La Crosse Encephalitis

Etiology

La Crosse encephalitis is a viral illness caused by the La Crosse virus, primarily transmitted by the Aedes triseriatus mosquito. The viral transmission cycle includes both vertical and horizontal transmission. Horizontal transmission primarily occurs when adult mosquitoes acquire the virus through blood meals from infected vertebrate reservoirs, such as chipmunks, squirrels, and woodchucks. Once infected, the mosquito can transmit the virus to other animals or humans during subsequent blood meals.[5] Humans serve as dead-end hosts because they do not develop viremia levels sufficient to infect feeding mosquitoes. In rare instances, horizontal transmission can also occur between mosquitoes during mating.[6]

Vertical transmission occurs when an infected adult female mosquito transmits the virus to her offspring through the ovaries and developing eggs. The virus overwinters in dormant, infected mosquito eggs, and when the eggs hatch in the spring, the larvae develop into adult mosquitoes already infected with La Crosse virus.[7] Vertical transmission enables the virus to persist in the environment from year to year without requiring a mammal host.[8] 

Epidemiology

La Crosse encephalitis is a relatively uncommon disease, although it is the most common cause of pediatric neuroinvasive arboviral disease in North America. The disease is endemic in the central and eastern United States, primarily in the upper Midwestern, mid-Atlantic, and Appalachian regions. Most cases occur during peak mosquito season, which runs from July through September.

Results from a study of La Crosse virus surveillance data from 2003 to 2019 identified 1281 reported human cases, 92% of which involved neuroinvasive disease. The median age was 8; 88% of affected individuals were younger than 18, and 59% were male. The average annual national incidence of neuroinvasive disease caused by La Crosse virus was 0.02 cases per 100,000 persons, with West Virginia, North Carolina, Tennessee, and Ohio accounting for 80% of cases.[9] 

As with infections caused by other arboviruses, such as West Nile virus, most La Crosse virus infections are mild or asymptomatic. An estimated 96% to 99% of La Crosse virus infections are completely asymptomatic or cause very mild, influenza-like symptoms. Results from a seroprevalence survey conducted in northwestern Virginia found an overall seroprevalence of nearly 2% among wild mammals surveyed, including eastern gray squirrels, eastern cottontails, and red foxes. In humans, seroprevalence rates have reached 35% in highly endemic areas.[10] Thus, only the most severe infections (such as those that cause neuroinvasive disease) are diagnosed and reported.[11] 

Pathophysiology

La Crosse virus is transmitted subcutaneously when an infected mosquito penetrates the skin during feeding. Two surface glycoprotein subtypes are involved in viral attachment. The G1 protein mediates attachment primarily to human cells, whereas the G2 protein mediates attachment to mosquito cells.[12] The proteins are located on a spherical lipid envelope that encapsulates the single-stranded viral RNA. 

Viral replication may begin in muscle adjacent to the site of penetration, resulting in systemic infection and viremia involving the reticuloendothelial system and chondrocytes. Viral entry through vascular endothelial cells can result in neuroinvasion and subsequent infection of neurons and glia. This process represents the proposed mechanism underlying the encephalitic syndrome associated with La Crosse virus infection.

Results from postmortem studies of brain tissue from patients with La Crosse encephalitis showed lesions characterized by neurodegeneration, patchy inflammation, and vasculitis.[13] Although the exact pathophysiology of viral encephalitis remains incompletely understood, reversible cerebral edema may play a significant role in the pathogenesis of La Crosse encephalitis. The edema is postulated to result from vasogenic mechanisms associated with endothelial cell involvement.[14]

Histopathology

Histopathologic evaluation of La Crosse encephalitis is usually performed on postmortem brain tissue. Indirect immunofluorescence examination showed prominent staining of neurons and capillary endothelial cells. Light microscopic examination revealed perivascular infiltration by mononuclear cells and necrosis.[13] The strong immunofluorescence staining of endothelial cells further supports the hypothesis that La Crosse virus infects both endothelial and neuronal cells.[14] 

History and Physical

Most La Crosse virus infections are asymptomatic and undiagnosed. Approximately 1% to 4% of infections cause symptoms. Symptomatic La Crosse encephalitis can range from a mild febrile illness lasting a few days to fatal encephalitis. The overall case-fatality rate among patients with diagnosed La Crosse encephalitis is approximately 1%.[9] However, severe encephalitis can cause substantial morbidity.[13]

The incubation period for La Crosse virus is 5 to 15 days. Among patients who develop symptoms, 80% to 90% have a mild clinical course, most commonly characterized by headache, fever, and vomiting for 1 to 3 days, followed by improvement over the subsequent week. Lethargy, behavioral changes, and seizures may also occur. Approximately 50% of individuals hospitalized with La Crosse encephalitis have seizures, including focal or generalized seizures in 40% to 60% and status epilepticus in 10% to 15%.[14]

Children may present with meningoencephalitis, encephalopathy, and seizures, whereas adults more commonly present with fever, headache, and hyponatremia. Altered mental status is common among adults, although seizures occur less frequently. Adults with more complicated La Crosse encephalitis may develop cerebral edema and respiratory compromise requiring intubation in up to 25% of patients.[4]

Common symptoms include:

• Fever
• Lethargy
• Headache
• Confusion
• Vomiting
• Seizures (more common in children) 

Less common symptoms include:

• Hyponatremia (more common among adults)
• Neck stiffness
• Photophobia
• Respiratory distress
• Coma

Evaluation

The most common diagnostic test for La Crosse encephalitis is an enzyme-linked immunosorbent assay to detect immunoglobulin M (IgM) antibodies in serum or cerebrospinal fluid (CSF). Results from one study showed a sensitivity of 75% and a specificity of 98%.[15] A 4-fold increase in antibody titers in convalescent samples obtained 2 weeks later is diagnostic.[13] La Crosse virus IgM tests are available commercially, at selected state health department laboratories, and at the Centers for Disease Control and Prevention (CDC). Because the IgM assay can cross-react with related viruses, positive La Crosse virus IgM test results require confirmation using a serum or CSF neutralizing antibody test performed by a state public health laboratory or the CDC.

Molecular testing with polymerase chain reaction (PCR) may also be performed and is particularly useful early in the illness and in severely immunocompromised individuals who may not develop an effective antibody response to the virus. PCR testing is highly specific for La Crosse virus, but its sensitivity varies with the specimen and the timing of collection. Sensitivity is high during the brief period of active viremia and in central nervous system tissue but low in CSF and after the acute phase of infection. PCR testing is sometimes used postmortem because viral concentrations may be high in central nervous system tissue.

CSF analysis often reveals lymphocytic pleocytosis, elevated protein levels, and normal glucose levels. Cerebrospinal fluid viral culture is less useful and frequently yields negative results. Additionally, a basic metabolic panel and a complete blood count can identify leukocytosis and electrolyte abnormalities, including hyponatremia, which is associated with La Crosse encephalitis.

Head CT and brain MRI findings may be normal because La Crosse encephalitis has no characteristic imaging features. In some cases, head CT findings may demonstrate cerebral edema and possible cerebral herniation resulting from increased intracranial pressure. Basal ganglia hemorrhage has also been reported in a few cases.[13] Additionally, brain MRI findings in some children with neuroinvasive La Crosse encephalitis have demonstrated cortical gadolinium enhancement.[16] Electroencephalographic findings may demonstrate nonspecific abnormalities, including unilateral slowing, periodic lateralized epileptiform discharges, or seizures in up to 90% of individuals.[4]

Treatment / Management

No specific treatment is available for La Crosse encephalitis, and management focuses on supportive and symptomatic care, particularly the prevention and control of cerebral edema and seizures associated with more severe disease. Patients with milder illness presenting with fever and headache may be treated conservatively with analgesics, rest, and hydration. In individuals presenting with acute encephalopathy and a high clinical suspicion of viral encephalitis, intravenous acyclovir can be used until herpes simplex virus encephalitis has been ruled out.[13](B3)

Intravenous ribavirin has been used to treat La Crosse encephalitis, but its effectiveness is unproven.[14] Viral RNA-dependent RNA polymerase is the proposed target of intravenous ribavirin. Results from earlier studies involving children suggested adequate penetration of ribavirin into CSF, with concentrations reaching approximately 70% of plasma levels.[17][18](B3)

However, results from more recent clinical trials did not support these findings. Oral ribavirin is not considered a viable treatment option for La Crosse encephalitis because CSF concentrations are lower than those achieved with intravenous administration.[19] Results from one in vitro study showed that relatively low ribavirin concentrations (0.3 μmol/L) inhibited La Crosse virus replication.[20] (A1)

Individuals who develop seizures may require antiseizure medications to achieve seizure control. Long-term use of antiseizure medications may be considered for individuals who subsequently develop epilepsy. Furthermore, individuals who develop coma with respiratory compromise may require airway support and mechanical ventilation. In some cases of La Crosse encephalitis, central venous pressure monitoring may help maintain appropriate intravascular volume in the setting of associated hyponatremia.[13](B3)

Differential Diagnosis

The differential diagnoses for La Crosse encephalitis are broad and require careful consideration of numerous etiologies, including infectious, vascular, autoimmune, drug-induced, toxic, and metabolic causes.

Infectious

• Other causes of viral meningitis and encephalitis
  • Herpes simplex virus 
  • Other California serogroup viruses (eg, Jamestown Canyon virus, Snowshoe hare virus)
  • Enteroviruses
  • Other arboviruses (eg, West Nile virus, St. Louis encephalitis virus, Powassan virus, Eastern equine encephalitis virus)
  • Varicella-zoster virus
  • Rabies
  • Mumps
• Bacterial causes
  • Streptococcus pneumoniae
  • Neisseria meningitidis 
  • Haemophilus influenzae 
  • Rocky Mountain spotted fever 
  • Tuberculosis
  • Toxoplasmosis
• Fungal causes
  • Cryptococcosis
  • Coccidioidomycosis
  • Histoplasmosis 
• Parasitic causes
  • Amebic infection 

Vascular

• Cerebral vasculitis 
• Subarachnoid hemorrhage
• Dural venous sinus thrombosis 

Autoimmune

• Autoimmune vasculitis 
• Sarcoidosis
• Behçet disease

 Drug-Induced Meningitis

• Immune checkpoint inhibitors (eg, nivolumab and ipilimumab)
• Antimicrobials (eg, amoxicillin and sulfonamides)
• Nonsteroidal anti-inflammatory drugs 

Prognosis

The prognosis for La Crosse encephalitis is relatively favorable, with a low mortality risk. Most infections are asymptomatic, and fewer than 1% are fatal. The morbidity associated with La Crosse encephalitis is discussed further in the Complications section. Approximately 5% to 15% of individuals who recover develop recurrent seizures.[13]

Complications

La Crosse encephalitis is associated with a diverse range of complications. During the acute illness, complications may be mild and self-limited or may cause critical illness and death. Beyond the acute illness, La Crosse encephalitis can cause long-term sequelae.

Acute complications include:

• Hyponatremia
• Seizures
• Cerebral edema
• Brain herniation
• Basal ganglia hemorrhage [13]
• Coma
• Death

Long-term sequelae include:

• Seizures
• Cognitive impairment
• Poor academic performance [2]
• Behavioral changes
• Attention deficit hyperactivity disorder [19]
• Cognitive delays in children 
• Personality disorders [21]
• Neuromotor delay [22]