West Nile Virus

Viral Entry and Initial Replication

• Mosquito inoculation introduces WNV into the dermis and subcutaneous tissues, where the virus replicates in dendritic cells, fibroblasts, and macrophages
• Viral RNA is recognized by pattern recognition receptors (TLRs 3 and 7), triggering innate immune responses including interferon-alpha/beta production
• Viremia develops within 2-3 days, typically lasting 1-7 days before antibody neutralization

Blood-Brain Barrier Penetration

• WNV crosses the blood-brain barrier through both transcellular and paracellular mechanisms
• The virus targets endothelial cells of cerebral vasculature, expressing viral proteins that disrupt tight junction proteins (claudins, occludin, ZO-1)
• CD14+ monocytes serve as Trojan horses, carrying virus across the BBB while minimizing viral protein exposure to antibodies
• Viral proteins (NS1, NS5) directly damage endothelial cells through proteasomal degradation of junction proteins
• Production of pro-inflammatory cytokines (IL-6, TNF-α, IL-8) by infected endothelial cells increases vascular permeability

Central Nervous System Invasion and Neuronal Damage

• Once in the CNS, WNV targets neurons, glial cells, and dendritic cells
• Neuronal cell bodies are preferentially infected, particularly in the spinal cord anterior horn, brainstem, and cortex
• Viral replication induces apoptosis through caspase-3 activation and mitochondrial dysfunction
• Excitotoxicity develops from excessive glutamate release by infected neurons and glial cells
• Cytokine storm occurs with TNF-α, IL-1β, and IL-6 driving microglial activation and recruitment of leukocytes into the CNS
• Neuroinflammation with CD8+ T-cell infiltration causes both antiviral defense and bystander neuronal damage
• In severe cases, neuronal death and demyelination occur, particularly in poliomyelitis-like syndrome affecting motor neurons

Vector and Transmission

• Culex pipiens mosquitoes (northern US), Culex quinquefasciatus (southern US), and related species serve as primary vectors
• Avian amplifying hosts (American robins, jays, cardinals) develop high viremia without clinical illness
• Occupational exposure (outdoor workers, farmers) and geographic residence in endemic areas increase risk
• Peak transmission occurs July-September in temperate climates

Host Risk Factors for Neuroinvasive Disease

• Age >60 years confers 4-10 fold increased risk for severe neuroinvasive disease
• Immunocompromise including HIV/AIDS (CD4 <200), organ transplantation, chemotherapy, and immunosuppressive biologics substantially increase CNS invasion risk
• Comorbidities: diabetes mellitus, hypertension, chronic kidney disease, and malignancy
• Male gender shows slight predominance in severe disease (male-to-female ratio ~1.5:1)
• Genetic factors: HLA-B35 and HLA-A24 alleles associated with increased susceptibility

Asymptomatic Infection (80%)

• No symptoms despite documented viremia and seroconversion
• Represents the majority of infected individuals

West Nile Fever (Febrile Illness - 20%)

• Fever (38-40°C) with abrupt onset, often biphasic ("saddle-back pattern" in ~20% of cases)
• Myalgias and arthralgias (especially back, joints), often severe and incapacitating
• Headache (frontal or occipital, often severe)
• Malaise, fatigue, and chills
• Rash (maculopapular, pruritic) on trunk and extremities appearing on day 3-8 in ~40% of cases; occasionally involving palms and soles
• Lymphadenopathy (cervical, axillary)
• Nausea, vomiting, diarrhea (less common than with other arboviruses)
• Symptoms typically resolve within 1-2 weeks, though fatigue may persist for months

Neuroinvasive Disease

• Fever with nuchal rigidity
• Photophobia, phonophobia
• Headache (severe)
• Altered mental status (variable severity)
• CSF pleocytosis with lymphocytic predominance
• Normal or mildly elevated protein; normal glucose (unlike bacterial meningitis)

• Fever and altered mental status (confusion, disorientation, lethargy, coma)
• Seizures (present in 20-40% of encephalitis cases, often focal)
• Behavioral changes, personality changes, delirium
• Headache (usually present)
• Focal neurologic deficits: hemiparesis, aphasia, visual field defects
• Tremors, myoclonus (occasionally)
• Nuchal rigidity may be absent in pure encephalitis (unlike meningitis)

• Acute flaccid paralysis affecting one or more limbs, mimicking acute poliomyelitis
• Asymmetric weakness (often one arm or leg initially, then progression)
• Predominantly lower motor neuron pattern (hyporeflexia, fasciculations, eventual atrophy)
• Respiratory failure requiring mechanical ventilation when diaphragm/intercostal muscles involved
• Spinal cord gray matter involvement (anterior horn cells selectively damaged)
• Pain and paresthesias less prominent than with other paralytic causes
• Progression over hours to days; minimal improvement over months to years

• Ascending paralysis with areflexia
• Post-infectious pattern may occur

Other Neurologic Manifestations (Rare)

• Optic neuritis
• Peripheral neuropathy
• Cranial nerve palsies (especially CN VII and VIII)
• Movement disorders (parkinsonism, tremor)

Physical Examination Findings

• Fever (core temperature elevation)
• Rash (maculopapular, blanching, on trunk and extremities; may resemble measles or rubella)
• Lymphadenopathy (cervical, axillary, inguinal)
• Meningeal signs: Kernig's sign, Brudzinski's sign (in meningitis)
• Altered mental status (confusion, lethargy, disorientation, coma in encephalitis)
• Focal neurologic deficits: hemiparesis, cranial nerve palsies, gaze abnormalities
• Flaccid paralysis with hyporeflexia (poliomyelitis-like syndrome)
• Tremor, myoclonus, nystagmus (in some cases)

Clinical Suspicion Triggers

• Fever + rash + myalgias during mosquito season in endemic area
• Fever + meningitis with lymphocytic CSF pleocytosis (especially in summer/early fall)
• Fever + encephalitis with focal seizures or focal deficits in endemic region
• Acute flaccid paralysis during WNV season (should prompt WNV testing even without typical prodrome)
• Fever + myalgias + fatigue in a febrile illness cluster (suggests arboviral outbreak)

Serologic Testing (Gold Standard for Diagnosis)

• IgM ELISA (enzyme-linked immunosorbent assay):
• Becomes positive 3-8 days after symptom onset
• Peaks at 1-2 weeks, detectable for up to 3 months (occasionally longer)
• High sensitivity and specificity (>95%) for acute infection
• Can cross-react with other flaviviruses (dengue, yellow fever, Japanese encephalitis, Zika, St. Louis encephalitis), requiring confirmatory testing
• Positive IgM + negative prior serology in acute illness strongly suggests WNV

• IgG ELISA:
• Appears at day 7-10, persists for years
• Indicates prior or recent infection; distinguishes acute from past infection when paired with IgM
• Used for seroprevalence studies and blood bank screening

• Plaque Reduction Neutralization Test (PRNT) (confirmatory test):
• Gold standard for confirmation when cross-reactivity with other flaviviruses is concern
• Specific antibody neutralization identifies WNV with >90% specificity
• Time-consuming and performed only at reference laboratories
• Required for public health reporting in some jurisdictions

Nucleic Acid Testing (PCR)

• RT-PCR (reverse transcriptase PCR):
• Detects viral RNA in serum during acute viremia (typically positive for 3-8 days after illness onset)
• Higher sensitivity in CSF than in serum during neuroinvasive disease
• Often negative by the time neuroinvasive disease manifests (because neuroinvasive disease occurs after viremia has cleared)
• Useful in immunocompromised patients (may have prolonged viremia)
• Available at CDC and some reference laboratories; not routinely available at all hospitals

Cerebrospinal Fluid Analysis (for CNS Disease)

• Cell count and differential:
• Lymphocytic pleocytosis (typically 10-1000 cells/μL, sometimes up to 10,000)
• Lymphocyte predominance (70-90% of WBC), though early in illness may have neutrophil predominance
• RBC count usually normal or minimally elevated

• Chemistry:
• Protein: Normal to mildly elevated (50-100 mg/dL), typically <200 mg/dL (contrast with bacterial meningitis)
• Glucose: Normal to slightly low (>40 mg/dL), usually >50% of serum glucose (viral pattern, unlike bacterial)

• Gram stain and bacterial culture: Negative (rules out bacterial meningitis)

• Viral culture: Low yield; rarely performed

• WNV IgM and IgG: Most sensitive test for CNS WNV (~80% sensitivity in CSF, even higher than serum)
• CSF WNV IgM in appropriate clinical context is diagnostic of CNS WNV infection
• CSF IgG without IgM may indicate prior infection, but CNS infection still possible with recent intrathecal antibody production

• RT-PCR of CSF: Positive in ~40-80% of neuroinvasive cases when tested early

• Opening pressure: Normal to mildly elevated

Neuroimaging

• No imaging change in uncomplicated meningitis
• Encephalitis findings:
• T2/FLAIR hyperintense lesions in gray matter (basal ganglia, thalamus, brainstem, spinal cord)
• Lesions often bilateral and symmetric in deep structures
• No contrast enhancement typical (infection occurs after viremia clears, limited inflammation)
• Cortical involvement less common than subcortical

• Poliomyelitis-like syndrome findings:
• Anterior horn cell involvement with T2 hyperintensity in cervical or thoracic spinal cord (often bilateral)
• Involvement of anterior horn region on axial imaging
• Gray matter predominance
• Minimal or no enhancement (gray matter disease typically non-enhancing in WNV)
• Atrophy may develop chronically

• Less sensitive than MRI
• May show basal ganglia hypodensities (best seen on contrast CT)
• Used primarily to exclude hemorrhage or mass effect when MRI unavailable

Laboratory Tests

• Leukocytosis (WBC 5,000-11,000/μL in ~30% of cases)
• Lymphopenia in early febrile illness, then relative lymphocytosis
• Thrombocytopenia (in ~5% of cases, usually mild)

• Hyponatremia (SIADH-like, present in 20-30% of neuroinvasive disease)
• Mild elevation in liver enzymes (ALT, AST) in some cases
• Renal function normal unless severe disease/multiorgan involvement

Diagnostic Criteria for WNV Infection

• Probable case: Fever + myalgias/headache in endemic area + WNV IgM positive OR RT-PCR positive in serum/CSF
• Confirmed case: Fourfold rise in WNV antibody titer between acute and convalescent serum OR WNV IgM positive + confirmatory test (PRNT) positive OR RT-PCR positive
• Neuroinvasive disease: CNS symptoms + CSF or serum IgM positive (or RT-PCR positive) plus compatible CSF findings

Differential Diagnosis Considerations

• Bacterial meningitis: CSF shows neutrophil predominance, high protein, low glucose; Gram stain/culture positive
• Viral meningitis (enterovirus, herpes): Similar CSF findings; PCR testing differentiates
• Herpes simplex encephalitis: MRI shows temporal lobe involvement; CSF herpes PCR positive
• Polio: Stool culture positive; flaccid paralysis with sensory sparing
• Guillain-Barré syndrome: Ascending paralysis, albumin-cytologic dissociation in CSF (high protein, normal cells), normal neuroimaging
• Stroke: Non-infectious; neuroimaging shows ischemia/hemorrhage; negative CSF findings
• Other arboviruses (Eastern equine encephalitis, St. Louis encephalitis): Similar presentation; serology differentiates

Supportive Care (Cornerstone of Management)

• No specific antiviral therapy is currently FDA-approved for WNV
• Hospitalization indicated for all neuroinvasive disease and most cases with severe systemic illness
• ICU admission for encephalitis with altered mental status, seizures, or respiratory compromise
• Mechanical ventilation for respiratory failure (diaphragmatic paralysis in poliomyelitis-like syndrome)
• Supportive hydration and electrolyte repletion (maintain euvolemia; correct hyponatremia if symptomatic with hypertonic saline)
• Antipyretics for fever management (acetaminophen preferred to NSAIDs to minimize bleeding risk)
• Pain management with opioids for severe myalgias/headache
• Seizure management with levetiracetam (preferred, no drug interactions) or lorazepam for acute seizures; prophylactic antiepileptics not routinely recommended

Management of Specific Complications

Neurologic emergencies

• Neuromuscular respiratory failure (emergency): anterior horn cell destruction at C3-C5 denervates the diaphragm, producing hypercapnic failure without airway obstruction. Signaled by rising respiratory rate, paradoxical abdominal motion, weak cough, and a falling vital capacity or negative inspiratory force — not by oxygen saturation, which stays normal until late. Serial bedside spirometry, not pulse oximetry, drives the decision to intubate. Most survivors of ventilator-dependent WNV paralysis have incomplete motor recovery.
• Status epilepticus (emergency): cortical and thalamic neuronal injury plus glutamate excitotoxicity lowers seizure threshold. Escalate per the Neurocritical Care Society algorithm — benzodiazepine, then a second-line agent such as levetiracetam — and obtain EEG, since nonconvulsive status can masquerade as persistent obtundation.
• Cerebral edema with herniation (emergency): cytokine-driven blood-brain barrier breakdown; heralded by pupillary asymmetry, Cushing reflex, or abrupt GCS decline.
• Aspiration pneumonia: brainstem and cranial nerve involvement impairs swallowing; withhold oral intake until swallowing is formally assessed, as is standard supportive practice in any patient with depressed consciousness or bulbar dysfunction (the same bedside dysphagia-screening approach used in acute stroke care).

Systemic and delayed complications

• SIADH-associated hyponatremia: hypothalamic involvement causes inappropriate ADH release; look for seizure or worsening mental status disproportionate to imaging.
• Persistent flaccid paralysis with muscle atrophy: irreversible motor neuron loss, analogous to paralytic polio; EMG shows denervation with normal sensory responses.
• Post-WNV syndrome: months of fatigue, myalgia, and executive dysfunction after even non-neuroinvasive illness.
• Chorioretinitis: targetoid chorioretinal lesions on dilated exam; may cause persistent visual complaints.
• Immobility complications: venous thromboembolism, pressure injury, ventilator-associated pneumonia.

Treatment-related harms

• Osmotic demyelination: from overrapid correction of chronic hyponatremia with hypertonic saline; delayed quadriparesis and pseudobulbar signs days later.
• Empiric acyclovir nephrotoxicity: crystalline nephropathy while HSV is being excluded — prevent with volume expansion.
• Opioid oversedation confounding the neurologic exam; levetiracetam irritability and psychosis.
• Transfusion- and transplant-transmitted WNV: recipients are often immunosuppressed and progress to neuroinvasive disease rapidly.

• The classic stem: an older adult in the late summer to early fall with fever, headache, and asymmetric acute flaccid paralysis after outdoor exposure. Asymmetry plus preserved sensation is the fingerprint of anterior horn cell disease.
• Single best next step in suspected neuroinvasive disease: lumbar puncture for CSF WNV IgM — IgM is too large to cross an intact blood-brain barrier, so its presence in CSF implies intrathecal production and therefore CNS infection. Send CSF HSV-1/2 PCR simultaneously and start empiric acyclovir until herpes encephalitis is excluded (IDSA encephalitis guideline); this is the one intervention that changes mortality.
• The association examiners test: WNV is the leading cause of arboviral neuroinvasive disease in the continental United States and is transmissible by blood transfusion and solid organ transplantation — hence universal, FDA-guidance-driven nucleic acid screening of donated blood, implemented by US blood centers under AABB standards. A febrile encephalopathic transplant recipient weeks after grafting is a set-up.
• Serology caveat: flavivirus IgM cross-reacts (dengue, Zika, St. Louis encephalitis, prior yellow fever or Japanese encephalitis vaccination). The plaque reduction neutralization test is the confirmatory step, per CDC case definitions.
• Distractor to avoid — Guillain-Barré syndrome: GBS is symmetric, ascending, areflexic, and shows albuminocytologic dissociation (high protein, few cells). WNV poliomyelitis is asymmetric with a CSF pleocytosis. Do not reflexively order IVIG or plasma exchange.
• Second distractor — bacterial meningitis: early WNV CSF may be neutrophil-predominant, but glucose stays normal and Gram stain is negative; the differential shifts to lymphocytes on repeat tap.
• No approved antiviral and no licensed human vaccine — a vaccine exists for horses only. Corticosteroids, interferon, and ribavirin are unproven; management is supportive.
• Prevention is the tested "management": DEET-containing repellent, permethrin-treated clothing, and elimination of standing water around the home (CDC).