La Crosse Encephalitis

Etiology

La Crosse encephalitis is a viral illness that occurs from the transmission of the La Crosse virus by the Aedes triseriatus mosquito, also known as the treehole mosquito. The transmission cycle of the virus follows both vertical transmission as well as horizontal transmission. Horizontal transmission occurs between adult mosquitoes via venereal transmission as well as to small mammals such squirrels. These serve as reservoir hosts. When humans are infected, they serve as dead-end hosts as they do not develop high enough levels to infect feeding mosquitos. Vertical transmission occurs from the female adult mosquito directly to offspring mosquitos, which can then further infect other mammals and humans.[1][4]

Epidemiology

La Crosse encephalitis is a relatively uncommon disease, with most cases occurring during the summertime and in children, with roughly 75% of all cases being pediatric. Geographically endemic areas include the rural areas of the central and midwestern states, and most cases are reported to occur between the months of July and September. Over the last several years, on average, there are sixty to eighty annual cases of La Crosse encephalitis reported in the United States.[1] 

A study found a total of 665 La Crosse encephalitis cases between 2003 and 2012.[5] According to another study, almost 81% of all pediatric La Crosse cases between 2003 and 2012 occurred in the states of Ohio, North Carolina, West Virginia, and Tennesse.[2] According to the Center for Disease Control and Prevention, between the years 2009 and 2018, there have been, on average, 68 annual reported cases of La Crosse encephalitis neuroinvasive disease though there is likely under-reporting of less severe cases.

Pathophysiology

La Crosse virus is transmitted subcutaneously through penetration of the skin by a feeding mosquito. Two surface glycoproteins subtypes are involved in the transmission of the virus. The G1 protein mediates the attachment primary to human cells, whereas the G2 protein serves as an attachment to mosquito cells.[6] The proteins are located on a spherical lipid envelope that encapsulates the single-stranded virus RNA. 

The replication of the virus can begin in the adjacent muscle to the site of penetration and therefore result in systemic infection, including viremia in the reticuloendothelial system and chondrocytes. The entrance of the virus through vascular endothelial cells can result in neuro-invasion and subsequent infection of neurons and glia. This is the proposed mechanism of the encephalitis syndrome in La Crosse virus infection. Post-mortem studies of brain tissue in patients with La Crosse encephalitis have shown lesions that demonstrate neurodegeneration with patchy inflammation and vasculitis.[1]

Though there is limited understanding of the exact pathophysiology of the viral encephalitis, reversible cerebral edema, which is postulated to occur as a result of vasogenic edema from the endothelial cell involvement, may potentially play a significant role in the pathogenesis of La Crosse encephalitis.[7]

Histopathology

Histopathological studies for La Crosse encephalitis have involved post-mortem analysis of brain biopsies. Examination under indirect immunofluorescence has found prominent staining of neurons as well as capillary endothelial cells. Light microscopy examination reveals perivascular infiltration with mononuclear cells and necrosis.[1] The strong immunofluorescence staining of endothelial cells further confirms the postulation that the La Crosse virus infects both endothelial and neuronal cells.[7]

History and Physical

The majority of cases of La Crosse encephalitis are asymptomatic and likely go undiagnosed, with roughly 4% of cases being symptomatic. Symptomatic La Crosse encephalitis can vary from a mild febrile illness lasting a few days to more severe and rare cases of fatal encephalitis. Overall fatality with La Crosse encephalitis is reported to be less than 1%. There is, however, concern for substantial morbidity with the complicated severe forms of encephalitis discussed below.[1]

The mild clinical course which occurs in almost 80% to 90% of the symptomatic cases of La Crosse encephalitis presents with headaches, fevers, and sometimes vomiting that occur over 1 to 3 days, followed by improvement over a week. Lethargy with behavioral changes, along with brief seizures, may occur. Almost 50% of hospitalized cases of pediatric La Crosse encephalitis have associated seizures. Of the seizures seen, 40% to 60% are typically focal and/or generalized seizures, with about 10%-15% advancing to status epilepticus.[7]

In children, the illness may present as meningoencephalitis with encephalopathy and seizures, compared to adult cases of La Crosse encephalitis that present with fevers, headaches, and hyponatremia. Altered mental status is commonly seen in adult cases, but seizures are less frequently seen. In more complicated cases of adult La Crosse encephalitis, associated cerebral edema with respiratory compromise can require intubation in up to 25% of patients.[3]

Common symptoms:

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

Less common symptoms:

• Hyponatremia (more common in adults)
• Stiff neck
• Photophobia
• Respiratory distress
• Deep coma

Evaluation

The mainstay of diagnosis for La Crosse encephalitis is enzyme-linked immunosorbent assay (ELISA) testing for IgM and IgG antibodies in the serum. Convalescent titers in two weeks that demonstrate a four-fold increase is diagnostic.[1]

The Center for Disease Control and Prevention suggests a preliminary diagnosis for La Crosse encephalitis be made based on clinical features of the symptoms described above as well as places or dates of travel for those living in a non-endemic region. Testing for cerebrospinal fluid or serum La Crosse virus IgM is recommended, whose results can take between a week to 14 days. In fatal cases, nucleic acid amplification and histopathology of brain tissue on autopsy can confirm the diagnosis. Cerebrospinal fluid analysis often reveals a lymphocytic pleocytosis with elevated protein and normal glucose. Cerebrospinal fluid viral culture is not as helpful and often yields a negative culture. Basic metabolic panel and complete blood count are also helpful in evaluating for leukocytosis and electrolyte derangements such as hyponatremia associated with La Crosse encephalitis. 

Imaging modalities such as head computed tomography (CT) and magnetic resonance imaging (MRI) do not have any characteristic findings associated with La Crosse encephalitis and can oftentimes be normal. In some cases, however, CT head may show cerebral edema and possibly cerebral herniation due to increased intracranial pressure. Basal ganglia hemorrhage has also been reported in a few cases.[1] In some pediatric cases of neuroinvasive La Crosse encephalitis, cortical gadolinium enhancement has also been seen on MRI of the brain.[8] 

Electroencephalography (EEG) can demonstrate non-specific abnormal findings such as unilateral slowing, periodic lateralized epileptiform discharges, or seizures in up to 90% of patients.[3]

Treatment / Management

There is no established treatment for La Crosse encephalitis, and the approach is primarily focused on symptomatic management.  

Intravenous ribavirin has been studied in La Crosse encephalitis; however, its effectiveness remains unclear. Ribavirin has been associated with in vitro inhibition of RNA virus replication and has an off label use in La Crosse encephalitis.[9] The RNA dependent RNA polymerase is the likely target of intravenous ribavirin though its effectiveness is highly questioned. Earlier studies in pediatric patients suggested evidence of adequate ribavirin penetration through the CSF, reaching almost 70% of plasma levels. However, more recent clinical trials do not support such findings. Oral ribavirin for La Crosse encephalitis is not deemed to be a viable option due to even lower CSF levels compared to intravenous administration.[10] The work of Cassidy and Patterson to date remains the strongest indicator of potential ribavirin benefit in La Crosse encephalitis, which demonstrated that in vitro relatively low concentrations of ribavirin (0.3umol/L) inhibited replication of La Crosse virus.[11] (A1)

Milder forms of the disease that present with fevers and headaches are often treated conservatively with analgesics, rest, and hydration. In patients presenting with acute encephalopathy, where a high clinical suspicion for viral encephalitis exists, it is reasonable to initiate treatment with intravenous acyclovir until HSV encephalitis has been ruled out.[1](B3)

In patients who develop seizures, antiseizure medications may be indicated to achieve seizure control. Long term use of antiseizure medications can be considered in patients who develop epilepsy. 

For patients who develop coma with respiratory compromise, airway management, and ventilatory support, including mechanical intubation, may be required. In some cases of La Crosse encephalitis, central venous pressure monitoring may be useful in maintaining normal intravascular volume in the setting of hyponatremia associated with La Crosse encephalitis.[1](B3)

Differential Diagnosis

The differential diagnoses for La Crosse encephalitis are vast and require careful consideration for numerous etiologies, including vascular, toxic, metabolic, and infectious causes.

Vascular

• Ischemia/infarct
• Subarachnoid hemorrhage

Toxic/metabolic

• Hyperglycemia/hypoglycemia
• Hyponatremia
• Uremia
• Wernickes encephalopathy
• Drug intoxication

Epileptic

• Focal seizures
• Generalized seizures with post-ictal encephalopathy

Traumatic

• Epidural hematoma
• Subdural hematoma
• Fat Embolus

Autoimmune / paraneoplastic / limbic / vasculitic encephalitides 

Infectious

• Cryptococcal meningitis
• Enteroviral meningitis 
• Histoplasmosis
• Varicella-zoster virus encephalitis
• Herpes simplex virus encephalitis
• Arboviral encephalitides: dengue, Japanese encephalitis, St. Louis encephalitis, West Nile virus, Western equine encephalitis, chikungunya.[12]

Prognosis

The prognosis for La Crosse encephalitis is relatively favorable with a low risk of mortality. 

Most cases are asymptomatic and less than 1% of all cases result in fatality. Around 1% of all hospitalized patients can have mortality associated with the complications of La Crosse encephalitis. The morbidity associated with La Crosse encephalitis is discussed further in complications. Roughly 5% to 15% of all recovered patients may develop recurring seizures.[1]

Complications

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

Acute complications:

• Fever
• Headache
• Vomiting
• Hyponatremia
• Photophobia
• Seizures
• Cerebral edema
• Herniation
• Basal ganglia hemorrhage [1]
• Coma
• Death

Long Term Sequelae:

• Seizures
• Cognitive impairment
• Poor academic performance[2]
• Behavioral changes
• Attention deficit hyperactivity disorder[10]
• Cognitive delays in children 
• Personality disorders[9]
• Neuromotor retardation[13]