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Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic Manifestations and Outcome of West Nile Virus Infection. JAMA. 2003;290(4):511–515. doi:10.1001/jama.290.4.511
Context The neurologic manifestations, laboratory findings, and outcome of patients
with West Nile virus (WNV) infection have not been prospectively characterized.
Objective To describe prospectively the clinical and laboratory features and long-term
outcome of patients with neurologic manifestations of WNV infection.
Design, Setting, and Participants From August 1 to September 2, 2002, a community-based, prospective case
series was conducted in St Tammany Parish, La. Standardized clinical data
were collected on patients with suspected WNV infection. Confirmed WNV-seropositive
patients were reassessed at 8 months.
Main Outcome Measures Clinical, neurologic, and laboratory features at initial presentation,
and long-term neurologic outcome.
Results Sixteen (37%) of 39 suspected cases had antibodies against WNV; 5 had
meningitis, 8 had encephalitis, and 3 had poliomyelitis-like acute flaccid
paralysis. Movement disorders, including tremor (15 [94%]), myoclonus (5 [31%]),
and parkinsonism (11 [69%]), were common among WNV-seropositive patients.
One patient died. At 8-month follow-up, fatigue, headache, and myalgias were
persistent symptoms; gait and movement disorders persisted in 6 patients.
Patients with WNV meningitis or encephalitis had favorable outcomes, although
patients with acute flaccid paralysis did not recover limb strength.
Conclusions Movement disorders, including tremor, myoclonus, and parkinsonism, may
be present during acute illness with WNV infection. Some patients with WNV
infection and meningitis or encephalitis ultimately may have good long-term
outcome, although an irreversible poliomyelitis-like syndrome may result.
Most human infections with West Nile virus (WNV) are subclinical or
manifest as a mild febrile illness, but a small proportion of patients (<1%)
develop acute neurologic illness.1-4 Although
recent WNV outbreaks have been associated with severe neurologic disease,1-5 retrospective
studies have failed to identify clinical features that distinguish WNV from
other viral encephalitides.1,5-9 The
US outbreak of WNV in 200210 presented an opportunity
to assess neurologic manifestations, laboratory and neurodiagnostic findings,
and outcome associated with WNV infection.1,7,11
From August 1 to September 2, 2002, patients from St Tammany Parish,
La, with suspected WNV infection were identified through state-based surveillance
at local hospitals and regional medical centers. Suspected WNV infection was
defined as illness with evidence of an acute infectious process (eg, temperature
≥39°C; elevated white blood cell count; or cerebrospinal fluid [CSF]
pleocytosis) along with clinical evidence of meningitis, encephalitis, or
acute focal weakness (Box).
Infection with WNV was confirmed if WNV-specific antibodies were detected
in acute-phase serum or CSF samples by IgM antibody-capture enzyme-linked
immunosorbent assay (MAC-ELISA)12 and were
confirmed by plaque-reduction neutralization assay.13
West Nile Meningitis
A. Clinical signs of meningeal inflammation, including nuchal rigidity,
Kernig or Brudzinski sign, or photophobia or phonophobiaB. Additional
evidence of acute infection, including 1 or more of the following: fever (>38°C)
or hypothermia (<35°C); cerebrospinal fluid pleocytosis (≥5 leukocytes/mm3); peripheral leukocyte count >10 000/mm3; neuroimaging
findings consistent with acute meningeal inflammation
West Nile Encephalitis
A. Encephalopathy (depressed or altered level of consciousness, lethargy,
or personality change lasting ≥24 hours)B. Additional evidence of
central nervous system inflammation, including 2 or more of the following:
fever (≥38°C) or hypothermia (≤35°C); cerebrospinal fluid pleocytosis
(≥5 leukocytes/mm3); peripheral leukocyte count >10 000/mm3; neuroimaging findings consistent with acute inflammation (with or
without involvement of the meninges) or acute demyelination; presence of focal
neurologic deficit; meningismus (as defined in A); electroencephalography
findings consistent with encephalitis; seizures, either new onset or exacerbation
of previously controlled
Acute Flaccid Paralysis
A. Acute onset of limb weakness with marked progression over 48 hoursB.
At least 2 of the following: asymmetry to weakness; areflexia/hyporeflexia
of affected limb(s); absence of pain, paresthesia, or numbness in affected
limb(s); cerebrospinal fluid pleocytosis (≥5 leukocytes/mm3)
and elevated protein levels (≥45 mg/dL); electrodiagnostic studies consistent
with an anterior horn cell process; spinal cord magnetic resonance imaging
documenting abnormal increased signal in the anterior gray matter
Eligible enrollees were assessed on presentation to medical care. Patients
were approached under the auspices of a public health event; oral consent
was obtained. Standardized case histories and initial symptoms and signs were
collected. One neurologist (J.J.S.) examined each patient; a second neurologist
verified findings for 7 patients. Laboratory results, neuroimaging and electrophysiologic
findings were recorded and updated 1 week following initial assessment, during
repeat neurologic evaluation.
Approximately 8 months later (March 15-April 4, 2003), patients with
confirmed WNV infection were reexamined. The Centers for Disease Control and
Prevention institutional review board approved the follow-up protocol. Using
a standardized questionnaire, patients were queried about symptoms, functional
status, and ability to perform daily activities. The neurologic assessment
was repeated (J.J.S.).
Exact Wilcoxon rank-sum test was used for comparison of medians. Statistical
analyses were performed using SAS, version 8.1 (SAS Institute, Cary, NC).
Of 39 patients evaluated, WNV infection was confirmed in 16 patients.
Discharge diagnoses of the 23 patients without WNV infection included viral
meningitis (n = 6), headache (n = 5), viral encephalitis (n = 4), unspecified
viral illness (n = 4), and encephalopathy (n = 1). Final diagnoses were unavailable
for 3 patients.
Eleven (69%) of the 16 WNV-seropositive patients were white (population
of St Tammany Parish is 74% white), and 9 were male. Of the 16 patients, 5
were classified as having West Nile meningitis (WNM), 8 as having West Nile
encephalitis (WNE), and 3 as having acute flaccid paralysis (AFP) (Table 1). One patient classified with AFP
also had encephalitis. Information regarding the initial presentation of 3
patients with AFP had been reported previously.14,15 Patients
with WNM (median age, 35 years) were younger than those with WNE (median,
70 years) (P = .003). One patient with severe WNE
had systemic lupus erythematosis and was treated with corticosteroids. No
other WNV-seropositive patient had a clear condition indicating immunocompromise.
The 16 WNV-seropositive patients were hospitalized a median of 2.5 days
after symptom onset; the median hospital stay was 12 days (Table 1). Five patients spent a median of 10 days (range, 3-19 days)
in intensive care.
Self-reported symptoms were similar among all patients presenting with
possible WNV infection (Table 1).
Eleven of the 15 WNV-seropositive patients with headache described it as frontal/retro-orbital,
and 5 of the 16 WNV-seropositive patients reported a rash. Fifteen WNV-seropositive
patients reported "shakiness" or "twitching," with 5 describing it as notable
in the evening prior to sleep. Among patients with WNE, the most common complaints
were behavioral or personality changes, manifested as irritability, confusion,
or disorientation. Two patients with WNM and 1 patient with WNE reported difficulty
with balance and gait. Five patients reported weakness, which was focal in
the 3 patients developing AFP and was generalized in 2 patients.
The 8 patients with WNE had a mean admission Glasgow Coma Scale score
of 11 (range, 4T [intubated] to 15). A median of 3 days passed between symptom
onset and changes in mental status. Cranial nerve and bulbar abnormalities
were observed in several patients with WNE. Results of formal strength testing
displayed mild-to-moderate diffuse weakness in 4 patients and focal weakness
in the 3 patients with AFP. New sensory abnormalities were not observed. Four
patients with WNE and 1 patient with WNM displayed abnormal hyperreflexia;
the 3 patients with AFP all had areflexia or hyporeflexia of the affected
Dyskinesias (ie, movements including tremor, myoclonus, and features
of parkinsonism) were observed in 15 of the 16 WNV-seropositive patients (Table 1). Tremor was observed in 15 patients;
9 had onset of tremor after day 5 of illness. Tremor in all 15 patients was
static or kinetic, asymmetric, and involved the upper extremities. Two patients
additionally displayed intentional movement dysmetria. Myoclonus was directly
observed in 10 patients. Parkinsonism was observed in all 3 patients with
AFP, 6 of 8 patients with WNE, and 2 of 5 patients with WNM. Resting tremor
was not observed. Seizures were documented using electroencephalography in
1 patient with WNE.
All 3 patients with AFP had asymmetric limb weakness within 48 hours
of initial symptom onset. Pain, paresthesias, or acute sensory loss were not
observed. All 3 patients experienced bowel and bladder dysfunction.
None of the WNV-seropositive patients showed acute abnormalities on
computed tomography. Magnetic resonance imaging of the brain was performed
on 10 of the 16 patients: the findings showed nonacute abnormalities in 8
patients and bilateral, focal lesions in the basal ganglia, thalamus, and
pons on T2- and diffusion-weighted sequences in 2 severely ill patients with
WNE (Figure 1). Findings of magnetic
resonance imaging of the cervical, thoracic, and lumbosacral spine for the
2 patients with AFP with lower extremity involvement showed enhancement of
the cauda equina and nerve root clumping consistent with meningitis. Findings
of magnetic resonance images of the cervical and thoracic spine in a patient
with AFP with right arm involvement showed diffuse degenerative changes without
spinal cord abnormalities.
Electroencephalograms were obtained for 7 patients with WNE. Abnormal
findings included electrographic seizures in 1 patient, focal sharp waves
in 1 patient, and diffuse irregular slow waves in 6 patients. No correlation
between electroencephalographic findings and the presence of myoclonus or
tremor was observed.
Electromyographs and nerve conduction studies were performed on the
3 WNV-seropositive patients and 1 WNV-seronegative patient with asymmetric
weakness from 3 to 42 days after onset of weakness. All WNV-seropositive patients
demonstrated findings consistent with a severe, asymmetric process affecting
anterior horn cells. The WNV-seronegative patient displayed overall findings
consistent with a combined axonal and demyelinating neuropathy (ie, Guillain-Barré
One patient with WNE remained comatose and ventilator-dependent until
death, which occurred 2.5 months after onset of illness. All surviving patients
eventually were discharged home. However, 3 patients with AFP and 2 patients
with WNE were initially discharged to long-term rehabilitation facilities.
At 8 months, 11 patients were home and functioning independently; 3 were home,
but dependent; and 1 was undergoing rehabilitation.
At 8 months, 10 WNV-seropositive patients reported persistent fatigue,
3 persistent myalagias, and 2 persistent headache. Four patients with WNE
reported persistent cognitive deficits, including difficulties with memory,
short-term recall, and slowness of thought. One patient had mental status
scores significantly below baseline levels.
Follow-up neurologic examination of the 15 WNV-seropositive patients
who survived revealed no neurologic deficits in the 5 patients with WNM. Among
patients with WNE and AFP, tremor was present in 5 patients and parkinsonism
in 5. A postural and/or kinetic tremor was observed in 5 patients following
recovery from WNE, and in 1 patient, it was severe enough to interfere with
grooming and eating. Parkinsonism persisted in 5 of the 11 patients. In all
but 1 patient (the patient with underlying systemic lupus erythematosis),
parkinsonism was mild and did not interfere with daily activities. One patient
with WNE with severe initial parkinsonism and postural instability was ambulatory
with a walker for 4 months following illness onset, but by 6 months was able
to climb ladders at work. Eight-month follow-up examination demonstrated only
minimal postural instability and bradykinesia. The 8-month follow-up examination
revealed 2 patients who demonstrated myoclonus of the upper extremities and
Five of 7 patients with severe encephalitis, as characterized by an
initial Glascow Coma Scale score of 12 or less or an initial mental status
score of 2 SDs below normal for age, had favorable outcomes, defined as achieving
or exceeding their level of functioning before illness. Two patients with
particularly guarded prognoses during acute illness were functioning at baseline
level by 6 months, with no residual symptoms. Recovery to normal or near-normal
functioning occurred within 4 months in all cases of improvement.
Patients with AFP showed no improvement in limb weakness. Bladder symptoms
in the patients with AFP had resolved. Electromyographs and nerve conduction
studies performed at the 8-month follow-up examination revealed chronic denervervation
and motor axon loss in affected limbs. One patient with AFP experienced continued
severe dyspnea. Chest and diaphragmatic fluoroscopy performed 3 months after
illness onset revealed right hemidiaphragmatic paralysis consistent with central
nervous system etiologic findings.
Patients with AFP reported the lowest overall functioning scores and
had the lowest scores on both Barthel and modified Rankin scoring systems
(data not shown). Five of 7 patients who survived WNE and 4 of 5 patients
who survived WNM reported normal functional scores (data not shown). Seven
of the 10 patients who were employed before WNV infection returned to work
within 4 months following hospital discharge. Five patients, including all
3 with AFP, described continuing difficulties with daily activities, such
as grooming, housekeeping, and mobility. All patients with AFP required use
of a wheelchair for ambulation, and 2 patients who had been independently
mobile before infection required walkers following recovery from WNE.
Movement disorders, in particular tremor, myoclonus, and parkinsonism,
were prominent among WNV-seropositive patients, but uncommon among WNV-seronegative
patients. While tremor and myoclonus have been documented prospectively in
patients with St Louis encephalitis virus 16-18 or
other viral infections,19,20 they
have not been described in contemporary WNV studies.1-3,5,6,9,21 Documentation
of these findings in 15 of 16 WNV-seropositive patients suggests that these
findings have diagnostic relevance.
Previous immunohistological assessments have detected WNV in the basal
ganglia, thalamus, and pons in patients with severe encephalitis,22 suggesting the possibility of viral involvement of
these structures with resultant parkinsonism and tremor. Magnetic resonance
imaging findings in 2 patients correlated clinically with the findings of
parkinsonism and tremor; however, in 8 patients, parkinsonian features were
present without abnormal findings on magnetic resonance imaging. Parkinsonism
has been observed with Japanese encephalitis virus infection,23-26 a
related flavivirus. Some prior studies have suggested long-term persistence
of signs,23-25 while
others have reported parkinsonism as a more transient feature.27 In
our study, the patient with severe persistent parkinsonism at 8-month follow-up
had shown persistence of abnormalities in the basal ganglia, thalamus, and
substantia nigra on magnetic resonance imaging.
All patients with WNM had favorable outcome; all returned to work and
reported normal or near-normal functioning at 8-month follow-up. In addition,
5 patients with severe WNE had excellent outcomes, achieving premorbid levels
of functioning without residual disability within 4 months of illness. Severe
encephalitis caused by other viral agents28-30 may
often be associated with severe persistent cognitive and neurologic deficits;
by comparison, this group of patients with WNE displayed a low incidence of
persistent sequelae. Severity of initial encephalopathy does not necessarily
portend poor long-term outcome in all patients.
Two of the 3 patients with AFP developed AFP without associated encephalopathy
or meningismus. Clinical findings and electrodiagnostic data suggested involvement
of anterior horn cells of the spinal cord, resulting in a poliomyelitis-like
8 months, none of the patients had improvement in weakness, and electromyographic
data suggested permanent motor neuron loss, indicating that significant recovery
in weakness is unlikely. Persistent dyspnea in 1 patient with AFP is most
likely due to poliomyelitis-like diaphragmatic and intercostal muscle weakness
with respiratory failure.33-35
We conclude that movement disorders, particularly tremor, myoclonus,
and parkinsonism, may be underrecognized manifestations of acute WNV illness
and have a generally favorable prognosis. However, complaints of persistent
fatigue, headache, and myalgia are common. Long-term outcome of patients with
WNE is variable, and severe initial encephalopathy did not necessarily portend
poor prognosis. A poliomyelitis-like syndrome can occur without associated
meningitis or encephalitis and has poor long-term outcome.