Download Successful Management of Severe Neuroinvasive Eastern Equine

Neurocrit Care
DOI 10.1007/s12028-013-9822-5
PRACTICAL PEARL
Successful Management of Severe Neuroinvasive Eastern Equine
Encephalitis
Linda C. Wendell • N. Stevenson Potter
Julie L. Roth • Stephen P. Salloway •
Bradford B. Thompson
•
Ó Springer Science+Business Media New York 2013
Abstract
Background Eastern Equine Encephalitis (EEE) virus is
an arbovirus that mostly causes asymptomatic infection in
humans; however, some people can develop a neuroinvasive infection associated with a high mortality.
Methods We present a case of a patient with severe
neuroinvasive EEE.
Results A 21-year-old man initially presented with
headache, fever, and vomiting and was found to have a
neutrophilic pleocytosis in his cerebrospinal fluid. He
eventually was diagnosed with EEE, treated with high-dose
methylprednisolone and intravenous immunoglobulin. His
course in the NeuroIntensive Care Unit was complicated by
cerebral edema and intracranial hypertension, requiring
osmotherapy, pentobarbital and placement of an external
ventricular device, and subclinical seizures, necessitating
multiple anti-epileptic drugs
Conclusions A multifaceted approach including aggressive management of cerebral edema and ICP as well as
treatment with immunomodulating agents and cessation of
seizures may prevent brain herniation, secondary neurologic injury and death in patients with EEE. Effective
management and treatment in our patient contributed to a
dramatic recovery and ultimate good outcome.
Keywords Eastern Equine Encephalitis Intracranial hypertension Cerebral edema Seizure
Introduction
Eastern Equine Encephalitis (EEE) virus is an arbovirus
that causes human infection via a mosquito vector. While
most infections with EEE virus are asymptomatic, symptomatic infections typically manifest as a generalized
illness with fever. Neuroinvasive illness is uncommon with
an incidence for all arboviruses in the United States of 0.20
per 100,000 persons [1]. In 2010, ten cases of EEE virus
were reported by the Centers for Disease Control. All ten
patients had encephalitis and required hospitalization. Five
of these patients died [2]. We present a case report and
successful management of a patient with EEE.
Case Report
L. C. Wendell (&) N. S. Potter B. B. Thompson
Departments of Neurology and Neurosurgery, Rhode Island
Hospital/Warren Alpert School of Medicine at Brown
University, 593 Eddy Street, APC 712, Providence,
RI 02903, USA
e-mail: [email protected]
J. L. Roth
Department of Neurology, Rhode Island Hospital/Warren Alpert
School of Medicine at Brown University, Providence, RI, USA
S. P. Salloway
Departments of Neurology, Butler Hospital/Warren Alpert
School of Medicine at Brown University, Providence, RI, USA
A 21-year-old man initially presented to the emergency
department of an outside hospital with 24 h of headache,
fever, and vomiting. He had a past medical history of beta
thalassemia minor, recent extraction of his wisdom teeth on
amoxicillin and recent exposure to mosquitos while golfing. Initial evaluation revealed a fever (103.8 °F), a normal
neurologic exam, a leukocytosis (11.9 9 109 per L) and
hyponatremia (133 mEq/L). Initial head CT was reported
as normal although there was a question of a right temporal
hypodensity. Lumbar puncture (LP) was performed in the
emergency department and demonstrated 585 nucleated
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cells/mm3 with a neutrophilic predominance (75 %), elevated protein (485 mg/dL) and negative Gram stain. Herpes
simplex virus (HSV) polymerase chain reaction (PCR) was
sent. He was started on ceftriaxone, vancomycin, metronizadole, and acyclovir for empiric coverage of bacterial
meningitis and HSV encephalitis. He was admitted, and his
hospital course was complicated by generalized convulsions, treated with phenytoin, and hypercarbic respiratory
failure, requiring noninvasive positive pressure ventilation
(NIPPV) and transfer to the ICU. The following day, he was
transferred to our hospital’s NeuroICU for further management. On exam, he opened his eyes to voice, had
decreased attention and concentration, was nonverbal, had
normal cranial nerves and normal strength, and followed
simple commands. MRI brain (Fig. 1) performed on hospital day (HD) #2 of his admission to our hospital revealed
T2 and FLAIR hyperintensities involving the bilateral
mesial temporal lobes, the left uncus and right insular
cortex without associated restricted diffusion or enhancement; leptomeningeal engorgement was most prominent
along the high bifrontal convexities; and basal cisterns were
patent. HSV PCR from the outside hospital was negative.
Repeat LP demonstrated an elevated opening pressure
(46 cm H20), 70 nucleated cells/mm3 with a lymphocytic
predominance (74 %), elevated protein (297 mg/dL), and
negative Gram stain. HSV PCR was resent, and the results
were again negative. Extensive serum and CSF work-up for
other viral encephalitides was also pursued. Doxycycline
was added to his antibiotic regimen for coverage of tickborne illnesses; however, work-up for these illnesses was
negative.
Fig. 1 Non-contrast axial FLAIR MRI brain at presentation demonstrating bilateral temporal hyperintensities
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On HD #3, head CT revealed bilateral mesial temporal
lobe hypodensities consistent with previous MRI findings
as well as right greater than left effacement of the Sylvian
fissures, small ventricles and diffuse sulcal effacement. He
received 1 g/kg boluses of 20 % mannitol IV q6 h and 3 %
hypertonic saline (HTS) continuous infusion for a target
sodium of 155 mEq/L to treat empirically for intracranial
hypertension (Fig. 2). Cerebrospinal fluid (CSF) culture
remained negative from his initial LP. Vancomycin and
metronidazole were discontinued given no evidence for
Streptococcus pneumonia infection or abscess from recent
dental work. He was continued on ceftriaxone, doxycycline, and acyclovir. His mental status continued to worsen,
and he required intubation for airway protection on HD #4.
On exam, he had no eye opening, equal and reactive pupils,
conjugate roving eye movements, positive corneal, gag and
cough reflexes, localization of his arms, and withdrawal of
his legs. He was monitored on continuous electroencephalography (EEG) (Table 1), which demonstrated severe
diffuse encephalopathy and subclinical seizures; levetiracetam was added for further seizure management. The
patient was found to have a mildly positive serum mycoplasma IgM (1:64). Ceftriaxone was discontinued, and
doxycycline was increased to cover possible CSF mycoplasma infection.
On HD #5, his exam worsened to extensor posturing of
his arms and triple flexion of his legs. An intracranial
pressure (ICP) monitor (Codman, Codman & Shurtleff,
Inc., Raynham, MA) was placed in the right frontal lobe.
Initial ICP was 21 mm Hg. He required 30 cc boluses of
23.4 % HTS and continuous infusion of 3 % HTS to keep
ICP <20 mm Hg. Repeat head CT on HD #6 demonstrated
continued diffuse sulcal effacement and partial effacement
of the basal cisterns. Serum EEE IgM was found to be
positive (1:128). CSF EEE IgM was confirmed positive by
the Massachusetts Department of Health. The remainder of
the work-up for other viral encephalitides was negative.
Doxycycline and acyclovir were discontinued. He was
started on methylprednisolone 1 g IV qday and intravenous
immunoglobulin (IVIg) 0.4 mg/kg qday on HD #8.
The patient continued to have elevated ICP despite universal measures, sedation with propofol and fentanyl,
maintenance of eucarbia and optimization of osmotherapy.
On HD #9, he required a single dose of pentobarbital
100 mg IV for sustained ICP >40 mm Hg, and ICP
improved from 57 to 12 mm Hg. An external ventricular
device (EVD) (Codman, Codman & Shurtleff, Inc., Raynham, MA) was then placed and allowed to drain at 0 cm
H20 above the level of the Foramen of Monroe with sustained improvement in ICP to <20 mm Hg (initial ICP
6 mm Hg). He had recurrent electrographic seizures on
continuous EEG requiring addition of valproic acid. Due to
development of a rash on his back and inadequate seizure
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Fig. 2 Hospital management of
patient’s intracranial
hypertension. ICP intracranial
pressure, LP lumbar puncture,
EVD external ventricular drain,
HTS hypertonic saline, solid
Line ICP in mm Hg, dotted line
serum sodium in mEq/L, black
triangle 20 % Mannitol 1 g/kg
IV, black diamond 23 % HTS
30 cc IV, open diamond 23 %
HTS 30 cc IV and pentobarbital
100 mg IV
Table 1 Results of electroencephalogram (EEG) monitoring during hospital course and anti-epileptic drug (AED) regimen used
Hospital Day
1
EEG Results
AED Regimen
Moderate-severe diffuse encephalopathy, occasional left hemisphere sharp waves
Phenytoin
3–4
Severe diffuse encephalopathy, burst suppression
Phenytoin
5–7
Frequent runs of left frontal or bifrontal 1–2 Hz rhythmic activity, consistent with ongoing
electrographic seizure; severe diffuse encephalopathy with burst suppression
Phenytoin, levetiracetam
8–9
Frequent runs of left frontal or bifrontal rhythmic 2–4 Hz activity lasting 10 s to 20 min
(15–20 per hour), consistent with ongoing electrographic seizure; severe diffuse
encephalopathy
Phenytoin, levetiracetam,
propofol
10
Runs of bifrontal and left temporal 2 Hz rhythmic activity (5–15 per hour) consistent with
electrographic seizures; severe diffuse encephalopathy
Phenytoin, levetiracetam,
valproate, propofol
11–12
Runs of bifrontal, rhythmic 1–2 Hz activity (15 per hour), consistent with electrographic
seizure which resolves with phenobarbital; severe diffuse encephalopathy
Pheyntoin, levetiracetam,
valproate, phenobarbital
12–13
Intermittent runs of bifrontal 1.5–2 Hz rhythmic activity (1–5 per hour); moderate-severe
diffuse encephalopathy
Phenytoin, levetiracetam,
phenobarbital
13–14
Runs of bifrontal rhythmic 1 Hz activity (15 per hour); moderate diffuse encephalopathy
Phenytoin, levetiracetam,
phenobarbital
14–15
Runs of generalized or bifrontal rhythmic 1.5 Hz activity (2–10 per hour); moderate
encephalopathy
Phenytoin, levetiracetam,
phenobarbital
18
Moderate diffuse encephalopathy
Phenytoin, levetiracetam,
phenobarbital
Six-month
follow-up
Normal background rhythms (9–11 Hz) with left posterior temporal sharp waves
Levetiracetam, weaning off
phenobarbital
control, valproic acid was discontinued and phenobarbital
was added with good effect. After five doses of methylprednisolone and IVIg and better seizure control (HD #12),
the patient’s exam had improved to opening eyes spontaneously, tracking and regarding the examiner but not
following commands, localizing both arms (left greater than
right), and withdrawing both legs.
He was weaned off sedation and successfully extubated
on HD #14 though he initially required NIPPV for hypercarbia. His exam had improved to being alert, saying
occasional words, following commands and displaying
purposeful and spontaneous movement of his arms and legs.
EVD was weaned successfully and removed on HD #20.
Repeat MRI brain on HD #21 (Fig. 3) demonstrated
increased T2 hyperintensity in the bilateral medial thalami
and left anterior putamen and patchy enhancement of the left
hippocampus, mesial temporal lobe and amygdala. He
continued to improve and became more conversant but with
mild inattention and slowness in responding to questions. He
was discharged on HD #30 to an acute rehabilitation facility.
At one year, his Glasgow Outcome Scale-Extended
(GOS-E) score was 6, indicating upper moderate disability.
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independently and enroll in limited college coursework.
Levetiracetam had been weaned off, and he remained seizure free.
Discussion
Fig. 3 Non-contrast axial FLAIR MRI brain on hospital day #21
demonstrating thalamic and basal ganglia FLAIR hyperintensities
He was living at home with his parents, struggled with
short-term memory difficulties and was being treated for
anxiety. A routine EEG performed five months after presentation demonstrated a return of normal background
rhythms, though with occasional epileptiform discharges in
the left hemisphere. He had been seizure free for several
months on levetiracetam monotherapy. MRI brain demonstrated improvement in previously seen hyperintensities
but ventricular enlargement with basal ganglia and mesial
temporal atrophy, including hippocampal volume loss that
may correlate with his cognitive and behavioral symptoms
(Fig. 4). At two years, his GOS-E was seven, indicating
lower good recovery. His short-term memory continued to
improve, and he could complete activities of daily living
Fig. 4 Non-contrast axial
FLAIR MRI brain one year
post-discharge demonstrating
resolution of previous FLAIR
hyperintensities
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We described a 21-year-old man with EEE who developed
seizures, cerebral edema and intracranial hypertension,
requiring aggressive management to prevent brain herniation and death. EEE is associated with a high rate of
morbidity and mortality. One case series of 36 EEE
patients reported that only one patient fully recovered and
36 % of patients died [3]. No specific antiviral treatment
for EEE exists; thus, supportive care is the cornerstone of
management [4].
With any encephalitis, the first steps in management
begin with identifying the pathogen, which is commonly a
virus. Neuroimaging, preferably with MRI, and CSF
analysis are paramount in identifying a diagnosis [4]. The
thalami and basal ganglia are most frequently involved in
EEE as was seen in our patient. Cortical involvement can
be in differing locations [3]. Depressed level of consciousness and coma are prominent in EEE [3], and
patients must be monitored closely for ability to protect the
airway, impending respiratory failure and necessity for
intubation [5].
In patients with worsening consciousness, it is also
imperative to suspect cerebral edema and intracranial
hypertension. Encephalitic patients with coma or imaging
findings concerning for intracranial hypertension should be
considered for ICP monitoring [6]. Three-fourths of patients
with viral encephalitis will require specific treatment for
cerebral edema, and the Glasgow Coma Scale (GCS) is not
predictive of initial ICP [7, 8]. The importance of monitoring
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for intracranial hypertension in these patients has been
described in a small case series of ten patients with viral
encephalitis, mostly herpes encephalitis. An ICP >20 mm
Hg was associated with mortality, but transient elevations in
ICP did not prohibit survival. Intracranial hypertension
peaked on average at day 12 in patients with viral encephalitis [8]. Our patient had multiple episodes of intracranial
hypertension that peaked eleven days into his hospital
course. He had elevations of ICP >40 mm Hg which ultimately improved with aggressive medical treatment and
placement of an EVD. Decompressive craniectomy can also
be considered in patients with elevated ICP who fail
aggressive medical therapy and has been reported as a lifesaving treatment in a patient with bacterial meningitis and
refractory intracranial hypertension [9]. Given that our
patient’s ICP improved after placement of an EVD, we
elected not to pursue this approach.
In addition to ventilatory support for airway protection
and management of cerebral edema and elevated ICP, our
patient required specific management for seizures. Since
encephalitis leads to cortical inflammation, seizures can be
a common feature [10]. Half of patients with EEE will have
seizures, most frequently generalized convulsions [3].
Titration of multiple anti-epileptic medications and monitoring with continuous EEG were required to control
seizures in our patient.
Despite having several findings that would have predicted a poor prognosis, including initial CSF white
count >500 cells/mm3 [3], initial ICP >12 mm Hg [8],
and GCS score <7 [7], our patient had a good outcome
secondary to effective management and treatment of cerebral edema, intracranial hypertension, and seizures. In
addition to control of seizures and ICP, high-dose methylprednisolone and IVIg may have contributed to improved
outcome. Complete recovery was reported in a comatose
man with EEE who received steroids and IVIg [11]. A more
recent case of severe cytomegalovirus encephalitis also
demonstrated improved outcome after use of steroids and
IVIg [12]. While EEE can cause direct neuronal injury, it
also produces inflammatory damage, leading to necrosis
and demyelination of neurons. Immunosuppression might
seem counterintuitive in the setting of infection, but IVIg
and methylprednisolone may contribute to halting cytotoxic
edema secondary to the inflammatory cascade triggered by
EEE infection and help to improve outcome [11].
A multi-faceted approach including aggressive management of cerebral edema and elevated ICP as well as
treatment with immunomodulating agents and cessation of
seizures may prevent secondary neurologic injury and
death in patients with EEE. Effective management and
treatment in our patient contributed to a dramatic recovery
and ultimate good outcome.
Disclosure
None.
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