the basal ganglia and thalamus.

In toxoplasmosis, contrast-enhanced head CT typically reveals several nodular or ring-enhancing lesions. Because lesions may be missed without contrast, MRI should be performed in patients for whom use of contrast material is contraindicated.

In HSE, electroencephalography (EEG) often documents characteristic paroxysmal lateral epileptiform discharges (PLEDs), even before neuroradiography changes. Eventually, PLEDs are positive in 80% of cases; however, the presence of PLEDs is not pathognomonic for HSE.


Analysis of Cerebrospinal Fluid

CSF analysis is essential. Typical patterns of findings in the CSF pressure and CSF analysis follow in the Table 1 regarding bacterial versus viral versus fungal (including cryptococcal) meningitis or encephalitis.

Table. Cerebrospinal Fluid Findings by Type of Organism (Open Table in a new window)

CSF Finding (Normal)

Bacterial Meningitis

Viral Meningitis*

Fungal Meningitis

Pressure (5-15 cm water)

  • Increased

  • Normal or mildly increased

  • Normal or mildly increased in most fungal and tuberculous CNS infections

  • Patients with AIDS and cryptococcal meningitis are at increased risk of blindness and death unless pressure maintained at < 30 cm

Cell counts, mononuclear cells/µL

Preterm (0-25)

Term (0-22)

6 mo+ (0-5)

  • Normal cell count excludes bacterial meningitis

  • Typically thousands of polymorphonuclear cells, but counts may not change dramatically or even be normal (classically in very early meningococcal meningitis or in extremely ill neonates)

  • Lymphocytosis with normal CSF chemistry results observed in 15-25% of patients, especially if counts < 1000 or if patient is partially treated

  • About 90% of patients with ventriculoperitoneal shunts and CSF WBC count >100 cells/µL are infected, though CSF glucose level often normal, and bacteria often less pathogenic

  • Cell count and chemistry levels normalize slowly (days) with antibiotics

  • Usually < 500, nearly 100% mononuclear

  • < 48 hours, clinically significant polymorphonuclear pleocytosis may be indistinguishable from early bacterial meningitis, particularly with EEE

  • Nontraumatic RBCs in 80% of patients with HSV meningoencephalitis, though 10% have normal CSF results

  • 100s of mononuclear cells

Microorganisms (none)

  • Gram stain 80% effective

  • Inadequate decolorization may cause Haemophilus influenzae to be mistaken for gram-positive cocci

  • Pretreatment with antibiotics may affect stain uptake, causing gram-positive species to appear to be gram-negative and decrease culture yield by an average of 20

  • No organism

  • India ink 80-90% effective for detecting fungi

  • AFB stain 40% effective for TB; increase yield by staining supernatant from at least 5 mL of CSF


Euglycemia (>50% serum)

Hyperglycemia (>30% serum)

  • Decreased

  • Normal

  • Sometimes decreased

  • In addition to fulminant bacterial meningitis, TB, primary amebic meningoencephalitis, and neurocysticercosis cause low glucose levels


Preterm (65-150 mg/dL)

Term (20-170 mg/dL

6 mo+ (15-45 mg/dL)

  • Usually >150 mg/dL

  • May be >1000 mg/dL

  • Mildly increased

  • Increased >1000 mg/dL, with relatively benign clinical presentation suggestive of fungal disease

*Some bacteria (eg, Mycoplasma, Listeria, Leptospira, Borrelia burgdorferi [Lyme disease]) cause alterations in spinal fluid that resemble the viral profile. An aseptic profile is also typical of partially treated bacterial infections (>33%, especially those in children, are treated with antimicrobials) and of the 2 most common causes of encephalitis—the arboviruses and the potentially curable HSV.

Wait 4 hours after glucose load.

AFB—acid-fast bacillus; CSF—cerebrospinal fluid; EEE-eastern equine encephalitis; HSV—herpes simplex virus; RBC—red blood cell; TB—tuberculosis; WBC—white blood cell.

The most important diagnostic test in the emergency department (ED) to rule out bacterial meningitis is prompt Gram staining and, if available, polymerase chain reaction (PCR) of the CSF in patients with suspected HSV encephalitis. PCR for HSV DNA is 100% specific and 75-98% sensitive within the first 25-45 hours. Types 1 and 2 cross-react, but no cross-reactivity with other herpes viruses occurs. Arguably, a series of quantitative PCRs documenting the decline of viral load with acyclovir treatment is strongly supportive of the diagnosis of HSV, and selected patients my avoid need for brain biopsy.


Brain Biopsy

Although most histologic features are nonspecific, brain biopsy is the criterion standard because of its 96% sensitivity and 100% specificity.

The presence of Negri bodies in the hippocampus and cerebellum are pathognomonic of rabies, as are HSV Cowdry type A inclusions with hemorrhagic necrosis in the temporal and orbitofrontal lobes.