Definition

West Nile virus (WNV) is a neurotropic virus that produces damage of varying severity and anatomic predilection. When the reactive inflammatory processes are restricted to the meninges, an aseptic meningitis with headache as the chief manifestation results. With additional brain parenchymal involvement, altered level of consciousness accompanies the headache and reflects the associated meningoencephalitis. Lancinating pains and focal areflexic weakness denote a myelitis, with inflammation of the spinal cord.

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Epidemiology

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 in New York. An exponential increase in WNV activity in the United States was observed, with at least 3737 cases and 201 fatalities in 2002. ⁵ Since its introduction, the virus has spread West and South to involve the majority of the continental United States. ⁶

The virus is amplified in birds and is transmitted to humans most commonly through infected Culex mosquito bites. Transmission through blood transfusion, organ transplantation, and breast-feeding have also been reported. ^7–9 Fortunately, most of the WNV seroconversions are subclinical, with overt clinical illness affecting 1 in 100 to 1 in 150 patients. ^10,11 The peak incidence of infection is in August and September. ^4,12 Elderly men are most susceptible to severe disease, with the median age of hospitalized patients in the seventh or eighth decade ^10–13 and a male-to-female ratio of 3:1. Patients seldom recall a specific mosquito bite, but they are often self-reported active persons with significant outdoor—and therefore mosquito—exposures. ¹²

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Pathophysiology

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 serologic testing. This virus group belongs to the Flaviviridae, a family of single-stranded RNA viruses transmitted by arthropods, mostly Culexmosquitoes in the case of WNV. ^4,14 After a phase of initial replication and seeding of the reticuloendothelial system, a secondary viremia occurs with seeding of the central nervous system (CNS). ¹⁵ Viremia is usually a transient phenomenon that precedes onset of symptoms and disappears with development of specific immunoglobulin (Ig) G and IgM antibodies. ¹⁵ The presence of intact B cells plays a critical early role in the development of IgM antibodies and thus the defense against disseminated infection, ¹⁶ 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. ^7,12,17

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. ¹⁸Risk factors for increased mortality include host characteristics such as older age (>75 years), 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. ^10,19,20

WNV shares with the other Japanese encephalitis complex viruses a tendency to cause encephalitis and, less often, aseptic meningitis and paralytic poliomyelitis. ¹⁴Those Flaviviruses, including WNV, infect neurons throughout the CNS, but more severely in certain sites appropriate for the different clinical syndromes. More severe infections of the basal ganglia and thalamus, as suggested by neuroimaging were found in patients with prominent parkinsonism and movement disorders. ¹³ Prominent inflammation of the brainstem was pathologically confirmed in patients with bulbar and ophthalmoplegic symptoms. ¹¹ 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. ^11,12 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 pathologic changes are illustrated in Figures 1 and 2. Rarely, peripheral demyelination or axonal loss have been postulated. ¹⁰

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Clinical Presentation

Systemic Signs and Symptoms

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 patients. One fourth of patients have a nonpurulent, maculopapular erythematous rash, usually antedating any neurologic manifestations by several days. ^10–13

Neurologic Signs and Symptoms

Neurologic 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 different studies (Table 2).^10–13

Aseptic Meningitis

West Nile meningitis manifests as headache and fever following back pain, myalgias, and rash in 20% to 50% of patients. ²¹ Meningeal signs are often absent on physical examination, with neck stiffness and photophobia observed in only 19% to 27%. ^10,12 Aseptic meningitis tends to occur more in younger patients, ¹¹ and it usually resolves without major sequelae. ^11,13,21

Meningoencephalitis

Meningoencephalitis is the most common diagnosis in hospitalized WNV patients, affecting 50% to 84% of patients; ^11–13 it manifests with behavioral or personality changes such as irritability, confusion, or disorientation ¹³ that can evolve into stupor and even coma, with mental status changes persisting for up to several weeks. ¹²Reduced level of consciousness, a general symptom of encephalitis, is often 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. ^11,13

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%. ^10–13 Earlier studies suggested that older age and medical comorbid conditions could predispose to weakness. ¹⁰ Those factors have not been uniformly confirmed. ¹¹ In contrast to the headache and mental status alterations that are the usual manifesting symptoms, weakness often evolves and develops in the subacute phase of the illness. ^11,12 The limb weakness is of a lower–motor neuron pattern, with flaccid tone, areflexia, or hyporeflexia. It is typically asymmetrical and rapidly progressive, reaching nadir weakness within 2 to 8 days of symptom onset. ^11,13,22,23 The clinical pattern consists of flaccid quadriparesis, asymmetrical paraparesis, or monoparesis. ^11,12 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 occurs in the context of encephalitis, cases of isolated limb involvement have also occurred without the other features of headache or encephalopathy, posing a diagnostic challenge. ^11,13,24 Sphincteric dysfunction can develop, ^13,22 and respiratory muscle weakness can require prolonged mechanical ventilation. ^11–13

Other Neurologic Manifestations

Other neurologic manifestations include movement disorders, rhombencephalitis, and cerebellar dysfunction. Movement disorders such as parkinsonism, with rigidity, bradykinesia, and gait changes, were described in up to 69% of hospitalized WNV patients in one series. ¹³ Tremor can be static or akinetic and asymmetrical, and it involves the upper extremities. ¹³ Rhombencephalitis with associated bulbar dysfunction and swallowing difficulties can contribute to morbidity and prolonged hospitalization. ^11,13 Cerebellar involvement with gait or truncal ataxia was described ¹² and even appeared to correlate with overall morbidity and mortality. ²⁵ Most of the salient neurologic 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 patients, focal motor seizures have rarely also been described. ^10–13

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Diagnosis

Laboratory Findings

Complete blood counts on admission usually show no major abnormalities, although there may be absolute or relative lymphopenia. ^10,21 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. ^10,12Evidence of CNS inflammation comes from lumbar puncture results showing a cerebrospinal fluid (CSF) pleocytosis (white blood cells [WBC], 1 to 1444 cells/mL; median, 171 cells/mL) 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 after 2 weeks. Proteins are usually moderately to severely elevated (up to 300 mg/dL), and glucose is normal. ^11,12These 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. ^11,26 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. ^11,12

Serologic studies are the mainstay of diagnosis. An acute WNV infection is diagnosed by detecting 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; detecting IgM antibodies in CSF by capture enzyme-linked immunosorbent assay (ELISA) method; demonstrating more than a fourfold increase in the titer of specific neutralizing antibody using the plaque-reduction neutralization assay in paired serum or CSF samples; or detecting both IgG and IgM in a single serum specimen (Nash). ¹⁰ 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. ^12,17

Electrodiagnostic Studies

In more than 70% of the cases with acute flaccid paralysis, nerve conduction studies show reduced or absent compound motor action potentials with preserved sensory nerve action potentials, conduction velocities, and distal latencies. ^11,12,22,23 Such a pattern suggests anterior horn cell disease with or without additional motor root involvement, as is seen with poliomyelitis. Less commonly, patients have an additional reduction in sensory nerve action potentials. ^10,11 This pattern was previously attributed to a possible peripheral sensorimotor polyneuropathy but is now believed to represent dorsal root ganglia inflammation in the context of a myelitis. ^11,12

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. ^27–30 Needle electrode examinations show abnormal spontaneous activity such as fibrillation potentials and positive sharp waves in the acute setting, reflecting active denervation. ^11,12 Needle electrode examinations and nerve conduction studies can be abnormal in clinically unaffected muscles, reflecting a more widespread involvement with the WNV. ¹¹ Needle electrode examinations and nerve conduction studies at 8 months after disease onset show chronic denervation and motor axon loss in affected limbs. ¹²

Radiologic Findings

No acute abnormalities are detected in computed tomographic scans of the brains of patients with acute WNV infection. ^10–12 In the setting of WNV encephalitis, magnetic resonance imaging (MRI) of the brain is abnormal in 8% to 33% of patients, with hyperintense signal abnormalities affecting the cerebral cortex, the underlying subcortical white matter, or both on the T2 and FLAIR (fluid-attenuated inversion recovery) sequences. ^11,12 Similar changes were described in the thalamus, cerebellum, and brainstem in patients with prominent cerebellar, parkinsonian, or brainstem symptoms. ^12,13

In patients with WNV-associated flaccid paralysis, MRI of the spine is abnormal in 75% 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. ^11,12

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Treatment

The treatment of WNV is currently supportive, with particular attention to the risk of respiratory compromise secondary to muscle weakness and aspiration secondary to bulbar dysfunction. ^11,12 Trials of several medications, including intravenous immunoglobulins, ³¹ ribavirin, interferon, and steroids, have shown no 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 mosquitoes. ¹⁵ Lifestyle modifications include avoiding outdoor activities during the hours around dawn and dusk, when mosquitoes are most active, and wearing protective, light-colored clothing to limit insect bites. Insect repellents 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. ²¹ A vaccine has been developed for veterinary use in horses but is not approved for use in humans.

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Clinical Outcomes

Mortality from WNV infection ranges from 13% to 18%, typically due to complicating medical illnesses in the setting of severe disease. ^11–13 One study evaluating patients at 18 months following acute infection suggested a somewhat higher mortality rate (around 30%), mostly in patients initially presenting with respiratory failure. ³²

Acute morbidity is significant. 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. ^11,12 Most of these patients require long-term tracheostomy. ¹¹ The most common in-hospital complication was pneumonia (23%), followed by bacteremia (8%) and thromboembolic disease (6%). ¹²

Many neurologic deficits persist in patients with WNV infection. On discharge from the hospital, only one third of WNV encephalitis patients are fully ambulatory, ¹⁵ and most complain of continuing symptoms of fatigue, myalgias, headaches, and cognitive changes at 8 to 18 months of follow-up. ^13,32 WNV meningitis has a relatively better prognosis: More than 95% of patients recover fully, with normal functional recovery at 8 months of follow-up. ¹³ One study showed a similar trend of more favorable motor outcomes in meningitis patients as opposed to encephalitis patients (44% versus 32%) 1 year following the acute infection. ³³ Patients with WNV myelitis show no improvement in limb weakness if flaccid paralysis develops. ^13,15,32 The persistence of movement disorders is a less-defined feature, with conflicting results in various studies. ¹³

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Conclusions

WNV infection can be a significant cause of CNS morbidity and mortality. The virus can cause salient neurologic 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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Summary

• Although central nervous system involvement with West Nile virus (WNV) infection is rare, it can be devastating.
• WNV is asymptomatic in 80% of those infected; approximately 20% of patients present with clinical disease.
• Neurologic manifestations are very variable, mainly including meningitis, encephalitis, and a polio-like limb weakness.
• Trials are ongoing to find effective treatment.
• Mortality ranges from 10% to 30%.
• Long-term outcome studies suggest persistent weakness and neurocognitive complaints in up to one half the patients affected.

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Suggested Readings

• Acute anterior myelitis complicating West Nile fever. Arch Neurol. 36: 1979; 172-173.
• Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis. Transpl Infect Dis. 4: 2002; 160-162.
• Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 17-2003. A 38-year-old woman with fever, headache, and confusion. N Engl J Med. 348: 2003; 2239-2247.
• Long term outcome of patients with West Nile virus infection. Infect Dis Clin Pract. 13: 2005; 1-3.
• West Nile virus infection: A new acute paralytic illness. Neurology. 61: 2003; 55-59.
• Long-term prognosis for clinical West Nile virus. Emerg Infect Dis. 10: 2004; 1405-1411.
• A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med. 347: 2002; 1279-1280.
• The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med. 344: 2001; 1807-1814.
• West Nile virus. JAMA. 290: 2003; 524-528.
• Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003;290:511-515. Erratum in JAMA. 290: 2003; 1318.