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Table of Contents

Reviewed April 15, 2005

Lara Jeha, MD

Department of
Neurology

Cathy A. Sila, MD

Department of
Neurology

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Definition

Epidemiology

Pathophysiology

Clinical
Presentation

Diagnosis

Treatment and
Presentation

Clinical
Outcomes

Conclusions

References

Since its first isolation in the West Nile district in Uganda in 1937, WNV has become endemic throughout Africa and areas of the Middle East where the prevalence of WNV antibody among children is 3.5% to 8%.^1-3 Since the mid-1990s, numerous epidemics have also occurred in Europe.⁴ WNV was first recognized in the Western hemisphere in August 1999 when a report of 62 patients with meningoencephalitis, sometimes associated with weakness, was published from New York. An exponential increase in WNV activity in the United States was observed with at least 3,737 cases and 201 fatalities in 2002.⁵

WNV is a member of the Japanese encephalitis complex of viruses that also includes the Japanese encephalitis virus and St. Louis encephalitis virus, which accounts for cross- reactivity in serological testing. This virus group belongs to the Flaviviridae, a family of single-stranded RNA viruses transmitted by arthropods, mostly Culex mosquitoes in the case of WNV.^4,13 After a phase of initial replication and seeding of the reticuloendothelial system, a secondary viremia occurs with seeding of the CNS.¹⁴ Viremia is usually a transient phenomenon that precedes onset of symptoms and disappears with development of specific IgG and IgM antibodies.¹⁴ The presence of intact B-cells plays a critical early role in the development of IgM antibodies and thus the defense against disseminated infection,¹⁵ a fact that explains prolonged periods of viremia (up to 1 month), more severe CNS disease, and delays in the seroconversion of WNV-infected immunosuppressed patients.^6,11,16
Clinical symptoms develop in less than 1% of cases. This appears to be due to the strength of the host immune system but could partly be due to the difference in severity of neurovirulence among different WNV strains.¹⁷ Risk factors for increased mortality include host characteristics such as older age (>75 y.o.), diabetes mellitus, and level of immunosuppression, as well as measures of disease severity such as decreased level of consciousness, neuroimaging abnormalities, and the development of limb weakness.^9,18,19

WNV shares with the other Japanese encephalitis complex viruses a tendency to cause encephalitis and, less frequently, aseptic meningitis and paralytic poliomyelitis.¹³ Those Flaviviruses, including WNV, infect neurons throughout the CNS, but more severely in certain sites appropriate for the different clinical syndromes. More severe infection of the basal ganglia and thalamus as suggested by neuroimaging was found in patients with prominent parkinsonism and movement disorders.¹² Prominent inflammation of the brainstem was pathologically confirmed in patients with bulbar and ophthalmoplegic symptoms.¹⁰ Acute flaccid paralysis observed in WNV was correlated in multiple studies with perivascular lymphocytic infiltration and neuronophagia of the anterior horn cell region, similar to poliomyelitis.^10,11 Although the presence of specific viral receptors on motor neurons explains the anterior horn cell neurotropism with polioviruses, the pathogenesis of the preferential rostral and anterior horn cell infection with WNV remains poorly understood. The pathological changes described above are illustrated in Figures 1 and 2. Rarely, peripheral demyelination or axonal loss have been postulated.⁹

Like most viral illnesses, common complaints include fever, fatigue, myalgias, and gastrointestinal symptoms such as nausea and vomiting, abdominal pain, and diarrhea (Table 1). More characteristic features include back or limb pain in around one-third of the cases. One-fourth of cases have a nonpurulent, maculopapular erythematous rash, usually antedating any neurological manifestations by several days.^9-12

Neurological Signs and Symptoms:

Neurological dysfunction usually follows the systemic symptoms by several days. The most common symptoms include headache, altered level of consciousness, and focal weakness, observed in various combinations in the different studies (Table 2).

Aseptic Meningitis
West Nile meningitis usually presents as headache and fever following back pain, myalgias, and rash in 20% to 50%.²⁰ Meningeal signs are often absent on physical examination, with neck stiffness and photophobia observed in only 19% to 27%.^9,11 It tends to occur more in younger patients,¹⁰ and usually resolves without major sequelae.^10,12,20

Meningoencephalitis
Meningoencephalitis is the most common diagnosis in hospitalized WNV patients, affecting 50% to 84%.^10-12 It manifests as behavioral or personality changes, such as irritability, confusion, or disorientation¹² that can evolve to stupor and even coma, with mental status changes persisting for up to several weeks.¹¹ Reduced level of consciousness, a general symptom of encephalitis, is frequently associated with other more localizing signs such as tremor, bulbar dysfunction, ataxia, or focal weakness reflecting more specific areas of CNS involvement. Physical examination usually reveals hyperreflexia as would be expected with upper motor neuron injury, unless there is associated myelitis where areflexia becomes the rule.^10,12

Acute Flaccid Paralysis
Focal weakness develops in around one-half of patients with WNV CNS infection, with progression to frank paralysis in up to 35%.^9-12 Earlier studies suggested that older age and medical comorbid conditions could predispose to weakness.⁹ Those factors have not been uniformly confirmed.¹⁰ In contrast to headache and mental status alterations that are the usual presenting symptoms, weakness frequently evolves and develops in the subacute phase of the illness.^10,11 The limb weakness is of a lower motor neuron pattern with flaccid tone, areflexia, or hyporeflexia. It is typically asymmetric and rapidly progressive, reaching nadir weakness within 2 to 8 days of symptom onset.^10,12,21,22 The clinical pattern consists of flaccid quadriparesis, asymmetric paraparesis, or monoparesis.^10,11 The weakness typically involves proximal musculature, and the upper lumbar segments can be affected in isolation mimicking an upper lumbar radiculopathy or plexopathy. Although weakness usually happens in the context of encephalitis, cases of isolated limb involvement have also been reported to occur without the other features of headache or encephalopathy, posing a diagnostic challenge.^10,12,23 Sphincteric dysfunction can develop,^12,21 and respiratory muscle weakness can be responsible for prolonged mechanical ventilation.^10-12

Other Neurological Manifestations
Other neurological manifestations include movement disorders, rhombencephalitis, and cerebellar dysfunction. Movement disorders such as parkinsonism with rigidity, bradykinesia, and gait changes have been described in up to 69% of hospitalized WNV cases in one series.¹² Tremor can be static or akinetic, asymmetric, and involves the upper extremities.¹² Rhombencephalitis with associated bulbar dysfunction and swallowing difficulties can contribute to morbidity and prolonged hospitalization.^10,12 Cerebellar involvement with gait or truncal ataxia was recently stressed¹¹ and was even suggested to correlate with overall morbidity and mortality.²⁴ Most of those salient neurological manifestations become obvious several days or even weeks into the illness, as the patient is recovering from the meningoencephalitis and beginning rehabilitation. Although the tremors can be mistaken for seizure activity in severely affected individuals, focal motor seizures have rarely also been described.^9-12

Laboratory Findings
Complete blood counts on admission usually show no major abnormalities, although there may be absolute or relative lymphopenia.^9,20 Up to one-third of the patients develop significant hyponatremia, compatible with the syndrome of inappropriate antidiuretic hormone secretion, either during their illness or in the recovery period.^9,11 Evidence of CNS inflammation comes from lumbar puncture results showing a cerebrospinal fluid (CSF) pleocytosis (white blood cells [WBC] = 1 to 1,444; median = 171 cells/µL) with an initial neutrophilic predominance in the first week (median = 52%), followed by lymphocytic predominance in the second week (median = 59%), and then normalization of the CSF WBC count beyond 2 weeks. Proteins are usually moderately to severely elevated (up to >300 mg/dL), and glucose is normal.^10,11 These CSF findings support a diagnosis of meningitis or meningoencephalitis and help to exclude other conditions, such as Guillain-Barré syndrome, which is the main differential diagnostic consideration in patients with a rapidly progressive flaccid paralysis.^10,25 Reactive or atypical lymphocytes and Mollaret's cells, the monocyte variants originally described with recurrent aseptic meningitis, have also been reported and can be helpful in making the appropriate diagnosis.^10,11

Serological studies are the mainstay of diagnosis. An acute WNV infection is diagnosed by:

1. detection of virus itself by a positive real-time polymerase chain reaction (RT-PCR) which has a sensitivity of 55% in the CSF and 10% in serum samples,
2. presence of IgM antibodies in CSF by capture enzyme-linked immunosorbent assay (ELISA) method, or
3. demonstration of more than a four-fold increase in the titer of specific neutralizing antibody using the plaque-reduction neutralization assay in paired serum or CSF samples, or
4. the detection of both IgG and IgM in a single serum specimen (Nash).⁹ IgM capture ELISA in the serum has a sensitivity of 95% and a specificity of 90% when done within 8 days of symptom onset. However, immunosuppressed patients exhibit a prolonged period of viremia and a delayed antibody response.^11,16

Electrodiagnostic Studies
In more than 70% of the cases with acute flaccid paralysis, nerve conduction studies (NCS) show reduced or absent compound motor action potentials with preserved sensory nerve action potentials (SNAPs), conduction velocities, and distal latencies.^10,11,21,22 Such a pattern is suggestive of anterior horn cell disease with or without additional motor root involvement, as is seen with poliomyelitis. Less commonly, patients can have an additional reduction in SNAPs.^9,10 This pattern was previously attributed to a possible peripheral sensorimotor polyneuropathy but is now thought to represent dorsal root ganglia inflammation in the context of a myelitis.^10,11 Only a handful of cases have been reported to show electrodiagnostic findings compatible with an isolated demyelinating process or a combination of axonal and demyelinating processes.^26-29 Needle electrode examinations (NEE) show abnormal spontaneous activity such as fibrillation potentials and positive sharp waves in the acute setting reflecting active denervation.^10,11 NEE and NCS can be abnormal in clinically unaffected muscles, reflecting a more widespread involvement with the WNV.¹⁰ NEE and NCS at 8 months after disease onset show chronic denervation and motor axon loss in affected limbs.¹¹

Radiological Findings
No acute abnormalities are detected in computed tomographic scans of the brains of patients with acute WNV infection.^9-11 In the setting of WNV encephalitis, magnetic resonance imaging (MRI) of the brain is abnormal in 8% to 33%, with hyperintense signal abnormalities affecting either the cerebral cortex, the underlying subcortical white matter, or both on the T₂ and FLAIR (fluid attenuated inversion recovery) sequences.^10,11 Similar changes were described in the thalami, cerebellum, and brainstem in patients with prominent cerebellar, parkinsonian, or brainstem symptoms.^11,12

In patients with WNV-associated flaccid paralysis, MRI of the spine can be abnormal in 75% sensitive with T₂ and FLAIR hyperintensities involving the cord parenchyma at the level of the cervical or lumbar cord, and gadolinium enhancement in the cauda equina compatible with myeloradiculitis.^10,11

The treatment of WNV is currently supportive in nature, with particular attention to the risk of respiratory compromise secondary to muscle weakness and aspiration secondary to bulbar dysfunction.^10,11 Multiple medication trials, including intravenous immunoglobulins,³⁰ ribavirin, interferon, and steroids, have been tried without effect although none has been assessed in large clinical trials. In the absence of specific therapy, prevention becomes crucial. Approaches to prevention include reduction of the mosquito population with draining of water from mosquito breeding sites and use of mosquito larvicides and maturation inhibitors to reduce the numbers of mosquitos.¹⁴ Lifestyle modifications include avoiding outdoor activities during the hours around dawn and dusk, when mosquitos are most active, and wearing protective, light-colored clothing to limit insect bites. Insect repellants containing 10% to 50% N,N-diethyl-3-methylbenzamide (DEET) have also been recommended as an alternative to the organophosphate insecticides which have significant side effects.²⁰ A vaccine has been developed for veterinary use in horses but is not approved for use in humans.

Long-term outcome studies for WNV infection are lacking, but based on a limited number of case series, the following observations can be made. Mortality due to WNV infection ranges from 13% to 18%, typically due to complicating medical illnesses in the setting of severe disease.^10-12 Up to 25% to 40% of patients require intensive care unit admission with mechanical ventilation for either respiratory muscle weakness or depressed level of consciousness and airway compromise.^10,11 Most of these patients require long-term tracheostomy.¹⁰ The most common in-hospital complication was pneumonia (23%), followed by bacteremia (8%) and thromboembolic disease (6%).¹¹

Many neurological deficits persist in patients with WNV infection. Upon discharge from the hospital, only one-third of WNV encephalitis patients are fully ambulatory,¹⁴ and most complain of continuing symptoms of fatigue, myalgias, headaches, and cognitive changes at 8 months follow-up.¹² WNV meningitis has a relatively better prognosis, with more than 95% of patients recovering fully with normal functional recovery at 8 months follow-up.¹² Patients with WNV myelitis show no improvement in limb weakness if flaccid paralysis develops.^12,14 The persistence of movement disorders is a less defined feature with conflicting results in various studies.¹²

WNV infection can be a significant cause of CNS morbidity and mortality. The virus can cause salient neurological manifestations ranging from aseptic meningitis to flaccid quadriplegia. Heightened awareness is essential for early diagnosis, and prevention remains crucial in the absence of effective targeted therapy.

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