Journal of Clinical Virology 42 (2008) 418421

Case report

Eastern equine encephalitis leading to

multi-organ failure and sepsis
Anita J. Reddy a, , Christopher W. Woods b ,
Karen E. Welty-Wolf a,b
a

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Durham Veterans Administration
and Duke University Medical Centers, Durham, NC 27710, United States
b Division of Infectious Diseases, Department of Medicine, Durham Veterans Administration and
Duke University Medical Centers, Durham, NC 27710, United States
Received 6 March 2008; accepted 17 March 2008

Keywords: Eastern equine encephalitis; Multi-organ failure; Myocarditis; Neurologic dysfunction; Sepsis

1. Case presentation
A 51-year-old African American male presented to his
local physician in September with dysphagia and odynophagia to solids and cervical lymphadenopathy. A computed
tomographic (CT) scan of the neck was unremarkable, and
he was discharged with treatment for pneumonia with oral
antibiotics. He returned to the hospital a month later reporting cough productive of white sputum, shortness of breath
with mild activity, and an eight pound weight loss. A chest
X-ray (CXR) showed a new left lower lobe lung opacity and
cardiomegaly, and labs were notable for leukocytosis and
elevated myoglobin. Social history revealed that he was a
non-smoker and worked as a security officer. He had served
in the Army for 20 years, stationed in the Middle East, Southeast Asia and Japan. He was building his own home in a
woody lot but did not recall any tick bites. He was admitted
to the hospital and started on intravenous antibiotics for presumed community acquired pneumonia. Over the next few
days he had worsening odynophagia, persistent fevers, and
developed elevated cardiac troponin levels, prompting treatment for acute coronary syndrome and transfer to our facility
for further care.
Abbreviations: ARDS, acute respiratory distress syndrome; CDC, Centers for Disease Control; CT, computed tomography; CXR, chest radiograph;
EEE, Eastern equine encephalitis; MRI, magnetic resonance imaging.
Corresponding author at: 9500 Euclid Avenue, Desk A90, Cleveland
Clinic Health System, Cleveland, OH 44195, United States.
Tel.: +1 216 444 4506.
E-mail address: reddya3@ccf.org (A.J. Reddy).
1386-6532/$ see front matter 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2008.03.008

After transfer he complained of sharp short-lived chest

pain without associated nausea, vomiting, diaphoresis, lower
extremity edema, orthopnea, or paroxysmal nocturnal dyspnea. He did report myalgias and muscle weakness which
had started at the same time as his odynophagia. On neurologic exam, he did not exhibit any motor weakness or any
other focal abnormalities. Fevers persisted despite negative
blood cultures, and over the following week he developed
transaminitis, acute renal failure, thrombocytopenia, anemia,
altered mental status, and worsening pulmonary infiltrates
with hypoxemic respiratory failure requiring mechanical ventilation. Laboratory data on arrival was also notable for
leukocytosis with a neutrophilic predominance, metabolic
acidosis, and elevated CPK and aldolase. Arterial blood gas
revealed pH 7.41, PCO2 32.4 Torr (2.2 kPa), PO2 76.5 Torr
(5.2 kPa) on 0.6 FiO2 . A lumbar puncture was performed and
cerebrospinal fluid revealed 82 red cells, 10 white cells with
55% monocytes, 21% lymphocytes, 19% bands, and elevated
protein of 89 and glucose 92. Blood, sputum, and CSF cultures and cryptococcal antigen were negative. Sedimentation
rate was elevated to 87, but rheumatologic studies were otherwise unremarkable. Chest radiograph and chest CT revealed
bilateral infiltrates consistent with acute lung injury.
Because of the patients persistent, unexplained fever,
myositis and myocarditis, and altered mental status, a
search for unusual infectious etiologies was undertaken.
Bronchoscopy with bronchoalveolar lavage was performed
and cultures for bacteria, fungi, viruses and opportunistic
organisms were negative. A muscle biopsy showed muscle fiber atrophy but no evidence of inflammation. Electron

A.J. Reddy et al. / Journal of Clinical Virology 42 (2008) 418421

419

was also severe neuronal loss and gliosis in the dorsal motor
nucleus of the vagus nerve, possibly representing an older,
inactive inflammatory process and would most probably be
associated with symptoms of autonomic or cranial nerve dysfunction.

2. Discussion
2.1. Eastern equine encephalitis

Fig. 1. Brain magnetic resonance imaging: T2 (A) and T1 (B) weighted

images. T2 prolongation in bilateral thalami, bilateral basal ganglia and right
posterior parietal cortex.

microscopy of muscle tissue demonstrated focal clearing of

the mitochondrial matrix, occasional mitochondrial inclusions, and decreased cristae consistent with sepsis or viral
myositis. Head CT without intravenous contrast was unremarkable but subsequent brain magnetic resonance imaging
(MRI) showed T2 prolongation in bilateral thalami and basal
ganglia, as well as the right posterior parietal cortex (Fig. 1).
Serologies for Eastern equine encephalitis (EEE) revealed a
positive EEE IgG at a titer of 1:128 and EEE IgM titer of
1:16. Other arboviral titers, including West Nile virus and
Western equine encephalitis serologies were negative. Confirmatory testing for EEE by plaque reduction neutralization
test (PRNT) revealed a titer of 1:640, consistent with acute
EEE infection.
The patients hospital course was complicated by sepsis and continued multi-organ failures of the lung, liver,
heart, brain and kidneys. The patient also exhibited signs
of neurologic dysfunction, including uncontrollable tachypnea despite adequate ventilation and labile blood pressure.
Profound ventilatory drive persisted despite liberal use of
sedatives and narcotics. Despite aggressive treatment the
patient failed to improve neurologically and passed away after
withdrawal of care.
Autopsy showed diffuse alveolar damage consistent with
acute respiratory distress syndrome (ARDS), passive congestion in the liver, esophageal erosion, tracheitis, and cystitis.
Neuropathology revealed marked encephalitis in the right
basal ganglia and modest inflammation in the pons. There

Eastern equine encephalitis is a mosquito-borne viral

disease which occurs mostly in the eastern half of the
United States. The EEE virus is a member of the alphavirus
genus and Togaviridae family1 and is transmitted to humans
through mosquitos, although viral replication and transmission cycles take place between birds and mosquitos.
Horses are the most frequent incidental hosts, and outbreaks of infection in horses commonly precede human
cases. The most common species of mosquito infected with
EEE is Culiseta melanura, but infected Anopheles sollicitans and A. vexans are the most likely vectors for infection
in mammals.2
EEE causes only about 1% of all cases of viral encephalitis in the United States each year, but due to mortality rates
of approximately 33%, it is considered one of the most serious mosquito-borne diseases. Individuals older than 50 and
younger than 15 are at the greatest risk of developing severe
disease. There have been approximately 220 confirmed cases
in the U.S. from 1964 to 2004, with most cases occurring
between June and October.1
Symptomatic EEE typically presents as a mild flu-like illness 310 days after being bitten by an infected mosquito.
There are no specific laboratory abnormalities characteristic
of the disease, although these patients may have leukocytosis and hyponatremia. EEE infection may also lead to rapid
progression of encephalitis and coma by spread to the central nervous system through the blood. Involvement of the
brain is manifested histologically by necrosis, neutrophilic
infiltrates and meningitis, as well as an acute vasculitis.
Necrosis generally involves the gray matter and spares the
spinal cord.3
EEE is difficult to diagnose due to its nonspecific symptoms and the Centers for Disease Control case definition
requires the presence of at least one clinical and one laboratory criteria.4 Confirmation requires clinical symptoms
(neuroinvasive or non-neuroinvasive) and specific serologic
findings or documentation of the virus in cerebrospinal fluid
or brain tissue (Table 1). Laboratory diagnosis includes IgM
testing of serum and cerebrospinal fluid and neutralizing antibody testing of acute and convalescent phase serum. Imaging
studies of the brain typically indicate involvement of the basal
ganglia, thalami, and brainstem.3,5
There is no specific treatment available for EEE and therapy is directed towards supportive care. Approximately half
of the patients who survive EEE have mild to severe perma-

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Table 1
Centers for Disease Controls case definition for confirmed or probable EEE
Criteria (Denition of case requires at least one clinical and one
laboratory criteria)
CLINICAL
Neuroinvasive
Fever and one of the following (in the absence of a more likely
clinical explanation)
Acutely altered mental status (e.g., disorientation, obtundation, stupor,
or coma), or
Other acute signs of central or peripheral neurologic dysfunction (e.g.,
paresis or paralysis, nerve palsies, sensory deficits, abnormal reflexes,
generalized convulsions, or abnormal movements), or
Pleocytosis (increased white blood cell concentration in cerebrospinal
fluid [CSF]) associated with illness clinically compatible with meningitis
(e.g., headache or stiff neck)
Non-neuroinvasive
Presence of documented fever, and
Absence of neuroinvasive disease, and
Absence of more likely explanation for clinical illness
LABORATORY
Conrmed
Fourfold or greater change in virus-specific serum antibody titer, or
Isolation of virus from or demonstration of specific viral antigen or
genomic sequences in tissue, blood, CSF, or other body fluid, or
Virus-specific immunoglobulin M (IgM) antibodies demonstrated in
CSF by antibody-capture enzyme immunoassay (EIA), or
Virus-specific IgM antibodies demonstrated in serum by
antibody-capture EIA and confirmed by demonstration of virus-specific
serum immunoglobulin G (IgG) antibodies in the same or a later specimen
by another serologic assay (e.g., neutralization or hemagglutination
inhibition)
Probable
Stable (less than or equal to a twofold change) but elevated titer of
virus-specific serum antibodies, or
Virus-specific serum IgM antibodies detected by antibody-capture
EIA but with no available results of a confirmatory test for virus-specific
serum IgG antibodies in the same or a later specimen

inappropriate tachypnea. Viral encephalitis involving the

hypothalamus and brainstem has been shown in case reports
to be associated with Ondines curse and failure of automatic
control of ventilation,6 including central hyperventilation
syndromes. Viral infections involving the brain can also lead
to vagal impairment and systemic sympathetic upregulation
and subsequent change in receptor sensitivity of autonomic
reflexes.7 Another consideration could be dysfunction of the
autonomic centers in the thalamus or hypothalamus resulting in the condition termed paroxysmal autonomic instability
which can occur after various types of brain injury.8 Another
explanation for this patients tachypnea could be due to
damage or inflammation to the upper brainstem reticular
formation, resulting in central neurogenic hyperventilation
(CNH). Most cases of CNH in the literature are due to infiltrative processes or malignancy.9
One final characteristic of our case that has not been previously described with EEE is the prominent myocarditis,
which in our case was characterized by persistent elevation in cardiac markers, as well as atrial and ventricular
dysrhythmias. This was not attributable clinically to other
complicating events and was presumed due to his primary
viral infection. Although myocardial involvement is well
described in infection with other members of the Togavirus
family,10,11 it has not been reported with EEE in humans.
Notably, myositis is a reported, albeit unusual, feature of EEE
infection in other mammals,12 and it is possible that the previous absence in descriptions of the disease in humans is
related to the relative paucity of infections.
In summary, we report a patient with an unusual presentation of Eastern equine encephalitis, characterized by subacute
onset, clinical myocardial involvement, and abnormalities
in autonomic function and respiratory control complicating
supportive management.

Adapted from CDC website.4

nent neurologic damage. Studies have shown that patients

with an elevated white blood cell count in the cerebrospinal
fluid and severe hyponatremia had poorer outcomes. Patients
treated with anticonvulsants or steroids also had poorer outcomes that approached statistical significance.3
This patients course is particularly interesting in that his
subacute onset and presenting symptoms of odynophagia and
dysphagia were unusual. Sore throat has been previously
reported in acute presentation of EEE,5 though we did not
have early assessment of bulbar function to determine if his
dysphagia represented early neurologic involvement or vagus
nerve dysfunction.
In addition to the atypical presentation, our case illustrates
difficulties inherent in supporting critically ill patients with
infectious encephalitides. The pathologic examination of this
patients brain suggested involvement of areas responsible for
autonomic and respiratory control, and there was substantial clinical evidence of autonomic dysfunction, including
labile blood pressure and the patients uncontrollable and

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