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

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]

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] 

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]

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]

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]

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]

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]

Patient education entails both preventative measures as well as early identification of signs and symptoms.

Though there is no vaccine currently available for La Crosse encephalitis, there are certain measures that can be implemented to help reduce the risk of exposure. In endemic areas such as Midwestern states, increased outdoor activity in the summer can put patients at increased risk of exposure. Methods, including the use of insect repellants, protective clothing with long sleeves, and pants, have shown to be effective in reducing the risk of exposure. Furthermore, to avoid the risk of exposure to mosquitoes at home, screened windows, proper ventilation, and prompt discarding of waste materials may be considered.[2]

Patients and especially parents of young children should be made aware of maintaining a high index of suspicion for La Crosse encephalitis when symptoms such as confusion, headaches, or fever develop after recent exposure to mosquito bites. Even in the absence of known mosquito bites, recent travel and outdoor exposure to endemic areas such as midwestern states should raise suspicion for La Crosse encephalitis, and the development of symptoms should prompt medical evaluation.

La Crosse encephalitis can present as a diagnostic challenge due to its nonspecific constellation of symptoms and low index of suspicion. Management of La Crosse encephalitis can involve coordination between numerous interprofessional providers, including nurses, emergency medicine clinicians, primary clinicians, infectious disease specialists, neurologists, neurosurgeons, and intensivists/neurointensivists. For patients requiring critical care, in addition to clinicians and nurses, an interprofessional care team involving respiratory therapists, nutritionists, and physical and occupational therapists plays an integral role in management. Given the possibility of long term sequelae such as cognitive delay, personality changes, and behavioral changes, social workers, as well as mental health and developmental specialists, can provide essential support.

Epidemiologists and public health specialists are also essential in providing educational support and public health services to populations affected by this disease. The overall burden of La Crosse encephalitis, considering health care costs and long term medical expenses ranges from $49,000 to $3 million dollars. The functional cost for individuals severely affected by La Crosse encephalitis is estimated to impact 18% to 92% of productive life years.[2]