eMedicine Specialties > Infectious Diseases > CNS Infections

Eastern Equine Encephalitis: Differential Diagnoses & Workup

Author: Mohan Nandalur, MD, Staff Physician, Department of Internal Medicine, Section of Cardiovascular Medicine, Washington Hospital Center
Coauthor(s): Andrew W Urban, MD, Chief, Section of Infectious Diseases, Middleton Memorial Veterans Hospital; Clinical Assistant Professor, Department of Internal Medicine, University of Wisconsin at Madison
Contributor Information and Disclosures

Updated: Oct 31, 2007

Differential Diagnoses

Other Problems to Be Considered

Mumps
Stroke
Metabolic encephalopathy
Reye syndrome
Bartonella infection
Cytomegalovirus
Ebstein-Barr virus
Prion disease
Toxic ingestions
AIDS

Workup

Laboratory Studies

• Because of the numerous organisms that can produce signs and symptoms similar to those of eastern equine encephalitis (EEE), clinical diagnosis is difficult. Likewise, laboratory confirmation is challenging because it requires either specific serologic findings or virus isolation in brain tissue or CSF. If the possibility of EEE is considered early, recovery of the virus from the serum during the prodromal phase is possible; however, isolation from either the blood or CSF is often difficult.
• Blood cultures reveal nothing in this particular disease but may be performed if suspicion of bacterial infection is high.
• The current CDC diagnosis guidelines of an arbovirus require the presence of an acute febrile illness with encephalitis during a time when viral transmission is likely and one of the following criteria are evident:
  • Greater than 4-fold increase in the viral antibody titer between acute and convalescent sera (often 10 wk apart)
  • Viral isolation from the CSF, blood, or tissue
  • Immunoglobulin M (IgM) positive to the organism in the CSF: Presumptive positives can be made from the remaining biochemical assays (eg, hemoagglutinin inhibition, immunofluorescence, neutralization, complement fixation).
• Biochemical assays are valuable for EEE diagnosis. With early suspicion, obtain sera at 2- to 3-day intervals. A potential drawback is the slow turnaround time for these test results. Additionally, VecTest antigen assays and Vero cell plaque assays have been in use for arthropod surveillance programs and have also been effective in human diagnosis.¹ Potential assays for isolation include the following:
  • Enzyme-linked immunosorbent assay (ELISA) is used to detect IgM, primarily during convalescent stages or prolonged courses.
  • ELISA may be used to detect antiarboviral immunoglobulin G (IgG), which has similar results to the neutralization assay (current use primarily as an adjunct to the IgM ELISA).²
  • Serum hemoagglutinin-inhibition titer of at least 1:320 is most common.
  • Complement fixation titer of at least 1:128 primarily occurs in convalescing patients.
  • Immunofluorescence titer of at least 1:256 is uncommon.
  • Neutralization assay titer of at least 1:160 is common.
• Few laboratory test abnormalities are particular to EEE. The following are abnormal findings:
  • Leukocytosis has a 95% prevalence rate, with a median of 15,000 cells/µL. It is predominantly neutrophilic, but bands or lymphocytosis may not necessarily be visualized.
  • Hyponatremia often develops, but the exact relationship between the virus being directly responsible and a secondary syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has not been outlined.
• CSF findings
  • Increases in protein and protein concentration in the CSF, approximately 100 mg/dL, are common.
  • The CSF RBC count may be elevated.
  • The CSF WBC count may be elevated (initial WBC count 500-2000/µL with a median of 600 WBC/µL with a predominance of neutrophils).
  • Hypoglycorrhachia is not present.
• EEE-specific TaqMan reverse transcriptase polymerase chain reaction (PCR) analysis
  • Use this as a final alternative to analyze the various organisms known to cause encephalitis.
  • This analysis will hopefully provide rapid diagnosis in the future.
  • Recent studies are more promising for PCR because they indicate higher accuracy rates than the 10% likelihood of serological diagnostics for yielding positive virus results.
  • Other current advantages include the ability to target antiviral therapy, the ability to reduce the need for brain biopsies, and the ability to increase the speed of diagnosis (obtaining the panel can occur in 72 hours).
  • The current limitation is that this study likely requires a state or national effort, which may not be available for EEE.

Imaging Studies

Neuroimaging studies (eg, CT scanning, MRI) may aid in early virus identification and are routinely performed in patients with CNS symptoms. Relatively recent advances in imaging show that previous neuroradiographic manifestations of EEE were not precisely defined. Early studies (not entirely sensitive) revealed a predilection for the thalamic nuclei and the basal ganglia³ ; however, these changes are also common in infections with Japanese encephalitis, measles, mumps, echovirus 25, conjunctivitis (CJ) disease, cyanide poisoning, and carbon monoxide (CO) poisoning. Both CT scanning and MRI may play an important role in the early identification of EEE. Of note, most radiographic changes resolve in those patients who recover.

• CT scanning
• Perform this test to monitor the evolution of lesions or to determine primary areas of disease.
• The most common finding is a lesion of the basal ganglia.
• Lesions vary in size and may exhibit a secondary mass effect with edema.
• A CT scan may reveal areas of punctate hemorrhage, focal edema with a mass effect, poorly marginated lesions, or interventricular hemorrhage.
• In elderly patients, the findings can mimic early infarction or they may be nonspecific, which is common in elderly patients.
• Occasionally, meningeal enhancement may also be present, indicating a subarachnoid hemorrhage or meningitis.
• MRI
• MRI often is sensitive to early changes secondary to EEE and aids in a more prompt diagnosis in up to 60% of patients. Compared with CT scanning, MRI is more sensitive and reveals more abnormalities with increased detail.
• Use a T2-weighted image to best observe the lesions, which appear as areas of increased signal intensity.
• The most commonly affected areas of the CNS include the basal ganglia (unilateral or asymmetric with occasional internal capsule involvement) and thalamic nuclei. Other areas include the brain stem (often the midbrain), periventricular white matter, and cortex (most often temporally).
• The MRI findings are abnormal in all comatose patients, and normal MRI findings may indicate the need to consider another diagnosis.
• MRI also provides critical information in differentiating EEE from herpes encephalitis because EEE is common in the basal ganglia and herpes is not. If attenuation is present in the basal ganglia, herpes tends to occur laterally, whereas EEE has a medial preponderance.

Other Tests

• EEG: This test often reveals a generalized slowing and disorganization of the background. Later, this condition is followed by epileptiform activity that varies from isolated discharges to gross seizure activity.
• Culture growth: Previously, the recovery of EEE was limited because only a few facilities had the resources to amplify the virus. Recent studies indicate excellent growth of the virus recovered from patient CSF in A549 and MRC-5 cell cultures, which are mediums that virology laboratories routinely use to recover adenovirus, herpes simplex virus (HSV), and enterovirus.⁴
• Brain biopsy: This is rarely indicated and is simply a last resort for diagnosis.

Procedures

• Obtain a lumbar puncture (LP) as soon as possible when EEE is strongly suspected. Assess the CSF for elevated opening pressures and obtain a CBC count with differential, Gram stain, glucose, protein, bacterial culture, viral culture, fungal culture, acid-fast bacillus, India ink stain, and Venereal Disease Research Laboratory (VDRL) test.

Histologic Findings

CNS histopathology

The perikaryon and dendrites are primarily affected and demonstrate evidence of cytoplasmic swelling, eosinophilia, and nuclear pyknosis. Occasionally, mature viral particles are observed in extracellular spaces. The brain is grossly edematous, and inflammation is evident both parenchymally and perivascularly, as outlined above. Perivascular inflammation, vasculitis, thrombi, neurolysis, neuronophagia, and demyelination may be observed. The predominance of neutrophils in the inflammatory cell type is particularly important.

• Search for CME/CE on This Topic »

• West Nile Encephalitis (Infectious Diseases)
• CBRNE - Biological Warfare Agents (Emergency Medicine)
• Viral Encephalitis (Neurology)
• Encephalitis (Emergency Medicine)

• Encephalitis Causes
• Brain and Nervous System Center
• Encephalitis Overview
• Encephalitis Symptoms
• Encephalitis Treatment

• Human Febrile Illness Caused by Encephalomyocarditis Virus Infection, Peru