Approach

Diagnosis of EEEV infection is based on clinical suspicion, history, and physical examination, with laboratory testing to confirm diagnosis. A high index of suspicion is necessary to diagnose EEEV infection since cases tend to be sporadic, though occurring mainly along the eastern seaboard and Gulf Coast of North America. The virus has also been found in South America where it has caused human disease in eastern Panama and other Latin American countries, albeit very rarely. South American EEEV (now known as the Madariaga virus [MADV]) has a different genetic lineage to North American EEEV. It is also less virulent than North American EEEV and associated with significantly less mortality.

The clinical spectrum of disease overlaps with that caused by other viral infections; therefore, the differential diagnosis is broad. Although some patients with EEEV infection may be asymptomatic, typical presentation includes fever, headache, altered mental status, and/or seizures. The diagnosis of EEEV infection is suggested by these symptoms in conjunction with a recent history of travelling, working, or residing in endemic regions, particularly wooded wetlands in the Atlantic and Gulf Coast states of North America and the Great Lakes region. Other epidemiological and environmental factors that should raise suspicion include peak mosquito season, a recent period of high rainfall, or concurrent epizootic in horses. Confirmation of the diagnosis requires laboratory investigations, consisting of serology or detection of virus by reverse transcription-polymerase chain reaction (RT-PCR) or viral isolation.

EEEV infection is a notifiable disease in some countries, including the US.

History

Patients usually report a history of exposure to mosquitoes, and will have lived or worked in endemic regions. Patients may also be aware of horses becoming ill in areas close to where they were exposed to mosquitoes.

The incubation period of EEEV in humans is thought to range between 4 to 10 days.[34] Following the incubation period, 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. 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) is most commonly seen in patients aged over 50 years or under 15 years. However, neurological involvement due to MADV is more prevalent in children.[16] In the absence of neurological symptoms, resolution of febrile illness typically occurs in 1 to 2 weeks.[5] 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.[5][15][35] 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.[4]

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, and seizures.[5] Seizures are most frequently generalised in nature and less commonly partial complex.[36] An intense headache with neck stiffness/nuchal rigidity may suggest neurological involvement.

Initial investigations

Laboratory tests (e.g., FBC, basic metabolic panel) should be ordered in patients presenting with signs and symptoms suggestive of EEEV infection. FBC may reveal leukocytosis.[36] Hyponatraemia is often present in blood chemistries.[36]

A specific diagnosis can be made serologically (e.g., using ELISA) with paired acute and convalescent serum samples by detection of a 4-fold rise in EEEV-specific IgG, or the presence of EEEV IgM, in serum or cerebrospinal fluid. 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.

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. If neurological/CNS involvement is suspected, a lumbar puncture should be performed and analyzed for cell count, culture, standard chemistries (e.g., glucose, protein), and viral detection by either RT-PCR or viral isolation. Results usually reveal neutrophilic pleocytosis, elevated RBCs, and elevated protein in patients with EEEV infection.[2][36]

These specific diagnostics are usually only available in central laboratories in some endemic countries, and in some government disease surveillance entities (e.g., the Centers for Disease Control and Prevention [CDC] in the US).

While imaging is not necessary for the diagnosis of EEEV infection, it can be used to assess for CNS involvement. MRI is more sensitive than CT for the detection of CNS abnormalities.[36] Initial head CTs may be normal.[2] When lesions are seen on CT, they tend to be present in the basal ganglia, thalamus, or cerebral cortex.[2][36] T2-weighted images on MRI tend to reveal areas of increased signal intensity, also in the basal ganglia, thalamus, and cerebral cortex.

Other investigations

An electroencephalogram (EEG) can also be used to assess CNS involvement. EEG may show generalised slowing, subclinical status epilepticus, and epileptiform activity.[2]

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