Approach

Diagnosis is based on clinical suspicion, history, and physical examination, with laboratory testing to confirm the diagnosis. A high index of suspicion is necessary to diagnose the condition because cases tend to be sporadic, though occurring mainly along the eastern seaboard and Gulf Coast of North America, particularly during the epidemic season from July to September.

Suspect the diagnosis in any person presenting with a febrile or acute neurological illness with a history of recent exposure to mosquitoes (or less commonly, organ transplantation, or potentially blood transfusion), particularly in the summer months in geographical areas where virus activity has been reported.[1]​ Eastern equine encephalitis virus (​EEEV) infection is a notifiable condition; report all cases to your local health authority.

The clinical spectrum of disease overlaps with that caused by other viral infections; therefore, the differential diagnosis is broad. Consider arthropod-borne viruses (e.g., West Nile virus, St Louis encephalitis, Powassan viruses, La Crosse virus) in the differential diagnosis, as well as the more common causes of encephalitis (e.g., herpes simplex virus, enteroviruses).[1]

Confirmation of the diagnosis requires laboratory investigations, consisting of serology (preferred method), or detection of virus by reverse transcription-polymerase chain reaction (RT-PCR) or viral isolation.

History

Patients usually report a recent history of exposure to mosquitoes, and will have lived, visited, or worked in endemic regions. Other epidemiological and environmental factors that should raise suspicion include peak mosquito season or a recent period of high rainfall. Patients may also be aware of horses becoming ill in areas close to where they were exposed to mosquitoes.

The incubation period in humans is thought to range between 4 to 10 days, but can be longer in people who are immunocompromised.[1]​ Approximately 96% of patients remain asymptomatic and have no apparent illness.[44]

Among those who develop symptoms, patients may present with symptoms that resemble influenza or dengue fever (e.g., acute onset of fever, chills, severe headache, arthralgias, and myalgias), with or without neurological symptoms.[1]

  • The presence of an intense or moderate to severe headache, or a mild headache that progressively worsens, is suggestive of neurological involvement.

  • Neurological/central nervous system (CNS) involvement (e.g., encephalitis) occurs in <5% of patients, and is most commonly seen in patients aged over 50 years or under 15 years.[1]

In the absence of neurological symptoms, resolution of febrile illness typically occurs in 1 to 2 weeks.[4] When neurological symptoms/signs are present, they tend to appear several days into the course of illness, and include irritability, drowsiness, altered mental status, seizures, cranial nerve palsies, focal weakness, photophobia, and meningismus. This stage may also be accompanied by nausea, vomiting, abdominal pain, and diarrhoea. Severe cases almost always result in coma and death, which usually occurs 2 to 10 days after symptom onset.[1][4]​​[45]​​​​​ There has been one reported case of EEEV-associated haemophagocytic lymphohistiocytosis in an infant aged 5 months, which resulted in severe neurological injury and death.[3]

Physical examination

During the early stages of illness, the physical examination may reveal pyrexia. If there is neurological/CNS involvement, signs include neck stiffness (nuchal rigidity), altered mental status, tremors, focal decreased motor function, hemiparesis, cranial neuropathies, and seizures.[4][46]​ Seizures are most frequently generalised in nature and less commonly partial complex.[46] An intense headache with neck stiffness/nuchal rigidity may suggest neurological involvement.

Patients may also present with signs of cerebral oedema, intracranial hypertension, or aseptic meningitis.

Initial investigations

Specific diagnostics for EEEV infection are typically only available in central laboratories in endemic countries, and in some government disease surveillance agencies (e.g., US Centers for Disease Control and Prevention [CDC], state health departments).

Laboratory tests

  • Order routine laboratory tests (e.g., full blood count [FBC], basic metabolic panel, inflammatory markers) in patients presenting with signs and symptoms suggestive of infection.

  • FBC may reveal leukocytosis.[46]​ Patients may develop leukopenia and/or thrombocytopenia at a later stage.[14]

  • Hyponatraemia is often present in blood chemistries.[46]

  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may also be increased.[14]

Serological testing

  • Serological testing is the preferred method for diagnosis and is recommended in all patients with suspected infection.[1]

  • Serology (e.g., enzyme-linked immunosorbent assay [ELISA]) with paired acute and convalescent serum samples by detection of a fourfold rise in EEEV-specific immunoglobulin (Ig) G, or the presence of EEEV IgM, in serum or cerebrospinal fluid (CSF) is diagnostic.[47]​ Both IgM and IgG become positive approximately after 5 days of onset of illness. IgM remains positive for at least 1 month after onset of illness, whereas IgG likely remains positive for decades.

  • However, ELISA (especially IgG ELISA) has low specificity for EEEV as it tends to cross-react with other alphaviruses (e.g., Venezuelan equine encephalitis, Mayaro, and chikungunya viruses); therefore, if ELISAs are used for serology, further confirmation by plaque reduction neutralisation test (PRNT) is warranted.[1]

Molecular testing and immunohistochemistry

  • Viraemia is very transient in patients with EEEV infection, and the virus is rarely isolated or amplified by RT-PCR from peripheral blood; therefore, serological testing remains the primary method for diagnosis.

  • However, molecular testing may be required for immunocompromised patients.[1]​ Immunocompromised patients present a particular diagnostic challenge, particularly individuals with solid organ transplant, who are unable to mount an appropriate, measurable immune response, and present a higher mortality risk.[48][49]​ Serological testing can be challenging in these patients; therefore, they may require additional molecular testing for diagnosis.

  • RT-PCR testing or immunohistochemistry with virus-specific monoclonal antibodies of postmortem brain tissue can confirm the diagnosis in complex cases.[1]

CSF studies

  • If neurological/CNS involvement is suspected, perform a lumbar puncture and CSF analysis for cell count, culture, standard chemistries (e.g., glucose, protein), and viral detection by either RT-PCR or viral isolation.

  • Results usually reveal initial neutrophilic pleocytosis (followed by lymphocyte predominance), elevated red blood cells, normal glucose, and elevated protein.[1][33][46]​​​

Imaging

While imaging is not necessary for the diagnosis of EEEV infection, it can be used to assess for CNS involvement.

Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) for the detection of CNS abnormalities, and is the preferred imaging modality.[46][50]

  • Early stages of infection reveal a preference for deep grey matter structures, especially the basal ganglia, bilateral thalami, mesial temporal lobes, and brainstem.[46][51]​ Involvement of deep grey matter structures can help with early differentiation of EEEV infection from herpes simplex infection. MRI findings may reveal typical findings of symmetric T2 hyper-intensities in the lentiform nuclei. In some cases, meningeal enhancement may be seen.

  • Results between adults and children may differ. One study highlighted that children revealed 100% cortical involvement, while only 29% of adults exhibited cortical changes.[51]

​Initial head CT may be normal.[33] When lesions are seen on CT, they tend to be present in the basal ganglia, thalamus, or cerebral cortex.[33][46]​​

Other investigations

An electroencephalogram (EEG) can also be used to assess CNS involvement. EEG may show generalised slowing, subclinical status epilepticus, and epileptiform activity.[33]​ EEG studies can exhibit periodic 0.25 to 0.5 Hz transient epileptiform discharges. Notably, the voltage in EEEV infection is significantly lower compared with herpes encephalitis.[52]

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