St. Louis encephalitis

INTRODUCTION — St. Louis encephalitis (SLE) is an acute, mosquito-borne viral illness characterized by meningeal and brain parenchymal inflammation and injury. The disease occurs in endemic and epidemic form in North and South America. Epidemics of SLE in the United States have been responsible for at least 1,000,000 mild or subclinical infections, 10,000 clinical cases, and 1000 deaths since SLE virus was first isolated in 1933 during an outbreak in St. Louis, Missouri [1].

Studies of SLE virus evolution indicate that the virus was introduced into North America from tropical America in the late 19th Century [2]. There is evidence that West Nile (WN) virus, which was introduced into the United States in 1999, has displaced SLE by more efficient transmission and cross-protective immunity in wild birds [3,4]. The annual incidence of SLE and the occurrence of epidemics have substantially declined as WN virus has spread throughout North America, although small outbreaks occurred in Southern California and Arizona between 2015 and 2017 [5]. In contrast, there are increasing reports of SLE infections in tropical America.

VIROLOGY — SLE virus is a member of the family Flaviviridae, a group of small (40 to 60 nm), enveloped, positive-sense, single-stranded RNA viruses that replicate in the cytoplasm of infected cells. Other members of this virus family include West Nile (WN) virus, Japanese encephalitis (JE) virus, Murray Valley encephalitis virus, yellow fever virus, and dengue virus. SLE virus grows in a wide variety of avian and mammalian cell cultures and causes lethal encephalitis in infant mice or hamsters after intracerebral inoculation. SLE virus is antigenically closely related to JE and WN virus, which cause a similar disease (see "Arthropod-borne encephalitides"). This may result in diagnostic confusion, particularly if nonspecific serological tests are used. (See 'Diagnosis' below.)

SLE virus strains from the eastern and western United States and from tropical America are distinguishable at the nucleotide sequence level into at least eight genotypes and multiple clades [6-8]. Strains of SLE virus also differ with respect to the mosquito vectors responsible for transmission and the virulence for animal models [9] and wild avian hosts. As examples:

●Genotypes I and II are prevalent in the United States and are associated with epidemic disease.

●Genotype III is found in southern South America and has been associated with human disease outbreaks in California and Arizona [5]. Strains of this genotype have shown high virulence markers in animal experiments [10].

●Genotypes IV, VI, VII, and VIII have limited distributions in South America, while genotype V is widely distributed in the continent [8].

Although there is evidence for geographic separation and local persistence of strains (eg, Lineage I in California), analyses of SLE virus evolution suggest flow of neotropical strains, particularly from northern Central America, Mexico, and the Caribbean, into the United States by the agency of migratory birds [7,11]. One analysis identified circulation of an ancestral genotype of SLE circulating in Culex nigripalpus in southern Mexico, which may have given rise to cosmopolitan virus genotypes [11]. In California, where circulation of SLE was apparently absent from 2003 to 2014, the virus reappeared in 2015, along with an outbreak in neighboring Arizona [12]. The virus was genetically most closely related to a strain isolated during an outbreak in Argentina in 2005, suggesting it had been introduced by migratory birds [5,13]. Subsequent studies have confirmed the origin of the 2015 outbreak and have shown that Lineage III viruses have persisted in the Southwestern United States and have been responsible for interstate spread [14,15].

PATHOGENESIS — After inoculation of SLE virus into the human host via mosquito saliva, viral replication is initiated in local tissues and regional lymph nodes. The early steps in pathogenesis after inoculation in mosquito saliva have been partially elucidated for West Nile (WN) virus, and it is likely that the same mechanisms apply in the case of SLE. Mosquito saliva contains factors that enhance virus replication by diminishing innate immune responses and by recruiting susceptible target cells [16]. Subsequent spread of the virus occurs initially to extraneural tissues via the lymphatics and blood. SLE virus replicates in a wide array of cell types, including connective tissue, skeletal muscle, exo- and endocrine glands, and reticuloendothelial tissues. Viremia is terminated approximately one week after infection by neutralizing antibodies and cytotoxic T cells.

The mechanism by which SLE virus reaches the brain remains uncertain, but may include direct invasion at sites of compromised microvasculature or at the choroid plexus, where the endothelium is "fenestrated." In animal models, neuroinvasion appears to precede disruption of the blood-brain barrier; the olfactory neurons became infected early during the course of viremic infection, with subsequent axonal transport of virions to the olfactory lobe of the brain [17]. After the virus reaches the brain, infection spreads rapidly. Retrograde axonal transport from peripheral nerves to the spinal cord [18] may explain the occurrence of myelitis in cases of SLE [19]. As shown for WN virus in the mouse model, immune activation (through toll-like receptor 3) may play a critical role in neuroinvasion [20].

Neuronal damage is probably mediated in part by caspase-3-dependent apoptosis, as shown for WN, Japanese encephalitis (JE), and other flaviviruses [21]. The increased susceptibility of elderly persons to SLE virus (see 'Epidemiology' below) may be due to mechanical factors (eg, hypertension, atherosclerosis) that compromise the integrity of the blood-brain barrier or to reduced immune responsiveness. Overactivity of angiotensin I-converting enzyme (ACE-1) in advanced age may exacerbate a pathological host response to infection, as suggested for WN [22]. Increased production of ACE-1 results in increased angiotensin II, a powerful pro-inflammatory cytokine.

Most infections with SLE are subclinical. The hereditary and acquired factors responsible for overt and severe infection in a small subset of patients remain unknown. However, there is a substantial body of knowledge indicating that the type I interferon (IFN-I) system is critical to limiting the severity of infection, and it is likely that genetic factors influencing expression of receptors and transcription factors involved in the induction of interferons and inflammatory cytokines could be responsible for the outcome of infection.

Mice deficient in IFN-I receptors, interferon transcription factors, and RIG-I receptor family genes are also highly susceptible to flavivirus infection [23,24]. Susceptibility of mice to flavivirus infection has been linked to genes controlling 2', 5' oligoA synthetase, the antiviral factor induced by interferon, but the role of this gene in humans is uncertain.

Genetic susceptibility to fatal infection with WN virus in humans was linked to homozygosity for CCR5Delta32, a nonfunctional variant of chemokine receptor CCR5 [25]. A fatal case of another flavivirus infection (yellow fever vaccine-associated viscerotropic disease) was also associated with a possible defect in CCR5 and its ligand RANTES, which might have altered trafficking of CD8+ cells important to the antiviral immune response [26]. Experimental studies of WN infection indicate that trafficking of specific CD8+ T cells to the brain is critical to recovery and survival [27,28]. Cases of SLE have been reported in patients with HIV-1 infection, suggesting that impairment of T cell responses may have contributed to neuroinvasion or diminished viral clearance [29]. In the 2015 outbreak of SLE in Maricopa County, Arizona, 3 of 23 confirmed SLE cases occurred in organ transplant recipients, and one patient died [13].

Recovery from infection is mediated by neutralizing antibodies and CD8+ T cells [30]. In cases with central nervous system (CNS) infections, CD8+ T cells are recruited across the blood-brain barrier to clear virus from brain tissue. This appears to be under the control of the cytokine CXCR4 on endothelial cells and its receptor CXCR4 on lymphocytes [27]. Infection with SLE virus results in a long-lasting neutralizing antibody response that is responsible for protection against reinfection. Persistent infection with SLE, with prolonged viruria and kidney infection, has been demonstrated in hamsters [31]. Although there are no data indicating that this occurs in humans, this may simply reflect a lack of attempts to investigate the phenomenon. SLE antigen and virus particles were found in urinary sediment from SLE patients during the acute phase of the disease [32]. Persistent shedding of WN RNA in urine for up to nine years has been described and is associated with a higher risk of chronic kidney disease [33]; similar studies with SLE have not been conducted. Chronic infections of humans, sometimes with neurologic consequences, have been reported for related flaviviruses (Zika, JE, and tick-borne encephalitis).

Pathology — SLE virus produces a lymphocytic meningitis; pathologic changes in the brain, particularly the gray matter, include perivascular lymphocytic infiltrates, cellular nodules, and neuronal degeneration. While lesions are distributed throughout the brain, the most severely affected regions are the hypothalamus, cerebellar and cerebral cortex, basal ganglia, brainstem, and cervical spinal cord [19,34]. Rarely, SLE may present as acute demyelinating encephalomyelitis (ADEM) with prominent lesions in white matter [35]. Pathologic changes in extraneural tissues have not been described.

EPIDEMIOLOGY — SLE virus is widely distributed in the Americas. In temperate areas, SLE occurs during the summer months when mosquito vectors are active and peaks during August and September. Transmission may occur as late as December in warmer climates, such as Florida and southern California. Prior infection with dengue virus does not cross-protect against SLE.

SLE was a leading cause of epidemic viral encephalitis in the United States prior to the spread of West Nile (WN) virus, with more than 10,000 SLE cases reported over the last five decades. Epidemics occurred principally in the Ohio-Mississippi valley, eastern Texas, and Florida. A large outbreak occurred in 1933 in St. Louis, Missouri with over 1000 cases. A widespread SLE outbreak occurred in 1975 involving 2800 cases in 31 states. Attack rates during epidemics in the eastern United States ranged widely from 5 to 200 per 100,000 people. The highest attack rates have been reported in outbreaks affecting small towns. Occasional epidemics have also been reported in southeastern Canada and northern Mexico.

The incidence of SLE appears to have significantly diminished over the last decade, apparently due to interference by WN virus [36]. WN virus, which was introduced into the United States in 1999, is strongly cross-protective against SLE in shared avian host species and is transmitted more efficiently by vectors [3,37]. As an example, the annual incidence of SLE prior to the introduction and spread of WN virus varied from 0.003 to 0.752 per 100,000 population with a median number of approximately 35 reported cases per year [38,39]. However, from 2010 to 2014, the reported incidence of SLE in the United States has been 10, 6, 3, and 10 cases, respectively [40-43]. However, in 2015, an outbreak occurred in the Phoenix, Arizona area, with 23 confirmed cases (figure 1) [12].

There are increasing reports of SLE infections in tropical America. Prior to 2005, only sporadic cases were reported from tropical America. However, there have subsequently been several outbreaks of human disease caused by genotype III in Brazil and Argentina [44-46]. Sporadic human cases have also been reported from Central America and Peru.

TRANSMISSION CYCLE — In the United States and contiguous areas, SLE virus is transmitted by several species of Culex vector mosquitoes. The intermediate hosts are wild birds, principally small passerine species. Despite the reduced incidence of SLE in North America in the past 15 years, there is evidence for continued circulation of the virus in wild bird populations [13,47]. Thus, re-emergence of SLE remains a threat where conditions are favorable, such as the introduction of a virulent virus strain (as apparently happened in California and Arizona from 2015 to 2017 [13]) and/or a decrease in West Nile (WN) virus activity. Horses do not contribute to transmission of SLE virus, although these animals can have a high prevalence of antibodies indicating widespread subclinical infections. There is a single report of a horse in Brazil with neurological infection cause by SLE [48].

Humans are tangentially infected by mosquitoes that have fed on viremic birds and are dead-end hosts with respect to the transmission cycle. An extrinsic incubation period of 7 to 10 days is required in the mosquito vector between feeding on a viremic bird and infectivity for a second host. This interval is shortened by high environmental temperature. Compared to WN virus, SLE infection of wild birds results in a lower viremia; this fact and a narrower avian host range for the virus explain the lower transmission rates and incidence of human infection.

The biting habits and distribution of mosquito vector species, as well as virulence properties of the virus, are responsible for epidemiologic differences of the disease in different geographic regions.

●In the eastern United States (except Florida), the principal epidemic vectors are two closely related mosquito species (Culex pipiens and Culex quinquefasciatus) that breed ubiquitously in drainage ditches and other collections of polluted water in urban-suburban habitats. Vector densities may be high, and the mosquito bites in and around houses.

●In Florida, Culex nigripalpus is the principal vector which breeds in a wide variety of habitats, including swamps and drainage ditches. This mosquito bites mainly outdoors and may attain relatively high densities in wooded suburban habitats and parks in cities.

●In the western United States, SLE virus is transmitted by Culex tarsalis, which breeds in irrigated farmland. Human infections tend to occur in a sporadic or endemic pattern linked to outdoor exposure in rural areas where the enzootic cycle is maintained. In suburban and urban environments, Culex pipiens and Culex quinquefasciatus may be responsible for transmission.

●In Argentina and Brazil, outbreaks appear to be transmitted in a similar cycle involving birds and Culex quinquefasciatus and Culex interfor. However, it is likely that more complex cycles of transmission involve mammals, and as yet, poorly defined mosquito species.

SLE virus can be found every summer in mosquitoes and birds in the United States, but outbreaks have often occurred at intervals of 3 to 10 years, often affecting different localities [38]. The ecologic reasons for the increased virus amplification in epidemic years remain obscure, but probably involve a confluence of factors including rainfall and environmental temperature patterns that affect mosquito and avian host density and virus transmission rate.

In the eastern United States, spring to early summer drought conditions favor breeding of Culex vectors in concentrated sites. This also attracts congregation of avian hosts; summer rains expand vector populations and have been associated with SLE outbreaks [38,49]. As described above, interference by WN virus immunity in avian populations may play a more important role in determining the force of infection of SLE virus than environmental factors. (See 'Epidemiology' above.)

The bird species involved in SLE amplification appear to differ in North America and in Argentina, with Passeriformes (eg, the domestic sparrow Passer domesticus) playing a central role in the former and Columbiformes (dove) species in the latter [50].

Laboratory-acquired infection by aerosol exposure has been extremely rare. The virus is not shed in human secretions, and there are no recorded instances of person-to-person spread. SLE antigen is found in the urine of patients [32], but this is unlikely to be associated with transmission. The virus is not found in blood after the appearance of neurologic signs, and blood does not pose a significant infectious hazard in hospitals. SLE acquired by blood transfusion has rarely been described [17].

However, neuroinvasive SLE was reported in three unrelated solid organ transplant recipients during the SLE outbreak in Arizona, emphasizing the potential for transmission from donors with unrecognized infection to immunocompromised individuals [51]. In addition, prolonged shedding of Zika virus (another flavivirus) has been observed in saliva, urine, and semen (with associated sexual transmission) (see "Zika virus infection: An overview"), and there are reports of persistent infections of related flaviviruses in animal models. Thus, further investigations on transmission should be carried out in persons infected with SLE virus.

CLINICAL FEATURES — Human infection with SLE virus rarely results in clinical illness. The average ratio of asymptomatic infection to symptomatic illness is 300:1 [38]. The most important risk factor for developing symptomatic encephalitis is age. Although cases of SLE have been reported in very young children [52], elderly persons are at highest risk. As an example, the ratio of symptomatic to asymptomatic infection in children is 1:800 compared to a high of 1:85 in adults over the age of 60 years [38]. The reason for this age-related susceptibility has not been defined.

Among symptomatic patients, the incubation period for SLE has been estimated to be 4 to 21 days. The spectrum of clinical illness includes nonspecific fever with headache, aseptic meningitis, and fatal meningoencephalitis [53,54].

The severity of encephalitis and its lethality are greatest in the elderly [38,53]. It is less clear how the immune status impacts the clinical presentation. As an example, a fatal human case of SLE was described in an immunocompromised patient with lymphoma during the 2015 outbreak in California [55], and cases of SLE have been reported in patients infected with HIV [29]; however, in one small study, concomitant HIV infection did not affect the clinical presentation [56].

During a dengue outbreak in Brazil in 2006, six cases of SLE were diagnosed by nucleic acid methods; three had viral encephalitis, and the other three had signs of hemorrhagic disease [46]. Hemorrhagic signs had not been previously associated with SLE infections, and it is difficult to draw definitive conclusions regarding a causal link with SLE virus.

Prodromal symptoms — Prior to the appearance of central nervous system (CNS) signs, the patient with SLE virus infection experiences fever, generalized malaise, headache, and myalgias. Some patients have respiratory (cough, sore throat) or urinary tract (dysuria, urgency, incontinence) symptoms. Fever generally lasts for four to five days and may reach 40 to 41ºC. The headache is typically severe and may be accompanied by photophobia, nausea, and vomiting.

Neurologic signs — The appearance of CNS signs is generally rapid. Children and young adults often experience a milder case of SLE, with signs of meningitis only. In more severe cases with global brain parenchymal involvement, patients exhibit altered sensorium and a wide array of neurologic abnormalities. Tremors of the eyelids, tongue, lips, and extremities occur in as many as two-thirds of patients with SLE and may persist for weeks after recovery from the acute illness. Cranial nerve dysfunction occurs in 25 percent of patients, most frequently as unilateral facial motor weakness. Other signs include loss of oculomotor function, dysarthria, and rarely loss of the olfactory sense.

Signs of thalamus, brainstem, or cerebellum infection include tremors, myoclonus, opsoclonus, nystagmus, and ataxia. Pathologic reflexes are common, but motor and sensory deficits are rare. Focal or generalized seizures have been noted in fewer than 10 percent of cases. Signs of severe increased intracranial pressure have not been reported.

Postinfectious autoimmune syndromes have been rarely linked to SLE infection. There are two case reports of SLE presenting with a clinical diagnosis of Guillain-Barré syndrome [57]. There is also one case report of acute disseminated encephalomyelitis (ADEM) following three weeks after mild SLE infection [35].

Laboratory findings — The peripheral white blood cell (WBC) count is normal or may be mildly elevated, particularly in children. Alanine aminotransferase and creatine phosphokinase levels are modestly elevated in 50 to 75 percent of patients [53]. Proteinuria, microscopic hematuria, pyuria, and mild azotemia are also found in some patients. It is likely that these findings are related to the infection, as SLE viral antigen was found in urinary sediment in one study [32] and the kidney is a target organ of infection in an animal model [31]. Hyponatremia with fluid overload due to the inappropriate secretion of antidiuretic hormone (SIADH) has been documented in approximately 30 percent of patients; the syndrome is mild, and patients respond to water restriction.

Cerebrospinal fluid analysis — The most consistent laboratory abnormalities are found in the cerebrospinal fluid (CSF). The lumbar puncture opening pressure is mildly elevated at 200 to 250 mmHg in approximately one-third of cases. CSF protein concentrations are mildly elevated at 45 to 100 mg/dL and rarely exceed 200 mg/dL, while the glucose concentrations are normal or mildly depressed. The WBC count in the CSF can vary from a few to several hundred cells, but counts exceeding 500 cells/mm3 are very rare. The proportion of mononuclear cells increases from 40 to 50 percent in CSF obtained during the initial illness to more than 80 percent by day seven. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)

Electroencephalography — Electroencephalography (EEG) shows diffuse generalized slowing and delta wave activity; occasionally focal discharges and spike activity can be seen [54]. If EEG abnormalities are present, they do not appear to correlate well with the severity of clinical symptoms.

Imaging — In typical cases of SLE, no specific abnormalities have been identified on brain scans, computed tomographic scans, or magnetic resonance images; cortical edema, pathologic enhancement, and mass effect are not present. The case report of ADEM noted above that was due to SLE virus was notable for white matter signal abnormalities on magnetic nuclear imaging [35].

Studies of cerebral blood flow and metabolism in comatose patients with SLE showed reduced metabolic activity and oxygen uptake. However, blood flow was not affected [53].

OUTCOME OF INFECTION — Death due to the virus generally occurs within the first two weeks of the onset of the infection, accompanied by coma and respiratory depression. The case-fatality rate is higher in persons over 60 years than in younger individuals (20 versus 3 to 6 percent). Case-fatality rates adjusted for age are also higher in the eastern than in the western United States, possibly reflecting differences in virulence of the viral strains.

Direct injury to the brain by the virus causes death during the first two weeks of infection; later deaths are due to complications of hospitalization, especially bronchopneumonia and pulmonary embolism. Clinical features suggesting a poor prognosis include sustained high fever, convulsions, advanced age, and severely depressed state of consciousness. In some outbreaks, an association was noted between SLE and a variety of underlying diseases, including hypertension, diabetes mellitus, alcoholism, and chronic obstructive lung disease [35].

Convalescence — Most patients, particularly elderly patients, experience difficulty in regaining full health after an episode of SLE [58]. A period of prolonged convalescence, lasting weeks or even months, is characterized by headaches, anxiety, irritability, memory deficits, persistent tremor, and dizziness. Objective signs on physical examination include tremors and asymmetric reflexes. Classical Parkinsonism has not been a feature of the convalescent syndrome.

DIFFERENTIAL DIAGNOSIS — SLE should be considered in all cases of viral encephalitis occurring in the summertime, but particularly in elderly patients or when two or more similar cases cluster in a community. (See "Viral encephalitis in adults".)

The most important agent causing confusion is West Nile (WN) virus. Both SLE and WN virus produce a similar disease with a predilection for the elderly. Although flaccid paralysis and a polio-like syndrome appear to be more common in WN virus infection, in one report, no clinical features were helpful in differentiating patients with St. Louis and WN encephalitis [59]. SLE and WN infections must be distinguished by specific serologic tests. (See "Clinical manifestations and diagnosis of West Nile virus infection" and 'Diagnosis' below.)

SLE has, in occasional cases, been mistaken for stroke, heat stroke, or drug overdose. When the primary manifestation is aseptic meningitis, SLE may be difficult to distinguish from enteroviral infections. Other viral, mycoplasma, and bacterial infections of the central nervous system (CNS) can produce a similar clinical picture. By contrast, it is easier to differentiate typical cases of herpes simplex virus (HSV) encephalitis from SLE because the former is characterized by a focal presentation, convulsions, early behavioral disturbances, and an increased cerebrospinal fluid (CSF) pressure. (See "Herpes simplex virus type 1 encephalitis".)

Autoimmune encephalitis, due to the presence of neuronal antibodies to cell surface or synaptic proteins, is a potentially treatable cause of encephalitis that should also be differentiated from SLE. Clinically, autoimmune encephalitis is more likely to be associated with psychosis and autonomic instability and to have brain imaging that localizes to the limbic system [60]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

DIAGNOSIS — Clinically, SLE may be difficult to differentiate from other causes of summer season encephalitis, including West Nile (WN). (See 'Differential diagnosis' above.)

The diagnosis of SLE is generally made by serology, particularly the IgM enzyme linked immunosorbent assay (ELISA). The presence of IgM antibodies in a single serum provides a presumptive diagnosis, and a significant rise or fall between appropriately timed acute-convalescent or early-late convalescent sera is diagnostic. However, antigenic cross-reactions with other flaviviruses, particularly WN virus, can be a problem, although use of a discriminatory algorithm for analysis of IgM ELISA successfully differentiated the infections in one report [61]. Monoclonal blocking ELISA techniques are useful in providing a specific diagnosis and have been applied to WN diagnosis in hosts previously infected with SLE [62] (see "Clinical manifestations and diagnosis of West Nile virus infection", section on 'Diagnosis'). Noninfectious recombinant virus-like particle antigens are useful as diagnostic reagents.

A rapid microsphere-based IgM immunoassay has been developed [63]. The ratio of IgM ELISA antibody to WN and SLE is useful in differentiating these infections [64]. Recombinant virus-like particle antigens have also been engineered to have reduced cross reactivity and may be used as antigens in serological diagnosis [65]. Use of recombinant NS5 antigen in ELISA is reported to provide a virus species specific serodiagnosis. A specific neutralization test may be necessary for definitive serologic diagnosis [66]. Chimeric viruses have also been developed for use in type-specific neutralization tests having SLE envelope proteins in a yellow fever 17D vector and can be used at the BL2 containment level [67].

It is also valuable to submit cerebrospinal fluid (CSF) for antibody testing since the finding of IgM antibody in CSF indicates brain infection and local antibody production. Polymerase chain reaction (PCR) analysis of CSF to exclude herpes simplex virus (HSV) or enteroviral infection may also be useful. In one case, metagenomic next-generation sequencing from a sample of CSF was used to diagnose SLE [55].

Virus isolation from the blood or CSF has generally been unsuccessful. However, the virus may be recovered from brain tissue, including the basal ganglia, cervical cord, and cerebellum, following inoculation of mammalian or mosquito cell culture or baby mice. Viral antigen can also be detected by immunofluorescence in brain tissue sections. There are few data on the use of PCR for detection of SLE in clinical samples.

TREATMENT

Supportive care — The optimal supportive management of patients requires attention to electrolyte and fluid balance, with water restriction, if necessary, to correct hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion and to prevent brain edema. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Other measures may help to prevent nosocomial complications, such as nasogastric suction to reduce the risk of aspiration, skin care, prevention of deep vein thrombosis, cimetidine or omeprazole to prevent gastric ulcer, and steps to reduce the risk of bacterial superinfections of the respiratory and urinary tracts. Mechanical ventilation may be required in patients with respiratory failure.

Other therapies — No specific antiviral therapy is of proven efficacy and corticosteroids are not indicated, except in the rare case of acute demyelinating encephalomyelitis (ADEM). (See 'Neurologic signs' above.)

Some antiviral drugs have been evaluated for activity against related flaviviruses, as well as SLE virus in vitro. There is renewed interest in the use of antivirals against Zika and dengue. In addition, sofosbuvir, an agent used to treat hepatitis C virus (a different genus in the family Flaviviridae), targets the NS5 polymerase, inhibits multiple flaviviruses, and has been tested in patients with yellow fever. Other drugs showing inhibitory activity include thiosemicarbazones and phthalyl-thiazoles.

Interferon alfa reduced mortality in mice when given either subcutaneously or by aerosol at the time of exposure to the virus [68]. The potential efficacy of this approach in humans was evaluated in a pilot study in which 15 patients with SLE received interferon alfa-2b were compared to 17 untreated patients with SLE admitted to the same hospital during an outbreak [69]. Interferon alfa-2b was associated with a reduced likelihood of persistence of quadriplegia, quadriparesis, or respiratory insufficiency after the first week of hospitalization (13 versus 65 percent) and after the second week (7 versus 29 percent). Transient neutropenia and/or mild hepatitis occurred in 11 treated patients. Two patients with transplant-acquired neuroinvasive SLE were treated with interferon alfa-2b and intravenous immune globulin and were reported to have improved within 72 hours [51]. However, production of interferon alfa-2b has been discontinued; although pegylated interferon alfa-2a is still available, this agent has not been evaluated for treatment of SLE.

Administration of high-titer antibody to animals and human patients with West Nile (WN) may be effective even after the establishment of brain infection [70]. This treatment has not been tried with SLE. There are a number of promising small molecules under investigation for treatment of dengue and WN, but the work is at an early stage and beyond the scope of this review. Antisense (RNAi) has also shown promise in animal models, although there are daunting delivery issues [71].

PREVENTION — Surveillance for arbovirus infections in birds and mosquitoes has been adversely affected by funding cuts in many areas, and is currently of questionable predictive effectiveness [72]. However, mosquito control is indicated to interrupt transmission once human cases appear. Remaining indoors in properly screened areas during the late afternoon and evening may significantly reduce the risk of mosquito bites in areas where SLE cases have occurred in the past. A more detailed discussion on the prevention of insect bites is found elsewhere. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

There is no available vaccine against SLE virus, although several experimental approaches have shown promise, including chimeric attenuated virus vectors using yellow fever 17D and dengue viruses [67,73]. There is no commercial interest in a vaccine given the low incidence of SLE. However, novel strategies for vaccination may be warranted given the unpredictable nature of SLE epidemics. One strategy is to evaluate the efficacy of a vaccine against a closely-related virus in the Japanese encephalitis (JE) serocomplex. There is experimental evidence for cross-protection from live, attenuated JE vaccines (eg, Imojev) against heterologous members of the serocomplex [74]; it is unclear whether cross-protective antibodies are elicited to SLE virus.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis".)

SUMMARY AND RECOMMENDATIONS

●St. Louis encephalitis (SLE) virus is a member of the family Flaviviridae, which includes West Nile (WN) virus, Japanese encephalitis (JE) virus, yellow fever virus, and dengue virus. (See 'Virology' above.)

●After inoculation of the virus into the human host via mosquito saliva, viral replication is initiated in local tissues and regional lymph nodes. Subsequent spread occurs initially to extraneural tissues via the lymphatics and blood. The mechanism by which SLE virus reaches the brain remains uncertain, but may include direct invasion at sites of compromised microvasculature or at the choroid plexus, where the endothelium is "fenestrated." Immune activation may play a critical role in neuroinvasion. (See 'Pathogenesis' above.)

●SLE virus is widely distributed in the Americas. The incidence of SLE has declined in North America over the last decade due to interference in transmission cycles by WN virus. However, there are increased reports of SLE in South America, and more recently, the introduction of virulent South American strains has been associated with outbreaks in California and Arizona. SLE mainly occurs during the summer months when mosquito vectors are active. (See 'Epidemiology' above.)

●Human infection with SLE virus only rarely results in clinical illness. The ratio asymptomatic infection to symptomatic illness is 300:1. The most important risk factor for symptomatic encephalitis is older age. (See 'Clinical features' above.)

●Symptoms of SLE include a prodrome of fever, malaise, headache, and myalgias, followed by changes in sensorium. (See 'Clinical features' above.)

●Cerebrospinal fluid (CSF) protein concentrations are mildly elevated at 45 to 100 mg/dL while the glucose concentrations are normal or mildly depressed. The white blood cell (WBC) count in the CSF can vary from a few to several hundred cells, but counts exceeding 500 cells/mm3 are rare. (See 'Cerebrospinal fluid analysis' above.)

●The case-fatality rate is higher in persons over 60 years than in younger individuals. (See 'Outcome of infection' above.)

●There is no specific antiviral treatment or vaccine for SLE. (See 'Treatment' above and 'Prevention' above.)