Arthropod-borne encephalitides

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 the patients with suspected central nervous system (CNS) infection are discussed separately. (See "Viral encephalitis in adults".)

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 a sufficient number of 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 in close proximity to 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.

GEOGRAPHIC DISTRIBUTION — 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 or traveling to parts of Asia. Dengue is a rare cause of encephalitis throughout the tropical world. (See "Epidemiology and pathogenesis of West Nile virus infection" and "St. Louis encephalitis".)

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.

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 recently 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 antibody 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).

WEST NILE, ST. LOUIS, AND DENGUE — These three causes of arthropod-borne encephalitis are discussed separately:

●West Nile virus encephalitis (see "Epidemiology and pathogenesis of West Nile virus infection")

●St. Louis encephalitis (see "St. Louis encephalitis")

●Dengue virus infection (see "Dengue virus infection: Clinical manifestations and diagnosis")

EASTERN EQUINE ENCEPHALITIS VIRUS — 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 [2,3]. EEE virus is associated with severe clinical disease, whereas human disease from Madariaga virus is infrequent [4].

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 are capable of creating 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 [5,6]. 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. From 2010 to 2019, 107 cases of EEE were reported, with the largest number of cases identified in Massachusetts, Michigan, Florida, New York, North Carolina, and Georgia [7]. In 2019, a multistate outbreak involving 38 cases was the largest ever recorded; the reasons for this increase are unknown [8].

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, with fever, headache, nausea, and vomiting being common. 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.

Leukocytosis and hyponatremia are common on laboratory testing. Cerebrospinal fluid (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 [9], although these findings were not observed in a series that evaluated a younger population with EEE [10].

Both magnetic resonance imaging (MRI) and computed tomography (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 [11]. Cortical lesions, meningeal enhancement, and periventricular white-matter changes are less common.

Electroencephalography reveals generalized slowing and disorganization of the background, and epileptiform discharges may be seen [9,12].

Diagnosis — The diagnosis of EEE can be made by demonstration of immunoglobulin M (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 [13]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

Outcome — EEE virus is the most severe of the arboviral encephalitides, with a mortality of at least 30 percent [9]. 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 is less severe.

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 [9]. Several case reports have suggested a possible benefit of intravenous immune globulin (IVIG) therapy [12,14-16]. One series suggested improved patient outcomes with early IVIG administration; however, results were inconclusive due to small sample size and possible confounding factors [12].

Prevention focuses primarily upon 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.

WESTERN EQUINE ENCEPHALITIS VIRUS — 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.

Fewer than 1 in 1000 infected adults develop encephalitis, but the frequency is greater in children, particularly infants [17]. Following an incubation period of about seven days, headache, vomiting, stiff neck, and backache are typical; restlessness, irritability, and seizures are common in children. Although rare in adults and older children, neurologic sequelae are relatively common in infants. The case fatality rate is 3 to 7 percent.

The diagnosis of WEE can be made by demonstration of IgM antibody by capture immunoassay of cerebrospinal fluid (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 [13]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

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.

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".)

LA CROSSE ENCEPHALITIS VIRUS — La Crosse virus (LAC, family Bunyaviridae, genus Bunyavirus) is the most pathogenic member of the California encephalitis serogroup, which includes the California encephalitis, trivittatus, snowshoe hare, and Jamestown Canyon viruses. LAC is transmitted via Aedes triseriatus (eastern tree hole mosquito), and mammalian hosts include the eastern chipmunk, tree squirrels, and foxes.

Human infections occur in the central and eastern United States, mostly in school-aged children from July through September [18,19]. Most infections are asymptomatic. Approximately 30 to 120 La Crosse encephalitis neuroinvasive disease cases are reported annually.

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 [18]. 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 have 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 of 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.

Leukocytosis is common, with polymorphonuclear cells predominating [18]. Cerebrospinal fluid (CSF) shows pleocytosis with either neutrophilic or lymphocytic predominance. Electroencephalography is abnormal in two-thirds of patients, mainly with slowing or epileptiform discharges [18]. 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 [18]. Magnetic resonance imaging (MRI) may show focal areas of gadolinium enhancement.

The diagnosis of LAC can be made by demonstration of IgM antibody by capture immunoassay of CSF, a fourfold rise in serum antibody titers against LAC virus, or isolation of virus from or demonstration of viral antigen or genomic sequences in tissue, blood, or CSF [13]. Viral isolation from the CSF is rare [20]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

Treatment is supportive, with emphasis on control of cerebral edema and seizures [18]. Ribavirin has been used, but efficacy is unproven [21].

Prevention rests on avoidance of mosquito bites [20]. A case of possible congenital infection has also been reported with IgM antibodies identified in the umbilical cord blood; however, the newborn was asymptomatic and development was normal [22]. No seroconversion was documented in this case because the mother declined further testing.

MURRAY VALLEY ENCEPHALITIS — Murray Valley encephalitis (MVE) virus (family Flaviviridae, genus Flavivirus), occurs in Australia, New Guinea, and Irian Jaya [23]. 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. Most cases occur from February to June, with highest risk in years with heavy rains and flooding.

Only 1 in 150 to 1000 infections results in clinical illness [23], which resembles Japanese encephalitis. 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 [24]. Seizures are more common in children. In severe cases, there may be cranial nerve palsies, Parkinsonism, peripheral neuropathy, tremor, flaccid paralysis, seizures, coma, and death [23].

Computed tomography (CT) scan is normal in about two-thirds of patients [24,25]. Magnetic resonance imaging (MRI) is more sensitive, and findings include bilateral hyperintensity of the deep gray matter, especially the thalami, on fluid attenuation inversion recovery or T-2 weighted images [23,26]. 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 cerebrospinal fluid (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 [13]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

Treatment is supportive. Corticosteroids have been administered to patients with MVE but have not been assessed in controlled trials. Approximately 15 to 30 percent of patients with MVE die and about half the survivors have residual neurologic deficits [27]. Children and older adults are at highest risk.

There is no vaccine for MVE virus. Prevention relies on mosquito control and avoidance of mosquito bites.

VENEZUELAN EQUINE ENCEPHALITIS VIRUS — Six subtypes (I-VI) within the Venezuelan equine encephalitis (VEE) virus (family Togaviridae, genus Alphavirus) complex have been identified. Four antigenic variants exist within subtype I (IAB, IC, ID, IE) [28]. 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 upon their apparent virulence and epidemiology:

●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.

Epizootic strains are transmitted by many mosquitoes, and enzootic strains by Culex mosquitoes.

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.

After an incubation period of one to six days, 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.

The diagnosis of VEE can be made by demonstration of IgM antibody by capture immunoassay of cerebrospinal fluid (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 [13]. Viremia is usually not detectable in serum. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

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, human vaccines are not commercially available.

TICK-BORNE ENCEPHALITIS VIRUS — Tick-borne encephalitis (TBE) is caused by three closely related viruses (family Flaviviridae, genus Flavivirus) [29]:

●The Russian spring-summer encephalitis subtype (also called far eastern subtype)

●The Siberian subtype also called Vasilchenko virus

●The Central European encephalitis subtype (also called western subtype)

Vector — 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 [30]. Ixodes ovatus is the vector in Hokkaido. Tick-borne encephalitis exists over a wide geographical area [29,31].

Transmission — 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. 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 [31]. 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 [31].

Outbreaks have occasionally followed ingestion of unpasteurized milk products from infected sheep and goats [32]. Transmission of TBE virus via organ transplantation has also been reported [33].

Age, severity of illness in the acute stage, and low initial neutralizing antibody titers are associated with illness severity [31,34]. The CCR5 delta 32 allele may predispose individuals to TBE [35]. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Alterations in the CCR5 coreceptor'.)

Clinical manifestations — Approximately two-thirds of patients report a tick bite, and illness onset occurs a median of 8 days (range 4 to 28) following the bite. The disease is characterized by a biphasic illness. In the first viremic phase, fever, fatigue, malaise, headache, and arthralgia predominate [29,31]. Neurologic manifestations hallmark the second phase, with a clinical spectrum ranging from mild meningitis to severe encephalitis, which may be accompanied by myelitis and acute flaccid paralysis [29,31].

Reports of chronic and progressive disease have been noted primarily with the Siberian subtype; however, this occurs uncommonly [29].

Evaluation and diagnosis — Magnetic resonance imaging (MRI) abnormalities may be noted in approximately 18 percent of patients with lesions located in the thalamus, cerebellum, brainstem, and caudate nucleus; electroencephalogram is abnormal in 77 percent of patients [31]. Both modalities demonstrate only nonspecific findings.

Cerebrospinal fluid (CSF) examination generally shows pleocytosis. Although polymorphonuclear cells may predominate at first, the CSF profile is later marked by dominance of mononuclear cells [31]. 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 [13,36]. Serum IgM antibodies alone should be confirmed by demonstration of virus-specific neutralizing antibodies.

Testing for TBE can be performed at the United States Centers for Disease Control and Prevention (CDC) Special Pathogens Branch (404-639-1115) or Arboviral Diseases Branch (970-221-6400) [37].

Outcome — Case fatality rates with the Siberian subtype rarely exceed 8 percent and there is a greater tendency to developing nonparalytic encephalitis and chronic TBE [29]. 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 [38]. Up to one-half of patients report symptoms 6 to 12 months postencephalitis, with severe impairment noted in 30 percent.

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 [39]. 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 [40]. Mass vaccination has been undertaken in Austria, with protection rates of at least 96 percent [41]. 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 [42].

In the United States, a tick-borne encephalitis vaccine was approved by the US Food and Drug Administration (FDA) in August 2021 [43]. This is an inactivated vaccine that has been licensed and used in Europe for about 20 years. When it becomes available, travelers with extensive outdoor exposures from camping or related activities in endemic regions during the spring and summer months should consider being vaccinated. Updated evidence-based recommendations for vaccine administration to travelers and laboratory workers will be considered by the Advisory Committee on Immunization Practices (ACIP) in 2022. (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 and insect bites: Repellents and other measures".)

POWASSAN VIRUS — 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 [44]. 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 a variety of hosts, including white-footed mice. Ixodes scapularis also transmits Lyme disease, babesiosis, Borrelia miyamotoi, and anaplasmosis.

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 [45,46], and from 2010 through 2019, 166 cases of neuroinvasive disease were reported to the United States Centers for Disease Control and Prevention (CDC), mostly from Minnesota, Wisconsin, New York, and Massachusetts [45]. Infection mostly occurs from June to September.

The reported incubation periods range from 8 to 34 days [47,48]. 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 central nervous system (CNS) symptoms is unknown. CNS symptoms and signs include altered sensorium ranging from confusion to coma, seizures in children, hemiplegia, paresis, tremors, facial palsies, and pyramidal tract signs [49].

Serum and cerebrospinal fluid (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 [13]. Serum IgM antibodies alone should be confirmed by demonstration of neutralizing antibodies.

The case-fatality rate is approximately 10 percent, with a high incidence of residual neurological dysfunction among survivors, including hemiplegia, headaches, minor memory impairment, and persistent ophthalmoplegia [47,50,51].

There is no specific treatment or vaccine. Prevention of tick bites by using repellents, avoiding or clearing brushy areas, 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 [52].

COLORADO TICK FEVER VIRUS — 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 [53]. Transmission via blood transfusion has been described [54].

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 [55]. 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 about one week, fever may recur several days later, and fatigue is often prolonged. Five to 10 percent of children develop meningitis or encephalitis [56].

Serologic tests are often not positive for 10 to 14 days after symptom onset. In comparison, reverse transcriptase polymerase chain reaction (PCR) may be diagnostic from the first day of symptoms [57]. 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 is supportive and the prognosis is generally favorable. Prevention consists of avoidance of tick bites in endemic areas.

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) [58]. 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. A number of outbreaks have subsequently been identified in several Indian states [59].

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 [60], while an outbreak in 39 children in Maharashtra in 2007 had a mortality of 44 percent [61].

The diagnosis of Chandipura virus can be made by detecting one of the following in cerebrospinal fluid (CSF) or serum: viral RNA by polymerase chain reaction (PCR) testing, IgM antibody against the virus by capture immunoassay, or virus via culture.

TOSCANA VIRUS — Toscana virus (genus Phlebovirus, family Bunyaviridae) is transmitted to humans in southern Europe and North Africa by infected Phlebotomus sandflies [62]. 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 [62,63]. Prognosis is generally favorable. Cerebrospinal fluid (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.

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 5^th to 6^th 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 10^th to 12^th 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

●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.)

●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. (See 'Geographic distribution' above.)

●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 'Geographic distribution' above.)

●The close antigenic relationships among the flaviviruses may cause a problem with diagnosis due to cross-reactivity. (See 'Cross-reactivity' above.)

●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 (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 (LAC, 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 'La Crosse encephalitis virus' above.)

●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 about half the survivors have residual neurologic deficits. (See 'Murray valley encephalitis' above.)

●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 (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. Powassan virus is related to the eastern hemisphere's tick-borne encephalitis viruses. (See 'Tick-borne encephalitis virus' above and 'Powassan virus' above.)