St. Louis encephalitis is a mosquito-borne flavivirus infection transmitted by Culex species mosquitoes, with birds as amplifying hosts. First described during a 1933 outbreak in St. Louis, Missouri, it remains an endemic arboviral cause of neuroinvasive disease in the United States, with a case fatality rate of 5–15% that increases with age. [1-3] The vast majority of infections are asymptomatic (ratio of apparent to inapparent infection ranges from 1:100 to 1:1000). [2-3]
1. History
- Onset and prodrome: Incubation period of 5–15 days (range 2–14 days) after mosquito bite, followed by a nonspecific febrile prodrome [4-5]
- Symptom characterization: Fever, headache, malaise, myalgia, nausea/vomiting, anorexia; may progress to confusion, disorientation, dizziness, tremors, and unsteadiness [2][6]
- Timing and seasonality: Outbreaks occur July through September during peak mosquito activity [7]
- Key HPI questions:
- Outdoor exposure, especially at dusk/dawn in endemic areas
- Travel to southern/central/western U.S. (Arkansas, Arizona, Mississippi, California, Florida) [1][8]
- Timeline from mosquito exposure to symptom onset
- Progression from febrile illness to neurologic symptoms
- Important negatives: No person-to-person transmission; no rash (rash is uncommon in SLE, unlike WNV where it occurs in ~33–50%) [5][9]
2. Alarm Features
- Altered mental status, confusion, or declining GCS
- Seizures, including subtle convulsive or nonconvulsive status epilepticus [4][7]
- Acute flaccid paralysis or focal neurologic deficits
- Signs of elevated intracranial pressure (papilledema, Cushing reflex) — ~30% of SLE patients have elevated CSF opening pressures [4]
- Respiratory failure requiring intubation
- Rapid progression of quadriparesis or quadriplegia [10]
3. Medications
- No FDA-approved antiviral therapy exists for SLE or any flavivirus encephalitis [4][6]
- Empiric acyclovir should be started immediately in all suspected encephalitis cases until HSV is excluded [11-12]
- Interferon α-2b ± IVIG: Anecdotal benefit reported in a pilot study (reduced severity/duration of complications) and in immunocompromised transplant recipients, but no RCT data supports routine use [6][10]
- Supportive medications: Antipyretics, antiemetics, antiepileptic drugs for seizure management
- Avoid: Corticosteroids are not routinely indicated unless autoimmune encephalitis is being considered in the differential
- Caution: Ribavirin has been used empirically in WNV but lacks evidence for SLE [4]
4. Diet
- Hydration is critical, especially in febrile patients with nausea/vomiting
- No specific dietary triggers or restrictions
- Patients with altered mental status may require NPO status and IV fluids pending swallow evaluation
- Long-term: Standard nutrition support during recovery; no disease-specific dietary modifications
5. Review of Systems
- Neurologic: Headache, confusion, memory difficulties, tremor, ataxia, seizures, focal weakness
- Constitutional: Fever, rigors, malaise, fatigue
- GI: Nausea, vomiting, diarrhea, anorexia (common in SLE) [6]
- Musculoskeletal: Myalgia, arthralgia
- Ophthalmologic: Retro-orbital pain, photophobia
- Respiratory: Assess for respiratory insufficiency (may indicate brainstem involvement or aspiration risk)
- Urinary: Urinary retention (reported in post-infectious myelitis) [13]
6. Collateral History and Family History
- Collateral: Baseline cognitive function, timeline of behavioral changes, witnessed seizures, recent outdoor activities
- Exposure history: Geographic location, outdoor occupation/hobbies, mosquito bite history, use of repellents/screens
- Family history: Not directly relevant (no hereditary predisposition), but household contacts with similar symptoms may suggest a cluster/outbreak
- Social context: Homelessness or lack of air conditioning increases mosquito exposure risk; report suspected cases to local/state public health department [14-15]
7. Risk Factors
- Age >60 years — strongest risk factor for neuroinvasive disease and death; all deaths in 2003–2017 U.S. surveillance were in patients >45 years [1][3]
- Immunosuppression, particularly solid organ transplant recipients [6]
- HIV coinfection — may increase risk of symptomatic infection [7]
- Hypertension, diabetes, chronic renal disease, cerebrovascular disease (extrapolated from WNV data) [15]
- Geographic: Endemic in western and southeastern U.S.; highest incidence in Arkansas, Arizona, Mississippi [1]
- Seasonal: Late summer (July–September)
- Culex mosquito exposure — peridomestic, crepuscular/nocturnal feeders
8. Differential Diagnosis
- West Nile virus encephalitis — most important mimic; clinically indistinguishable from SLE; serologic cross-reactivity makes differentiation challenging [9][14]
- Herpes simplex encephalitis (HSV-1) — temporal lobe predilection on MRI, hemorrhagic CSF; must be empirically treated until excluded [11]
- Other arboviral encephalitides: Eastern equine encephalitis (higher mortality), La Crosse, Powassan, California encephalitis viruses [16]
- Bacterial meningitis/meningoencephalitis — higher CSF WBC, low glucose, positive Gram stain
- Autoimmune encephalitis (anti-NMDAR, LGI1) — more subacute onset, psychiatric features, movement disorders [12]
- VZV encephalitis — vasculopathy, stroke-like presentation [12]
- Enteroviral meningoencephalitis
- Tuberculous or fungal meningitis — subacute, low glucose, high protein
- Metabolic encephalopathy — must exclude with basic labs
9. Past Medical History
- Prior flavivirus infection or vaccination (yellow fever, Japanese encephalitis) — may cause false-positive serologies due to cross-reactivity [15][17]
- Immunosuppressive conditions or medications
- Organ transplant history [6]
- HIV status [7]
- History of seizure disorder
- Chronic medical conditions (hypertension, diabetes, CKD)
10. Physical Exam
- Vital signs: Fever (often high), tachycardia; watch for relative bradycardia with hypertension (Cushing response)
- Neurologic exam (critical):
- Mental status: Orientation, GCS, attention, language
- Tremor (particularly parkinsonian-type tremor — correlates with substantia nigra involvement) [7]
- Cranial nerves: Nystagmus, facial weakness
- Motor: Tone, strength, acute flaccid paralysis
- Reflexes: Hyperreflexia or areflexia depending on level of involvement
- Cerebellar: Ataxia, dysmetria
- Meningeal signs: Nuchal rigidity, Kernig/Brudzinski signs
- Skin: Rash is uncommon in SLE (only ~7% vs. 33% in WNV) [9]
- Fundoscopy: Papilledema (elevated ICP)
11. Lab Studies
- CSF analysis (essential):
- Lymphocytic pleocytosis (typically 10–200 cells/μL), though neutrophils may predominate early [18-19]
- Mildly elevated protein
- Normal glucose
- Elevated opening pressure in ~30% [4]
- Serum and CSF arboviral serology:
- IgM capture ELISA — detectable 3–8 days post-symptom onset; IgM in CSF is highly suggestive of CNS infection [4][17]
- No commercially available SLEV-specific test — testing must be performed at public health laboratories [14]
- Plaque reduction neutralization test (PRNT) required to confirm and differentiate from WNV due to cross-reactivity [20]
- Routine labs: CBC (may show leukocytosis), CMP (hyponatremia from SIADH), LFTs, blood cultures (to exclude bacterial causes)
- CSF PCR panel: HSV-1/2, VZV, enterovirus — to exclude treatable causes [11][21]
- RT-PCR for SLEV: Low sensitivity due to transient/low-level viremia; not routinely useful [4][16]
12. Imaging
- MRI brain with contrast (preferred):
- May show T2/FLAIR hyperintensities in deep grey matter structures (thalami, basal ganglia) — similar to other arboviral encephalitides [18]
- Substantia nigra edema — a distinctive finding reported in SLE [7]
- May be normal in mild cases
- Helps exclude HSV (temporal lobe involvement), abscess, or mass lesion
- CT head:
- Less sensitive than MRI; primarily used to exclude contraindications to lumbar puncture (mass effect, herniation) [12]
- May show diffuse cerebral edema in severe cases
- Imaging is unnecessary in mild febrile illness without neurologic symptoms
The following table from a case series of 11 SLE patients during the 1995 Dallas epidemic illustrates the heterogeneity of clinical, CSF, imaging, and EEG findings:
13. Special Tests
- PRNT (plaque reduction neutralization test): Gold standard for differentiating SLEV from WNV and other flaviviruses; performed at reference/public health laboratories; time-consuming (requires live virus manipulation) [15][20]
- Metagenomic next-generation sequencing (mNGS): Can be considered when standard testing is negative [12]
- Convalescent serology: Paired acute and convalescent sera (collected 7–14 days apart) showing seroconversion or ≥4-fold rise in titer supports diagnosis [15][17]
14. ECG
- ECG findings are not a primary feature of SLE, but should be obtained as part of the general workup
- Myocarditis has been rarely described with flavivirus infections (more commonly WNV) [15]
- Monitor for arrhythmias in critically ill patients, especially those on QT-prolonging medications
- Rule out other causes of encephalopathy (e.g., cardiac arrhythmia causing syncope/altered mental status)
15. Assessment
- Clinical spectrum: Ranges from asymptomatic infection → mild febrile illness → aseptic meningitis → encephalitis (most common neuroinvasive presentation, 60%) [1]
- Severity stratification:
- Mild: Febrile headache without neurologic findings
- Moderate: Meningitis with preserved consciousness
- Severe: Encephalitis with altered mental status, seizures, focal deficits, or respiratory failure
- Case fatality rate: 5–15% overall; 6% in recent U.S. surveillance (2003–2017), with all deaths in patients >45 years [1-2]
- Atypical presentations: Acute disseminated encephalomyelitis (ADEM) as a post-infectious complication; parkinsonian features due to substantia nigra involvement [7][13]
- Complications: Status epilepticus, SIADH/hyponatremia, aspiration pneumonia, respiratory failure, prolonged neurocognitive deficits [4][22]
16. Treatment Plan
Initial stabilization:
- ABCs; secure airway if GCS ≤8 or respiratory failure
- Empiric IV acyclovir (10 mg/kg q8h) until HSV is excluded [11-12]
- Consider empiric antibiotics if bacterial meningoencephalitis cannot be excluded
- Seizure management: Benzodiazepines for acute seizures; levetiracetam or other AEDs for ongoing seizure prophylaxis/treatment
- ICP management if signs of elevated intracranial pressure (head of bed elevation, osmotic therapy)
Definitive management:
- Supportive care is the mainstay — there is no proven antiviral therapy [4]
- IFN-α2b ± IVIG may be considered in severe neuroinvasive disease, particularly in immunocompromised patients, based on limited anecdotal evidence [6][10]
- Fluid management: Monitor for SIADH; fluid restrict if hyponatremic
- DVT prophylaxis for immobilized patients
- Early rehabilitation referral (PT/OT/speech therapy)
Reporting:
- nationally notifiable diseaseMMWR + 1[14-15]
17. Disposition
- Admit all patients with:
- Neuroinvasive disease (encephalitis, meningitis, acute flaccid paralysis)
- Altered mental status, seizures, or focal neurologic deficits
- Inability to tolerate oral intake
- ICU admission for: GCS ≤8, status epilepticus, respiratory failure, hemodynamic instability
- Observation may be appropriate for: Mild febrile illness with headache, pending CSF results
- Discharge criteria: Resolving symptoms, stable neurologic exam, ability to tolerate PO, reliable follow-up
- Specialist consultation triggers:
- Neurology: All neuroinvasive cases (seizure management, EEG monitoring, prognostication)
- Infectious disease: Diagnostic confirmation, consideration of IFN/IVIG in immunocompromised patients
- Critical care: Respiratory failure, refractory status epilepticus
- Public health: All suspected/confirmed cases
18. Follow Up / Return Precautions
- Follow-up timing: Neurology follow-up within 1–2 weeks of discharge; repeat at 6 months and 12 months for neurocognitive assessment [22-23]
- Neurocognitive sequelae: Attention, working memory, processing speed, and cognitive efficiency deficits are common; depression is frequently observed; improvement may occur over 6–12 months but may be incomplete [12][22]
- Return precautions — instruct patients/families to return for:
- New or worsening confusion, seizures, or focal weakness
- Recurrent fever
- Difficulty breathing or swallowing
- Worsening headache or vision changes
- Patient counseling:
- No person-to-person transmission
- Mosquito bite prevention: DEET-containing repellents, permethrin-treated clothing, screens, avoiding outdoor activity at dusk/dawn [1]
- No vaccine is available for SLE
- Recovery may be prolonged; neuropsychological rehabilitation may be beneficial [22]
- Expected recovery: Mild cases typically resolve within weeks; neuroinvasive disease may result in persistent cognitive and functional deficits in up to 50% of survivors [12][18]
References
1. St. Louis Encephalitis Virus Disease in the United States, 2003-2017. — Curren EJ, Lindsey NP, Fischer M, Hills SL. The American Journal of Tropical Medicine and Hygiene. 2018.
2. St. Louis Encephalitis Virus Disease in the United States, 2003-2017. — Curren EJ, Lindsey NP, Fischer M, Hills SL. The American Journal of Tropical Medicine and Hygiene. 2018.
3. St. Louis Encephalitis Virus Disease in the United States, 2003-2017. — Curren EJ, Lindsey NP, Fischer M, Hills SL. The American Journal of Tropical Medicine and Hygiene. 2018.
4. Detection of Saint Louis encephalitis virus in two Brazilian states. — Moraes MM, Kubiszeski JR, Vieira CJDSP, et al. Journal of Medical Virology. 2022.
5. Detection of Saint Louis encephalitis virus in two Brazilian states. — Moraes MM, Kubiszeski JR, Vieira CJDSP, et al. Journal of Medical Virology. 2022.
6. Viral Encephalitis. — Whitley RJ. The New England Journal of Medicine. 1990.
7. Viral Encephalitis. — Whitley RJ. The New England Journal of Medicine. 1990.
8. Flavivirus Encephalitis. — Solomon T. The New England Journal of Medicine. 2004.
9. Flavivirus Encephalitis. — Solomon T. The New England Journal of Medicine. 2004.
10. Pathogenic Flaviviruses. — Gould EA, Solomon T. Lancet. 2008.
11. Pathogenic Flaviviruses. — Gould EA, Solomon T. Lancet. 2008.
12. Neuroinvasive St. Louis Encephalitis Virus Infection in Solid Organ Transplant Recipients. — Hartmann CA, Vikram HR, Seville MT, et al. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017.
13. Neuroinvasive St. Louis Encephalitis Virus Infection in Solid Organ Transplant Recipients. — Hartmann CA, Vikram HR, Seville MT, et al. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017.
14. St Louis Encephalitis: A Review of 11 Cases in a 1995 Dallas, Tex, Epidemic. — Wasay M, Diaz-Arrastia R, Suss RA, et al. Archives of Neurology. 2000.
15. St Louis Encephalitis: A Review of 11 Cases in a 1995 Dallas, Tex, Epidemic. — Wasay M, Diaz-Arrastia R, Suss RA, et al. Archives of Neurology. 2000.
16. Epidemiologic and Environmental Characterization of the Re-Emergence of St. Louis Encephalitis Virus in California, 2015-2020. — Danforth ME, Snyder RE, Feiszli T, et al. PLoS Neglected Tropical Diseases. 2022.
17. Epidemiologic and Environmental Characterization of the Re-Emergence of St. Louis Encephalitis Virus in California, 2015-2020. — Danforth ME, Snyder RE, Feiszli T, et al. PLoS Neglected Tropical Diseases. 2022.
18. Comparison of Characteristics of Patients With West Nile Virus or St. Louis Encephalitis Virus Neuroinvasive Disease During Concurrent Outbreaks, Maricopa County, Arizona, 2015. — Venkat H, Krow-Lucal E, Kretschmer M, et al. Vector Borne and Zoonotic Diseases. 2020.
19. Comparison of Characteristics of Patients With West Nile Virus or St. Louis Encephalitis Virus Neuroinvasive Disease During Concurrent Outbreaks, Maricopa County, Arizona, 2015. — Venkat H, Krow-Lucal E, Kretschmer M, et al. Vector Borne and Zoonotic Diseases. 2020.
20. Effect of Interferon-Alpha2b Therapy on St. Louis Viral Meningoencephalitis: Clinical and Laboratory Results of a Pilot Study. — Rahal JJ, Anderson J, Rosenberg C, Reagan T, Thompson LL. The Journal of Infectious Diseases. 2004.
21. Effect of Interferon-Alpha2b Therapy on St. Louis Viral Meningoencephalitis: Clinical and Laboratory Results of a Pilot Study. — Rahal JJ, Anderson J, Rosenberg C, Reagan T, Thompson LL. The Journal of Infectious Diseases. 2004.
22. State of the Art: Acute Encephalitis. — Bloch KC, Glaser C, Gaston D, Venkatesan A. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2023.
23. State of the Art: Acute Encephalitis. — Bloch KC, Glaser C, Gaston D, Venkatesan A. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2023.
24. Encephalitis. — Binks SNM, Saylor D, Easton A, Thakur KT, Irani SR. Lancet. 2026.
25. Encephalitis. — Binks SNM, Saylor D, Easton A, Thakur KT, Irani SR. Lancet. 2026.
26. Acute Disseminated Encephalomyelitis Following Saint Louis Encephalitis Virus Infection. — Pedrosa DA, de Paula Oliveira LKL, Bertanha R, et al. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2024.
27. Acute Disseminated Encephalomyelitis Following Saint Louis Encephalitis Virus Infection. — Pedrosa DA, de Paula Oliveira LKL, Bertanha R, et al. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2024.
28. Concurrent Outbreaks of St. Louis Encephalitis Virus and West Nile Virus Disease - Arizona, 2015. — Venkat H, Krow-Lucal E, Hennessey M, et al. MMWR. Morbidity and Mortality Weekly Report. 2015.
29. Concurrent Outbreaks of St. Louis Encephalitis Virus and West Nile Virus Disease - Arizona, 2015. — Venkat H, Krow-Lucal E, Hennessey M, et al. MMWR. Morbidity and Mortality Weekly Report. 2015.
30. West Nile Virus Surveillance and Control Guidelines. — United States Centers for Disease Control and Prevention (2025). 2025.
31. West Nile Virus Surveillance and Control Guidelines. — United States Centers for Disease Control and Prevention (2025). 2025.
32. Diagnostic Approach for Arboviral Infections in the United States. — Piantadosi A, Kanjilal S. Journal of Clinical Microbiology. 2020.
33. Diagnostic Approach for Arboviral Infections in the United States. — Piantadosi A, Kanjilal S. Journal of Clinical Microbiology. 2020.
34. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.
35. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.
36. Acute Encephalitis in Immunocompetent Adults. — Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. Lancet. 2019.
37. Acute Encephalitis in Immunocompetent Adults. — Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. Lancet. 2019.
38. Viral Encephalitis: Familiar Infections and Emerging Pathogens. — Whitley RJ, Gnann JW. Lancet. 2002.
39. Viral Encephalitis: Familiar Infections and Emerging Pathogens. — Whitley RJ, Gnann JW. Lancet. 2002.
40. Assessment of Immunoglobulin M Enzyme-Linked Immunosorbent Assay Ratios to Identify West Nile Virus and St. Louis Encephalitis Virus Infections During Concurrent Outbreaks of West Nile Virus and St. Louis Encephalitis Virus Diseases, Arizona 2015. — Curren EJ, Venkat H, Sunenshine R, et al. Vector Borne and Zoonotic Diseases. 2020.
41. Assessment of Immunoglobulin M Enzyme-Linked Immunosorbent Assay Ratios to Identify West Nile Virus and St. Louis Encephalitis Virus Infections During Concurrent Outbreaks of West Nile Virus and St. Louis Encephalitis Virus Diseases, Arizona 2015. — Curren EJ, Venkat H, Sunenshine R, et al. Vector Borne and Zoonotic Diseases. 2020.
42. Acute Viral Encephalitis. — Tyler KL. The New England Journal of Medicine. 2018.
43. Acute Viral Encephalitis. — Tyler KL. The New England Journal of Medicine. 2018.
44. The Neurobehavioural Consequences of St. Louis Encephalitis Infection. — Greve KW, Houston RJ, Adams D, et al. Brain Injury. 2002.
45. The Neurobehavioural Consequences of St. Louis Encephalitis Infection. — Greve KW, Houston RJ, Adams D, et al. Brain Injury. 2002.
46. Functional Outcome After Infectious Encephalitis: A Longitudinal Multicentre Prospective Cohort Study. — Fillâtre P, Mailles A, Stahl JP, et al. Clinical Microbiology and Infection : The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2025.
47. Functional Outcome After Infectious Encephalitis: A Longitudinal Multicentre Prospective Cohort Study. — Fillâtre P, Mailles A, Stahl JP, et al. Clinical Microbiology and Infection : The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2025.