Version July 2025
INTRODUCTION —
Arthropod-borne encephalitis viruses represent a significant public health problem throughout most of the world. These viruses, which belong to the families Flaviviridae, Togaviridae, Bunyaviridae, and Reoviridae, are usually highly adapted to particular reservoir hosts and are spread from animal to animal via the bite of an infected arthropod, usually a specific mosquito or tick species (table 1).
This topic will review the major characteristics of most of the arthropod-borne viral encephalitides. General issues related to viral encephalitis, including clinical manifestations, cerebrospinal fluid (CSF) findings, distinction from postinfectious encephalitis and meningitis, and an approach to patients with suspected central nervous system (CNS) infection are discussed separately. (See "Viral encephalitis in adults".)
GENERAL PRINCIPLES
Transmission cycle — The mosquito or tick becomes infected when feeding on the blood of the viremic animal. The virus then replicates in the mosquito or tick tissues, ultimately infecting the salivary glands. The mosquito or tick transmits the virus to a new host when it injects infective salivary fluid while taking a blood meal.
The natural animal hosts of these viruses usually remain unaffected and viral circulation generally remains undetected until one of the following occurs:
●Humans encroach on the natural enzootic focus
●Environmental or other conditions that favor substantial amplification in the primary vector-host cycle cause enough vectors to become infected so that the human risk is substantially increased
●The virus escapes the primary cycle via a secondary vector or vertebrate host, thereby bringing infected, human-biting vectors near human habitation
Although infected humans may become ill, they usually do not develop sufficient viremia to infect feeding vectors. As a result, humans do not usually contribute to the transmission cycle.
Cross-reactivity — The close antigenic relationships among the flaviviruses may cause a problem with diagnosis. Individuals who have been recently vaccinated with a heterologous flavivirus (eg, yellow fever, tick-borne encephalitis virus, or Japanese encephalitis vaccines) [1], or who have been previously infected with a related flavivirus, may have a positive serologic test to one or more flaviviruses not causing the current illness. The plaque reduction neutralization test (PRNT), which is the most specific test for the arthropod-borne flaviviruses, may identify serologic cross-reactions among the flaviviruses. However, some degree of cross-reaction in neutralizing antibodies may still cause ambiguous results, particularly in persons with previous exposure to a heterologous flavivirus. Cross reactivities of the bunyaviruses and togaviruses causing encephalitis are not as extensive (table 1).
SPECIFIC VIRUSES —
Among the mosquito-borne encephalitis viruses, the greatest public health threat in North America are posed by the West Nile, St. Louis encephalitis, and La Crosse encephalitis viruses (table 1). Venezuelan equine encephalitis virus is of concern in Central and South America, while Japanese encephalitis virus affects persons living in or traveling to parts of Asia. Dengue is a rare cause of encephalitis throughout the tropical world.
Among the tick-borne viruses that cause encephalitis, tick-borne encephalitis virus has the greatest public health impact worldwide and is of concern to residents of or visitors to northern parts of Eastern Europe and Asia. Powassan virus is a rare, tick-borne cause of encephalitis in the north central and northeastern parts of the United States, eastern Canada, and Russia.
Detailed information on specific viruses (organized alphabetically), is discussed below.
California serogroup viruses — The California serogroup (family Peribunyaviridae, genus Orthobunyavirus) consists of at least 18 related mosquito-borne viruses. La Crosse, snowshoe hare, Jamestown Canyon, Tahyna, and Inkoo viruses are known to cause neurologic disease in humans. All except Jamestown Canyon virus primarily cause neuroinvasive disease in children. La Crosse, snowshoe hare, and Jamestown Canyon viruses are present in the United States, with snowshoe hare and Jamestown canyon viruses extending into Canada. Tahyna virus is found in Europe, Africa, and Asia, and Inkoo virus is found mainly in Scandinavia.
La Crosse encephalitis virus
●Epidemiology – La Crosse virus is transmitted via Aedes triseriatus (eastern tree hole mosquito). Mammalian hosts include the eastern chipmunk, tree squirrels, and foxes. La Crosse virus is the most pathogenic of the California serotype viruses.
Human infections occur in the central and eastern United States, mostly in school-aged children from July through September [2,3]. Many infections are asymptomatic. Approximately 30 to 120 cases of La Crosse neuroinvasive disease are usually reported annually [4]. In 2022, 22 cases of La Crosse virus disease were reported in five states [5].
A case of possible congenital infection was reported with immunoglobulin (Ig)M antibodies identified in the umbilical cord blood; however, the newborn was asymptomatic and development was normal [6]. No seroconversion was documented in this case because the mother declined further testing.
●Clinical manifestations – The incubation period is 5 to 15 days. Nearly all infections are clinically inapparent. The characteristics of symptomatic disease, which begins after an incubation period of three to seven days, were evaluated in a review of 127 patients who required hospitalization [2]. The following findings were noted:
•All of the patients were school-aged children (range 0.5 to 15 years).
•Headache, fever, and vomiting were each present in at least 70 percent of patients and disorientation in 42 percent.
•Seizures occurred in 46 percent, 62 percent of which had a focal component and 24 percent of which progressed to status epilepticus.
•Approximately 20 percent had focal neurologic abnormalities. The findings of fever, focal neurologic signs, and focal seizures mimic herpes simplex encephalitis. (See "Herpes simplex virus type 1 encephalitis".)
•Aseptic meningitis alone, without evidence of encephalitis, occurred in 13 percent.
•Hyponatremia was present in 21 percent and was present in all 13 patients (11 percent) whose condition deteriorated in the hospital.
All patients survived, which is consistent with a very low mortality rate in other reports. However, 12 percent of children had residual neurologic sequelae, including focal neurologic, cognitive, and behavioral deficits.
●Evaluation and diagnosis – Leukocytosis is common, with polymorphonuclear cells predominating [2]. Cerebrospinal fluid (CSF) shows pleocytosis with either neutrophilic or lymphocytic predominance. Electroencephalography (EEG) is abnormal in two-thirds of patients, mainly with slowing or epileptiform discharges [2]. Focal features or periodic lateralizing epileptiform discharges, usually with involvement of the temporal lobe, may suggest herpes simplex encephalitis.
Computed tomography (CT) scan is generally normal but may show generalized cerebral edema [2]. Magnetic resonance imaging (MRI) may show focal areas of gadolinium enhancement.
The diagnosis of La Crosse can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against La Crosse virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Viral isolation or detection of viral RNA by polymerase chain reaction (PCR) from the CSF is rare [8]. Because of potential cross-reactivity of serologic assays to related viruses, such as Jamestown Canyon, positive serologic test results should be confirmed by demonstration of virus-specific neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the United States Centers for Disease Control and Prevention (CDC) website.
●Treatment and prevention – Treatment is supportive, with emphasis on control of cerebral edema and seizures [2]. Ribavirin has been used, but efficacy is unproven [9]. Approximately 1 percent of reported cases are fatal.
Prevention rests on avoidance of mosquito bites [8]. (See "Prevention of arthropod bites: Repellents and other measures".)
Jamestown canyon virus
●Epidemiology – Jamestown canyon virus has been identified in at least 26 mosquito species. White-tailed deer are likely the primary amplifying host, but other animals, such as moose, elk, and bison may also contribute to the transmission cycle. The distribution of Jamestown Canyon virus is likely widespread in North America; however, in the United States, more than half the cases were identified in Minnesota and Wisconsin.
A total of 281 cases were identified in the United States from 2011 to 2022, of which 186 were neuroinvasive [10]. It is likely that the actual number of symptomatic infections far exceeds the number clinically recognized and reported. Serologic studies demonstrating that upwards of 20 percent of the population at large in some areas have neutralizing antibodies to Jamestown canyon virus indicate that human infection is quite common in endemic areas [11]. In 2022, 12 cases of Jamestown Canyon virus disease were reported in five states [5].
Most infections occur from April through September. Infections occur in all age groups and have a male predominance.
●Clinical manifestations – Clinical manifestations range from a mild febrile illness to meningitis or meningoencephalitis [12,13]. Of the 12 cases that were reported in 2022, all but one patient had neuroinvasive disease [5].
●Evaluation and diagnosis – The diagnosis of Jamestown Canyon virus infection can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against the virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Additional information on diagnosing arboviral disease can be found on the CDC website.
Some patients diagnosed with La Crosse virus encephalitis based on serologic testing may have actually been infected with Jamestown Canyon virus because of serologic cross reactivity between the two viruses; thus, IgM antibody detection alone should be confirmed by demonstrating neutralizing antibodies. The sensitivity of detection of viral nucleic acid in CSF is unknown but is likely low [13].
●Treatment and prevention – Treatment is supportive. Prevention rests on avoidance of mosquito bites. (See "Prevention of arthropod bites: Repellents and other measures".)
Other California serogroup viruses — Recognized infections with snowshoe hare virus are rare, with symptoms ranging from a mild febrile illness to meningoencephalitis [14]. Seroprevalence in endemic areas range from 1 to 10 percent, suggesting that clinically apparent illness is uncommon.
In Central Europe, Tahyna virus is primarily found in woodland forests. Aedes vexans is likely the most important vector, and hares and rabbits are the primary reservoir hosts [15]. Illness in humans ranges from mild febrile disease to meningitis and rarely meningoencephalitis, with an incubation period of 7 to 14 days. In some endemic areas, 30 to 40 percent of the population may have antibodies to Tahyna virus, suggesting most infections are not clinically apparent.
Inkoo virus has been identified in Sweden, Norway, and Russia, and the high prevalence of antibodies in these countries suggests that nearly all infections are not clinically apparent. Among the few patients that have been identified, children are more likely to be hospitalized than adults [14]. Clinical manifestations range from a mild febrile illness to disorientation, nuchal rigidity, headache, drowsiness, and seizures.
Chandipura virus — Since the 1950's, outbreaks of encephalitis of unknown etiology and high mortality have occurred in children in India. In 2003 in Southern India, an outbreak of acute encephalitis in 329 children was associated with Chandipura virus (genus Vesiculovirus, family Rhabdoviridae) [16]. The affected children all tested negative for eight other potential viral causes including Japanese encephalitis (which is responsible for many encephalitis outbreaks in India), West Nile virus, dengue, and measles virus. Chandipura virus was identified by electron microscopy, complement fixation, and neutralization tests. The observation that IgM titers directed against this virus were more frequently identified after four days of illness compared with baseline values provided further evidence supporting its pathogenetic role. Several outbreaks have subsequently been identified in several Indian states [17].
Chandipura virus encephalitis may be transmitted by sandfly bites and has been identified in Aedes aegypti mosquitoes. Illness is characterized by the rapid onset of fever followed by vomiting, altered mental status, and seizures. The mortality rate in the 2003 outbreak was 56 percent. A similar outbreak occurred in 26 children in western India in 2004, with a mortality of 78 percent [18], while an outbreak in 39 children in Maharashtra in 2007 had a mortality of 44 percent [19].
The diagnosis of Chandipura virus can be made by detecting one of the following in CSF or serum: viral RNA by PCR testing, IgM antibody against the virus by capture immunoassay, or virus via culture.
Colorado tick fever virus
●Epidemiology – The Colorado tick fever virus (genus Coltivirus, family Reoviridae) is transmitted to humans in the western United States and Canada mainly by the Rocky Mountain wood tick, Dermacentor andersoni (picture 1). Small rodents are the natural hosts of the virus. The distribution of human disease corresponds to the wood tick's distribution in mountainous areas at 4000- to 10,000-foot elevations. Transmission occurs from March to September, but peaks from April to June [20]. Transmission via blood transfusion has been described [21].
●Clinical manifestations – The mean incubation period ranges from 1 to 14 days, and 90 percent of patients report tick bites or tick exposure. Fever, chills, myalgias, and prostration are common presenting symptoms [22]. Headache often occurs during the acute febrile phase.
Approximately 15 percent of patients experience a petechial or maculopapular rash and leukopenia is a common finding. Although the acute symptoms last approximately one week, fever may recur several days later, and fatigue is often prolonged. Five to 10 percent of children develop meningitis or encephalitis [23].
●Diagnosis – Serologic tests are often not positive for 10 to 14 days after symptom onset. In comparison, reverse transcriptase polymerase chain reaction (RT-PCR) may be diagnostic from the first day of symptoms [24]. The virus infects marrow erythrocytic precursors, which accounts for the ability to recover the virus from peripheral blood up to six weeks after illness onset.
●Treatment and prevention – Treatment is supportive and the prognosis is generally favorable. Prevention consists of avoidance of tick bites in endemic areas. (See "Prevention of arthropod bites: Repellents and other measures".)
Dengue virus — Dengue is a febrile illness caused by infection with one of four dengue viruses (DENV) transmitted by Aedes aegypti or Aedes albopictus mosquitoes. Encephalitis caused by dengue virus is discussed in detail separately. (see "Dengue virus infection: Clinical manifestations and diagnosis")
Eastern equine encephalitis virus
●Virology and epidemiology – The eastern equine encephalitis (EEE) virus complex (family Togaviridae, genus Alphavirus) consists of EEE virus (formerly EEE subtype I), found in North America and the Caribbean, and Madariaga virus (formerly EEE subtype II to IV), found in South and Central America and Haiti [25,26]. EEE virus is associated with severe clinical disease, whereas human disease from Madariaga virus is infrequent [27].
In North America, wild birds and Culiseta melanura, a mosquito that is found in swamp areas that support cedar, red maple, and loblolly bay trees, maintain the EEE virus. However, since C. melanura mosquitoes rarely bite humans, some Aedes, Coquillettidia, and Culex species that can create a bridge between infected birds and humans are responsible for transmission to humans. Laboratory-acquired EEE infections and transmission of EEE from an organ donor have also been reported [28,29]. In addition, EEE virus is a potential agent of bioterrorism through the aerosol route. The ecology of Madariaga virus is not well described.
Although infections can occur throughout the year, peak incidence is in August and September. In the United States, human infections are usually sporadic, and small outbreaks occur each summer, mostly along the Atlantic and Gulf coasts and the Great Lake Region. From 2003 to 2022, 189 cases of EEE were reported, with the largest number of cases identified in Massachusetts, Michigan, Florida, Georgia, North Carolina, and Georgia [30]. In 2019, a multistate outbreak involving 38 cases was the largest ever recorded; the reasons for this increase are unknown [31]. In 2021, five cases were reported from four states (Georgia, Michigan, North Carolina, and Wisconsin) [4]. In 2022, one human case was reported in the United States [5].
●Clinical manifestations – The incubation period is usually 4 to 10 days after the mosquito bite. The illness often begins with a prodrome lasting several days; this typically includes fever, headache, nausea, and vomiting. Approximately 2 percent of infected adults and 6 percent of infected children develop encephalitis. Once neurologic symptoms begin, the clinical condition deteriorates rapidly, with approximately 90 percent becoming comatose or stuporous. Seizures, and focal neurologic signs, including cranial nerve palsies, develop in approximately one-half of the patients.
●Evaluation and diagnosis – Leukocytosis and hyponatremia are common on laboratory testing. CSF analysis typically shows pleocytosis, often with a neutrophilic predominance and elevated protein concentration. In one case series of 36 patients with EEE, an elevated white cell count in the initial CSF examination and the severity of hyponatremia correlated with a poor prognosis [32], although these findings were not observed in a series that evaluated a younger population with EEE [33].
Both MRI and CT are often abnormal early in the course, with focal lesions in the basal ganglia, thalami, and brainstem being particularly common. However, MRI is more sensitive than CT and may also reveal a symmetric pattern of T2 hyperintensity in the lentiform nuclei [34]. Marked linear hyperintensities in the internal capsules, known as the "parenthesis sign," may help differentiate between EEE and other encephalitides [35]. Cortical lesions, meningeal enhancement, and periventricular white-matter changes are less common.
EEG reveals generalized slowing and disorganization of the background, and epileptiform discharges may be seen [32,36].
The diagnosis of EEE can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against EEE virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention – No specific treatment for EEE is available. In one series, patients treated with anticonvulsants or corticosteroids had worse outcomes than those not treated, a finding possibly resulting from patient selection [32]. Several case reports have suggested a possible benefit of intravenous immune globulin (IVIG) therapy [36-39]. One series suggested improved patient outcomes with early IVIG administration; however, results were inconclusive due to small sample size and possible confounding factors [36].
Prevention focuses primarily on avoiding mosquito bites, which includes mosquito control in suburban areas. Although inactivated vaccines are available for horses, there is no commercially available vaccine for humans. However, an inactivated vaccine has been used in laboratory workers and others at high risk of exposure [40].
●Prognosis – EEE virus is the most severe of the arboviral encephalitides, with a mortality of at least 30 percent [32]. Death can occur within three to five days of onset and, among survivors, complete recovery is uncommon. Sequelae include convulsions, paralysis, and intellectual disability. Infection with Madariaga virus may be less severe.
Japanese encephalitis virus — Japanese encephalitis is an arboviral encephalitis that is endemic throughout much of tropical East Asia. Issues related to Japanese encephalitis are discussed in detail separately. (See "Japanese encephalitis".)
Murray valley encephalitis virus
●Virology and epidemiology – Murray Valley encephalitis (MVE) virus (family Flaviviridae, genus Flavivirus), occurs in Australia, New Guinea, and Irian Jaya [41]. MVE virus is believed to be maintained in a natural cycle involving water birds and Culex annulirostris mosquitoes. Humans are likely dead-end hosts. Most cases occur from February to June, with the highest risk in years with heavy rains and flooding. Only 1 in 150 to 1000 infections results in clinical illness [41], which resembles Japanese encephalitis. (See "Japanese encephalitis", section on 'Clinical manifestations'.)
●Clinical manifestations – The incubation period is one to four weeks. There is usually a prodromal illness with headache, fever, nausea and vomiting, anorexia, and myalgias, followed by drowsiness, malaise, irritability, mental confusion, and meningismus [42]. Seizures can occur and are more common in children. In severe cases, there may be cranial nerve palsies, Parkinsonism, peripheral neuropathy, tremor, flaccid paralysis, seizures, coma, and death [41].
Approximately 15 to 30 percent of patients with MVE die and approximately one-half of the survivors have residual neurologic deficits [43]. Children and older adults are at the highest risk for severe outcomes.
●Evaluation and diagnosis – CT imaging is normal in approximately two-thirds of patients [42,44]. MRI is more sensitive; findings include bilateral hyperintensity of the deep gray matter (especially the thalami) on fluid attenuation inversion recovery or T-2 weighted images [41,45]. Changes may also be seen in the temporal lobes, red nucleus, and cervical spinal cord.
The diagnosis of MVE can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against MVE virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7,46]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies to reduce the possibility of serologic cross-reactivity with the Japanese encephalitis and Kunjin (West Nile virus) viruses, which cause similar clinical syndromes. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention – Treatment is supportive. Corticosteroids have been administered to patients with MVE but have not been assessed in controlled trials.
There is no vaccine for MVE virus. Prevention relies on mosquito control and avoidance of mosquito bites. (See "Prevention of arthropod bites: Repellents and other measures".)
Powassan virus
●Epidemiology – Powassan virus (family Flaviviridae, genus Flavivirus) is related to the eastern hemisphere's tick-borne encephalitis viruses. It is maintained in a cycle between ticks and rodents [47]. Two lineages of Powassan virus exist in North America. Lineage 1 Powassan virus is associated with Ixodes cookei ticks and groundhogs/mustelids, and Ixodes marxi ticks and squirrels. These ticks rarely bite humans. Lineage 2 Powassan virus, sometimes called deer tick virus, is associated with Ixodes scapularis ticks and several hosts including white-footed mice. Ixodes scapularis also transmits Lyme disease, babesiosis, Borrelia miyamotoi, and anaplasmosis, Borrelia mayonii, and Ehrlichia muris eauclairensis. Powassan virus has been transmitted by blood transfusion [48].
Since its discovery in 1958, Powassan virus has become recognized as an uncommon cause of encephalitis in Russia, eastern Canada, and the north central, northeastern, and upper midwestern United States. However, the incidence of Powassan virus infection appears to be increasing [49,50], and from 2004 through 2022, 267 cases of neuroinvasive disease were reported to the United States CDC, mostly from Minnesota, Wisconsin, New York, and Massachusetts [49]. Infection mostly occurs from June to September.
In 2021, 24 Powassan virus disease cases were reported from eight jurisdictions, with the highest number of neuroinvasive disease cases occurring in New England and West North Central US Census Bureau divisions [4]. Powassan virus disease was also reported for the first time from Ohio. In 2022, 47 cases of Powassan virus disease were reported from nine states [5]; this was the first time Powassan virus disease was reported from Vermont.
●Clinical manifestations – The reported incubation period of Powassan virus ranges from 8 to 34 days [51,52]. However, few patients recall a tick bite, since Ixodid ticks are small and can be easily overlooked.
Illness begins with a prodromal phase lasting one to three days, during which symptoms such as fever, chills, malaise, somnolence, and nausea and vomiting are commonly reported. The proportion of those infected who develop CNS symptoms is unknown. CNS symptoms and signs include altered sensorium ranging from confusion to coma, seizures, hemiplegia, paresis, tremors, facial palsies, and pyramidal tract signs [53]. In 16 patient series at an academic medical center, six presented with rhombencephalitis, four with meningitis, three with meningoencephalitis, two with meningoencephalomyelitis, and one with opsoclonus myoclonus syndrome [54].
●Diagnosis – Serum and CSF samples can be tested for IgM and neutralizing antibodies. The diagnosis of Powassan virus infection can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against the virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Serum IgM antibodies alone should be confirmed by demonstration of neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention – There is no specific treatment or vaccine. Prevention of tick bites by using repellents, avoiding or clearing brushy areas, and wearing light-colored clothing may be effective. Removing ticks soon after outdoor exposure is advisable. Experimental studies suggest that Powassan virus can be transmitted within 15 minutes of tick attachment [55]. (See "Prevention of arthropod bites: Repellents and other measures".)
●Prognosis – The case-fatality rate is approximately 10 percent, with a high incidence of residual neurologic dysfunction among survivors, including hemiplegia, headaches, minor memory impairment, postviral parkinsonism, gait disturbances, and persistent ophthalmoplegia [51,54,56,57].
St. Louis encephalitis virus
●Epidemiology – St. Louis encephalitis virus (family Flaviviridae, genus flavivirus) disease typically occurs in the western, midwestern, and southeastern United States. St. Louis encephalitis virus has created periodic outbreaks, the largest occurring in 1975, which resulted in 1815 documented cases with 102 deaths reported from 30 states. However, since West Nile virus has become endemic throughout the United States, few cases have been reported. For example, St. Louis encephalitis virus was detected annually in California through 2003, but after the arrival of West Nile virus, St. Louis encephalitis virus was not detected again until it re-emerged in Riverside County in 2015 [58]. In the United States, 17 cases of St. Louis encephalitis virus disease were reported in 2021 [4]. This increased to 33 cases in 2022; 27 patients had neuroinvasive disease [5].
The West Nile and St. Louis encephalitis viruses share the same maintenance vectors, with birds as the main hosts. Culex pipiens (northern house mosquito) is an important maintenance vector in the northern United States and Canada, Culex pipiens quinquefasciatus (southern house mosquito) is important in the southern United States, and Culex tarsalis is important in the western United States and Canada [59]
The illness onset mainly occurs from July to October. Cases have also been identified in more tropical areas (eg, Brazil and Argentina) [60-62]. While illness has been observed in all age groups, neuroinvasive disease is more common among older persons.
●Clinical manifestations – The incubation period for St. Louis encephalitis virus disease ranges from 4 to 14 days. Many patients with St. Louis encephalitis virus infection are asymptomatic, but when symptoms do occur, they typically include fever, headache, vomiting, and malaise. The disease can progress to encephalitis, meningoencephalitis, or aseptic meningitis, particularly in older adults [63].
●Evaluation and diagnosis – The diagnosis of St. Louis encephalitis should be considered in any person with a febrile or acute neurologic illness who has had recent exposure to mosquitoes, blood transfusion, or potentially organ transplantation, especially during the summer months in areas where virus activity has been reported. CSF examination should be performed as part of the evaluation. Patients with St. Louis encephalitis neuroinvasive disease typically have a moderate lymphocytic pleocytosis. CSF protein is elevated in approximately one-half to two-thirds of cases. CT brain imaging is usually normal; EEG results often show generalized slowing without focal activity.
The diagnosis of St. Louis encephalitis can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titer against St. Louis encephalitis virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Some patients diagnosed with West Nile virus based on serologic tests may have been in fact infected with St. Louis encephalitis virus because of the extensive serologic cross-reactivity between the two viruses. Thus, IgM antibody detection alone should be confirmed by demonstration of virus-specific neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention – Treatment of St. Louis encephalitis is supportive since there are no antiviral therapies proven to be effective.
Similarly, no St. Louis encephalitis virus vaccines are available for use in humans. Thus, prevention of St. Louis encephalitis virus infection depends on personal protective measures to decrease exposure to infected mosquitoes (eg, insect repellent, treating clothing and gear with 0.5% permethrin, and taking steps to control mosquitoes indoors and outdoors). (See "Prevention of arthropod bites: Repellents and other measures".)
People recently diagnosed with St. Louis encephalitis virus infections should not donate blood for 120 days (four months) after their illness since St. Louis encephalitis virus can be transmitted through blood transfusions [64].
●Prognosis – Approximately 5 to 10 percent of St. Louis encephalitis virus neuroinvasive disease cases are fatal; the risk of severe disease increases with age. For those with less severe disease, most symptoms resolve within months to years, although some patients with neuroinvasive disease might have symptoms that persist for longer (eg, gait and speech disturbances, tremors, or psychologic/behavioral problems).
Tick-borne encephalitis virus
●Virology and epidemiology – Tick-borne encephalitis (TBE) is caused by three closely related viruses (family Flaviviridae, genus Flavivirus) [65]: the Russian spring-summer encephalitis subtype (also called far eastern subtype); the Siberian subtype also called Vasilchenko virus; and the Central European encephalitis subtype (also called western subtype).
These viruses are maintained in natural cycles involving a variety of mammals and ticks. Ixodes persulcatus and Ixodes ricinus are responsible for transmission in Russia and Europe, respectively [66]. Ixodes ovatus is the vector in Hokkaido.
TBE virus is transmitted from the saliva of an infected tick within minutes of the bite; early removal of the tick may not prevent encephalitis [67]. In Europe, tick activity starts in the spring and declines in the fall. Nymphal forms of I. ricinus are most important in human transmission whereas adult ticks are the dominant vector for I. persulcatus [67].
TBE exists over a wide geographical area [65,67]. Human exposure occurs through work or recreational activities in the spring and summer months in temperate zones, and in fall and winter in the Mediterranean, when the ticks are most active. Outbreaks have occasionally followed ingestion of unpasteurized milk products from infected sheep and goats [68]. Transmission of TBE virus via blood transfusion [69] and organ transplantation have also been reported [70].
Age, severity of illness in the acute stage, and low initial neutralizing antibody titers are associated with illness severity [67,71,72].
●Clinical manifestations – Illness onset occurs a median of 8 days (range 4 to 28) following the bite. Approximately two-thirds of patients report a tick bite.
The disease is characterized by a biphasic illness. In the first viremic phase, fever, fatigue, malaise, headache, and arthralgia predominate [65,67]. Neurologic manifestations are seen in the second phase, with a clinical spectrum ranging from mild meningitis to severe encephalitis, which may be accompanied by myelitis and acute flaccid paralysis [65,67,73]. Reports of chronic and progressive disease have been noted primarily with the Siberian subtype; however, this occurs uncommonly [65].
●Evaluation and diagnosis – MRI abnormalities may be noted in approximately 18 percent of patients with lesions located in the thalamus, cerebellum, brainstem, and caudate nucleus. EEG is abnormal in 77 percent of patients [67]. Both modalities demonstrate only nonspecific findings.
CSF examination generally shows a pleocytosis. Although polymorphonuclear cells may predominate at first, the CSF profile is later marked by dominance of mononuclear cells [67].
The diagnosis of TBE can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against TBE virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7,74]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention
•Treatment – Treatment is mainly supportive. In a large study of 709 patients with TBE in Germany, 12 percent of patients required intensive care and 5 percent required assisted ventilation [75]. Of the 230 patients who had a subsequent examination, approximately one-quarter had moderate to severe sequelae.
•Prevention – Safe and effective TBE vaccines are available in Europe and Russia, and one vaccine is locally available in China [76]. Mass vaccination has been undertaken in Austria, with protection rates of at least 96 percent [77]. Between the early 1970s and early 1980s, the average TBE incidence rate in Austria was 5.7 per 100,000; it dropped to 0.9 per 100,000 between the mid-1990s and 2005 among vaccinated individuals, but remained high (6 per 100,000) among unvaccinated individuals [78].
In the United States, a TBE vaccine was approved by the US Food and Drug Administration (FDA) in August 2021 [79]. This is an inactivated vaccine that has been licensed and used in Europe for approximately 20 years. Vaccination is recommended for persons who are moving or traveling to a TBE-endemic area and will have extensive exposure to ticks based on their planned outdoor activities and itinerary [80]. In addition, vaccination may be considered for persons traveling or moving to a TBE-endemic area who might engage in outdoor activity in areas ticks are likely to be found. (See "Immunizations for travel", section on 'Tick-borne encephalitis vaccine'.)
Other prevention strategies include pasteurization of milk and avoiding tick bites (eg, using insect repellents). (See "Prevention of arthropod bites: Repellents and other measures".)
●Prognosis – Case fatality rates with the Siberian subtype rarely exceed 8 percent and there is a greater tendency to developing nonparalytic encephalitis and chronic TBE [65]. In comparison, the western European subtype typically produces the biphasic form and tends to be less severe, with case fatality rates of 1 to 2 percent. Children have a more favorable prognosis than adults [81]. Up to one-half of patients report symptoms 6 to 12 months following encephalitis, with severe impairment noted in 30 percent.
Toscana virus — Toscana virus (genus Phlebovirus, family Bunyaviridae) is transmitted to humans in southern Europe and North Africa by infected Phlebotomus sandflies [82]. High seroprevalence rates in populations in endemic areas suggest that most infections are asymptomatic or clinically inconsequential. The incubation period is from a few days to two weeks. The disease is characterized by fever, headache, and gastrointestinal symptoms; decreased consciousness, paresis, and ocular findings may also occur [82,83]. Prognosis is generally favorable. CSF examination generally shows pleocytosis. The diagnosis of Toscana virus can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against Toscana virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF.
West Nile virus — Encephalitis caused by West Nile virus is discussed in detail separately. (see "Epidemiology and pathogenesis of West Nile virus infection")
Western equine encephalitis virus
●Virology and epidemiology – Western equine encephalitis (WEE) virus (family Togaviridae, genus Alphavirus) is a complex of closely related viruses found in North and South America. Flooding, which increases breeding of Culex mosquitoes, may precipitate summer outbreaks. Large outbreaks in humans and horses occurred in the western United States in the 1950s and 1960s. However, a declining horse population, equine vaccination, and improved vector control have reduced the incidence of the disease. WEE is a potential agent of bioterrorism through the aerosol route.
●Clinical manifestations – Following an incubation period of approximately seven days, headache, vomiting, stiff neck, and backache are typical; restlessness, irritability, and seizures are common in children. Fewer than 1 in 1000 infected adults develop encephalitis, but the frequency is greater in children, particularly infants [84]. The case fatality rate is 3 to 7 percent.
●Evaluation and diagnosis – The diagnosis of WEE can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against WEE virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and Prevention – Treatment is supportive. Prevention focuses on mosquito control and personal measures to avoid mosquito bites. Inactivated vaccine is available for horses. Although inactivated vaccine has been used for laboratory staff and others at high risk of exposure, it is not commercially available for use in humans. No specific treatment is available.
Venezuelan equine encephalitis virus
●Virology and epidemiology – Six subtypes (I-VI) within the Venezuelan equine encephalitis (VEE) virus (family Togaviridae, genus Alphavirus) complex have been identified. Four antigenic variants exist within each subtype I (IAB, IC, ID, IE) [85]. These subtypes and variants are classified as epizootic (can produce outbreaks of illness in animals) or enzootic (infects animals in a region, but often produces asymptomatic or sporadic illness in animals), based on their apparent virulence and epidemiology.
Epizootic strains are transmitted by many mosquito species, and enzootic strains by Culex mosquitoes. Epizootic variants of subtype I (IAB and IC) cause equine epizootics and are associated with more severe human disease. Enzootic strains (ID, 1E, 1F [Masso das Piedras], II [Everglades], III [Mucambo, Tonate], IV [Pixuna], V [Cabassou], VI [Rio Negro]) do not cause epizootics in horses but may produce sporadic disease in humans.
VEE has a widespread geographic distribution from Florida to South America, where it is an important veterinary and public health problem. Focal outbreaks occur periodically, but occasionally, large regional epidemics occur, with thousands of equine and human infections. VEE is infectious via aerosols, making it an occupational risk to certain laboratory workers and a potential agent of bioterrorism.
●Clinical manifestations – The incubation period for VEE is one to six days. After that, there is a brief febrile illness of sudden onset, characterized by malaise, nausea or vomiting, headache, and myalgia. Less than 0.5 percent of adults and less than 4 percent of children develop encephalitis, characterized by nuchal rigidity, seizures, coma, and paralysis. Long-term sequelae and fatalities are uncommon.
●Evaluation and diagnosis – The diagnosis of VEE can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against VEE virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [7]. Viremia is usually not detectable in serum. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies. Additional information on diagnosing arboviral disease can be found on the CDC website.
●Treatment and prevention – Treatment is supportive. Effective prevention of both human and equine disease can be accomplished by immunizing equines, which serve as the primary amplification hosts for the epizootic VEE viruses and without which there would be little human disease.
During epidemics, mosquito vectors can be controlled by insecticides. Live attenuated and inactivated vaccines have been used for laboratory workers; however, these vaccines are not commercially available.
CONSIDERATIONS IN IMMUNOCOMPROMISED PERSONS —
Immunocompromised persons with arthropod encephalitides may have a worse clinical course and prognosis. Severe neuroinvasive disease following West Nile virus, tick-borne encephalitis virus, eastern equine encephalitis virus, Cache Valley virus, Jamestown canyon virus, and Powassan virus has been noted in patients taking anti-CD20 B-cell depleting agents (eg, rituximab, ocrelizumab) [86-88]. Among 19 patients taking rituximab who developed arboviral neuroinvasive disease, 79 percent died [86].
Among immunocompromised patients such as these, diagnosis can be more difficult as they may lack or have a delayed serologic response to arbovirus infections. In these instances, detection of viral nucleic acid by polymerase chain reaction (PCR) in serum or cerebrospinal fluid (CSF) may be more likely and considerably more prolonged than with immune-competent persons. As an example, in a report of 21 persons receiving rituximab, the diagnosis of arboviral infection required molecular testing in almost all of the patients since there was an absence of serologic response [86].
Immunocompromised patients, particularly those receiving rituximab and other B-cell-depleting therapies, should be counseled about mosquito bite prevention. (See "Prevention of arthropod bites: Repellents and other measures".)
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".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Encephalitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Virology and transmission – Arthropod-borne encephalitis viruses, which belong to the families Flaviviridae, Togaviridae, Bunyaviridae, and Reoviridae, are highly adapted to a particular reservoir host. These viruses are spread from animal to animal via the bite of an infected arthropod, usually a specific mosquito or tick species. (See 'Introduction' above.)
The mosquito or tick becomes infected when feeding on the blood of the viremic animal. The virus then replicates in the mosquito or tick, ultimately infecting the salivary glands. The vector then transmits the virus to a new host when it injects infective salivary fluid while taking a blood meal. (See 'Transmission cycle' above.)
Although infected humans may become ill, they usually do not develop sufficient viremia to infect feeding vectors. As a result, humans do not usually contribute to the transmission cycle. (See 'Transmission cycle' above.)
●Geographic distribution – Among the mosquito-borne encephalitis viruses, the greatest public health threat in North America is posed by the West Nile, St. Louis encephalitis, and La Crosse encephalitis viruses. Venezuelan equine encephalitis virus is of concern in Central and South America, while Japanese encephalitis virus affects persons living or traveling to parts of Asia. Among the tick-borne viruses that cause encephalitis, tick-borne encephalitis virus causes the greatest public health threat among residents or visitors to Eastern Europe and Asia. (See 'Specific viruses' above.)
●Specific viruses
•Eastern Equine encephalitis – The eastern equine encephalitis (EEE) virus complex (family Togaviridae, genus Alphavirus) consists of EEE virus (formerly EEE subtype I), found in North America and the Caribbean, and Madariaga virus (formerly EEE subtype II to IV), found in South and Central America and Haiti. EEE virus is the most severe of the arboviral encephalitides, with a mortality of at least 30 percent. By contrast, human disease from Madariaga virus is infrequent. There is no specific therapy for EEE. (See 'Eastern equine encephalitis virus' above.)
•Western equine encephalitis – Western equine encephalitis (WEE) virus is found in North and South America and is a potential agent of bioterrorism through the aerosol route. The case fatality rate is 3 to 7 percent. Although inactivated vaccine has been used for laboratory staff and others at high risk of exposure, it is not commercially available for use in humans. No specific treatment is available. (See 'Western equine encephalitis virus' above.)
•La Crosse virus – La Crosse virus (family Bunyaviridae, genus Bunyavirus) is the most pathogenic member of the California encephalitis serogroup. Human infections occur in the central and eastern United States, mostly in school-aged children from July through September. Most infections are asymptomatic; of those who present with encephalitis, the mortality rates are low. Treatment is supportive, with emphasis on control of cerebral edema and seizures. Ribavirin has been used, but efficacy is unproven. (See 'California serogroup viruses' above.)
•Murray Valley encephalitis – Murray Valley encephalitis (MVE) virus (family Flaviviridae, genus Flavivirus), occurs in Australia, New Guinea, and Irian Jaya. MVE virus is believed to be maintained in a natural cycle involving water birds and Culex annulirostris mosquitoes. Viremia has not been documented in humans, who are likely dead-end hosts. Only 1 in 150 to 1000 infections results in clinical illness; however, approximately one-third of patients with MVE die and approximately one-half of the survivors have residual neurologic deficits. (See 'Murray valley encephalitis virus' above.)
•Venezuelan equine encephalitis – Venezuelan equine encephalitis (VEE) has a widespread geographic distribution from Florida to South America, where it is an important veterinary and public health problem. Focal outbreaks occur periodically, but occasionally, large regional epidemics occur, with thousands of equine and human infections. VEE is infectious via aerosols, making it an occupational risk to certain laboratory workers and a potential agent of bioterrorism. Effective prevention of both human and equine disease can be accomplished by immunizing equines, which serve as the primary amplification hosts for the epizootic VEE viruses. (See 'Venezuelan equine encephalitis virus' above.)
•Tick-borne encephalitis – Tick-borne encephalitis (TBE) exists over a wide geographical area, including Russia and Europe. Human exposure occurs through work or recreational activities when the ticks are most active. TBE virus is transmitted from the saliva of an infected tick within minutes of the bite; early removal of the tick may not prevent encephalitis. Case fatality rates range from two to eight percent. Treatment is mainly supportive. An inactivated vaccine is available for persons at risk. (See 'Tick-borne encephalitis virus' above and 'Powassan virus' above.)
•St. Louis encephalitis – St. Louis encephalitis virus disease typically occurs in the western, midwestern and southeastern United States. The incubation period for St. Louis encephalitis virus disease ranges from 4 to 14 days. Many patients with St. Louis encephalitis virus infection are asymptomatic, but when symptoms do occur, they typically include fever, headache, vomiting, and malaise. The disease can progress to encephalitis, meningoencephalitis, or aseptic meningitis, particularly in older adults. Treatment of St. Louis encephalitis is supportive since there are no antiviral therapies proven to be effective. (See 'St. Louis encephalitis virus' above.)
•Other arthropod encephalitides – Dengue virus, West Nile virus, and Japanese encephalitis virus are arthropod-borne viruses that also cause encephalitis. They are discussed in detail in separate topic reviews. (See "Clinical manifestations and diagnosis of West Nile virus infection" and "Dengue virus infection: Clinical manifestations and diagnosis" and "Japanese encephalitis".)
