Clinical manifestations

Presentation and course

Arboviruses commonly cause inapparent infections or mild nonspecific illnesses. A minority of patients (the number varies with the specific arbovirus) develop acute encephalitis (or encephalomyelitis), meningitis, or a combination of both. Clinical illness usually develops in arboviral infections a few days after transmission of the arbovirus from the bite of a mosquito or tick vector. Patients with meningitis have fever, headache, neck stiffness, and signs of meningeal irritation; this presentation is less common than encephalitis. Patients with encephalitis may have fever, a depressed level of consciousness (ranging from drowsiness to coma), seizures, or focal neurologic signs (62; 66). Focal signs are only occasionally prominent in arboviral encephalitis (104). Patients may also have evidence of spinal cord involvement (94; 82). Acute flaccid paralysis has been noted in patients with West Nile encephalitis, and ventilatory support may be required (115). Cases with muscle weakness often have ventral horn cell involvement due to West Nile, Powassan, Japanese, and other arboviral infections (82; 103; 45), and rare patients have features of an atypical Guillain-Barré syndrome (01). Both delayed-onset and recurrent limb weakness occurring several weeks after illness have rarely been observed in West Nile virus infection (114). Acute flaccid paralysis has also been reported in Japanese encephalitis virus infection (131); movement disorders may also occur. In West Nile encephalitis, movement disorders include tremor, opsoclonus-myoclonus, parkinsonism, myoclonus, ataxia, and chorea, and the movement disorder usually resolves within a few weeks to months (80). Seizures and raised intracranial pressure may be important causes of death (131).

The severity of encephalitides caused by arboviruses ranges from mild to severe and fatal. The frequency and severity of neurologic sequelae are also variable. Certain arboviruses typically cause more severe disease and higher fatality rates than others. For example, eastern equine encephalitis virus causes a severe encephalitis with a mortality rate of about 70%. In contrast, La Crosse virus causes a relatively mild encephalitis (California serogroup encephalitis) with a low fatality rate. Arboviruses may cause disease in certain age groups. Encephalitis caused by La Crosse virus usually occurs in children, although infection can occur at any age. Adults in epidemic areas seldom develop Japanese encephalitis because they have developed immunity from childhood infection. Infants often have severe sequelae from western equine encephalitis (33), and elderly patients are more likely to have severe sequelae from St. Louis encephalitis (41). Risk factors for severe West Nile virus disease, including encephalitis, are chronic renal disease, a history of cancer, a history of alcohol abuse, diabetes, and hypertension (83). West Nile virus infection may be particularly severe in organ transplant recipients (74).

Zika virus infection does not commonly cause encephalitis but is associated with microcephaly of the fetus and infant after infection of pregnant women; the infection has also been associated with Guillain-Barré syndrome (16; 13; 113). A case of Zika virus infection was reported from Colombia with acute disseminated encephalomyelitis and Guillain-Barré syndrome, likely due to boosted immunity to other arboviruses (87).

Prognosis and complications

Focal or generalized seizures may occur in the acute phase of arboviral encephalitis. Hyponatremia due to inappropriate secretion of antidiuretic hormone is particularly frequent in St. Louis encephalitis (12). Dehydration, respiratory complications, nosocomial infections, and decubitus ulcers may occur in these acutely ill patients.

The morbidity and mortality vary in encephalitides caused by different arboviruses. Recovery from neurologic sequelae of West Nile virus infection, including cognitive deficits and weakness, may be prolonged and incomplete (28). The mortality rate is highest (about 35%) in eastern equine encephalitis, where neurologic sequelae are common and may be severe, especially in children (39; 105; 30). The average lifetime cost to a person with sequelae approaches $3 million (133). The mortality rate is about 10% in western equine encephalitis, and sequelae are moderate in infants, including mental retardation, seizure disorders, and motor impairment. Sequelae are low in other age groups (33). The mortality rate is low in Venezuelan equine encephalitis, in La Crosse encephalitis, and in encephalitis due to Colorado tick fever virus; neurologic sequelae are infrequent and usually mild. However, a fatal case of La Crosse encephalitis occurred in Minnesota in 1997 (21). Seizure disorders may occur after La Crosse encephalitis (29). In St. Louis encephalitis, the mortality rate increases from 2% in young adults to 20% in the elderly, and sequelae are more common and more severe in patients over 50 years of age (41). In Japanese encephalitis, one third of patients die, whereas half of the survivors have severe neuropsychiatric sequelae (122). Many children have been reported to develop relapsing illness after Japanese encephalitis and have NMDA receptor antibodies in CSF (86). Hence, like herpes simplex encephalitis, arboviral encephalitis may also be a trigger for the development of autoimmune encephalitis. The Far Eastern form of tick-borne encephalitis is more severe than the Central European form; the mortality rate is up to 20%, and sequelae are frequent (32). Epilepsia partialis continua may develop during the convalescent period or later (05), and there may be residual weakness due to bulbar or cervical cord involvement (117). Japanese encephalitis has a mortality rate of almost 50% in patients over 50 years of age and less than 20% in children (99). Sequelae occur in 30% to 40% of patients between 5 and 40 years of age (135) and include extrapyramidal features (especially dystonia), flaccid paralysis, and seizure disorders (122).

Clinical vignette

A 10-year-old boy from Illinois had fever, vomiting, headache, and confusion for a period of 2 days. He had two generalized convulsions and was hospitalized. On examination, his temperature was 38.2°C, and he had moderate nuchal rigidity. He was stuporous, but there was no focal weakness, and his deep tendon reflexes were normal. A CT head scan was normal. Cerebrospinal fluid analysis showed a pleocytosis with 120 leukocytes (95% mononuclear cells) and an elevated protein of 70 mg/mL. An EEG showed diffuse slowing but no epileptiform activity. He received antiepileptic therapy and made a complete recovery over a period of 2 weeks. The titer of neutralizing antibody against La Crosse virus in acute serum was less than 1:8, and it was 1:64 in convalescent serum; this confirmed a diagnosis of California serogroup (La Crosse) encephalitis.

Biological basis

Etiology and pathogenesis

More than 20 arboviruses that cause human encephalitis have been identified (65). The arboviruses are transmitted to vertebrate hosts after an obligatory cycle in hematophagous arthropods, including mosquitoes, ticks (130), and sandflies (07).

Humans are not necessary for the maintenance of arboviruses in nature. Arboviruses are the most common cause of epidemic encephalitis, and they are also responsible for other diseases, including yellow fever and hemorrhagic fevers. Although encephalopathy is more common, dengue virus infection may rarely cause encephalitis or other neurologic complications (132). The arboviruses are enveloped RNA viruses from different families, including the Togaviridae (Alphavirus genus), Flaviviridae (Flavivirus genus), Bunyaviridae (Bunyavirus genus), and Reoviridae (Orbivirus genus); these are transmitted to humans by a mosquito, tick, or, rarely, sandfly vector.

Table 1. Arthropod-Borne Viruses Causing Encephalitis

Arboviruses are ingested into the gut of the arthropod vector and replication occurs in its tissues. This infection is not usually associated with any cytopathology or detrimental effects on the vector (130). There is viral spread to the salivary glands of the arthropod, and transmission occurs to the vertebrate host, including humans, during probing or blood-feeding. After inoculation through the skin of the host, viral replication occurs close to the site of entry in subcutaneous tissues or muscle (02). This infection results in a high-titer viremia and dissemination to the CNS via the bloodstream. Transmission of arboviruses may also occur through transfusion of blood or blood components (46). There is either infection of CNS endothelial cells or the virus is transported across endothelial cells. Toll-like receptor 3 has been shown to be involved in brain penetration by West Nile virus (134). Cell-to-cell spread of the virus occurs in the CNS. Neurons are prominently infected, and there is variable involvement of other neural cells. The infection causes cytopathic changes in CNS cells and inflammatory changes, including infiltration of the leptomeninges and perivascular spaces with mononuclear cells. Individual arboviruses may be associated with different topographic distributions of pathological changes. For example, the West Nile virus characteristically involves the brainstem (111) and spinal cord or ventral nerve roots (82), causing flaccid paralysis. There is experimental evidence that arboviruses can induce apoptotic cell death in neurons in the brains of their hosts (81; 63). The infection may result in the death of the host, or there may be immune system-mediated clearance of the viral infection with complete recovery or neurologic sequelae (50). CNS involvement, sometimes with probable CNS invasion, may also occur in dengue virus (a flavivirus) infection, especially in fatal cases (03). Like herpes simplex encephalitis, there are reports that anti-N-methyl-D-aspartate receptor encephalitis may be associated with both Japanese encephalitis virus infection (127), tick-borne encephalitis virus infection (17), and chikungunya virus infection (98).

Epidemiology

Arboviral infections may occur either in epidemics or sporadically. There are complex ecological cycles between arthropod vectors and their natural hosts; this explains the geographic and seasonal (usually in the summer and early fall) occurrence of these infections (75). Outbreaks of arboviral encephalitis are often focal in their distribution, and specific arboviruses usually cause infections in particular geographic areas.

Epidemics of eastern equine encephalitis are relatively small and mostly occur in the eastern part of the United States. From 2003 to 2022, 4 to 38 human cases were reported in the United States each year. Western equine encephalitis occurs in the western United States and in Canada. Only three human cases of western equine encephalitis were reported in the United States during the 1990s (21), and none have been reported in recent years. Venezuelan equine encephalitis has occurred in large outbreaks in Central and South America. In 1971, a large epidemic in Mexico crossed the Texas border (35). In 1995, there was a large epidemic of Venezuelan equine encephalitis in Venezuela and Columbia (19; 20). In Venezuelan equine encephalitis, the horse is an important amplifying host, whereas in eastern and western equine encephalitis, the horse, like humans, is a dead-end host. St. Louis encephalitis has both urban and rural outbreaks. In 1975 an epidemic caused cases in 30 U.S. states and in Canada (85). The activity of St. Louis encephalitis virus infection decreased in the United States after the introduction of West Nile virus in 1999. There was an outbreak in Arizona from 2014 to 2015, and there were isolated cases in California from 2016 through 2017 (31). Chikungunya virus infection, which occurs in Africa, Asia, Europe, and more recently in the Americas (including Florida, Puerto Rico, and U.S. Virgin Islands), causes fever, rash, and arthralgias and can also cause encephalitis (43). Sporadic cases of Powassan encephalitis have been recognized in the northern United States and Canada (Ontario and Quebec), and the incidence is increasing (04; 44; 56; 34). The distribution of the disease has spread from the northeastern United States to involve the upper midwestern United States. There has been an increase in incidence, with 99 human cases reported in the United States from 2006 to 2016 (77). Powassan virus is transmitted by Ixodes ticks, and infections are sporadic. In 2009, fatal human encephalitis was reported in New York due to infection by another tick-borne encephalitis virus called deer tick virus (125). This virus is identical to the Powassan virus according to conventional taxonomic criteria (34). In Europe and Russia, about 10,000 cases of tick-borne encephalitis are reported annually; cases may occur in travelers (49). The incidence and geographical range of the disease is increasing in Europe and Asia (79). The severity of tick-borne encephalitis increases with age (68). Most cases of California serogroup encephalitis are caused by the La Crosse virus and occur in the central United States. There were 70 to 167 cases yearly from 1999 to 2007 (109). Most cases of La Crosse encephalitis occur in children, but adult cases have occasionally been recognized (126). Other California serogroup viruses less commonly cause encephalitis, including the Jamestown Canyon virus (26). The distribution of Jamestown Canyon virus infection is more widespread in the United States. California serogroup viral encephalitis has been the most under-recognized arboviral encephalitis in the United States (21).

Japanese encephalitis is the most common cause of epidemic encephalitis in the world, and now almost half of the human population lives in countries where the disease is endemic (38). Large summer epidemics and endemic disease in Asia is responsible for about 50,000 cases per year, with case fatality rates of about 25% (48). Infection should be considered by travelers to endemic areas. Japanese encephalitis virus is transmitted by the mosquito Culex tritaeniorhynchus, which breeds in rice fields. Water birds are natural hosts, and pigs may be important amplifying hosts in many countries.

In 1999, West Nile virus was responsible for an outbreak of encephalitis in New York City and neighboring counties with 62 cases and seven deaths (22). The mechanism of the virus’ introduction into North America is unknown. The virus quickly moved across the North American continent. In 2023, there were 2406 cases of West Nile virus infection, including 1599 (66%) with neuroinvasive disease. Elderly and immunosuppressed patients are particularly at risk for disease and a fatal outcome. Transmission may also occur by organ transplantation, infected blood products, and breast milk.

Prevention

Surveillance methods are important to predict the likelihood of outbreaks of infections (36). Environmental factors can be monitored. Mosquitoes can be sampled to estimate population levels, and infection rates can be assessed in mosquito pools. Recognition of infections and disease in sentinel hosts such as horses before disease occurs in humans is important. Sentinel chickens can be bled periodically to determine seroconversion, which indicates increased activity of an arbovirus.

Personal measures, including screening, protective clothing, and repellents, are useful in the prevention of arthropod bites and the subsequent development of arboviral infections. Avoiding outdoor activities at dusk, when mosquitoes are most active, is also useful. Prompt removal of ticks from the skin may decrease the risk of transmission of a tick-borne virus. Public health measures include modification of irrigation practices, which can eliminate aquatic habitats that are breeding places for mosquitoes. Effective preventive measures for California serogroup (La Crosse) encephalitis include removing water-holding containers, especially discarded tires, and filling basal tree holes (42). The application of insecticides may be useful in the emergency control of infected mosquitoes.

Vaccines are available for eastern equine encephalitis, western equine encephalitis, Venezuelan equine encephalitis, and West Nile encephalitis in horses. A live attenuated vaccine (TC-83) has been used to protect laboratory and field workers from Venezuelan equine encephalitis virus infection (96). Vaccines have also been developed for Japanese encephalitis (124; 121) and tick-borne encephalitis (54), and adverse effects of these vaccines must be considered (88).

Differential diagnosis

Confusing conditions

Arboviral encephalitis may be clinically indistinguishable from other forms of viral encephalitis. Focal neurologic signs are not usually prominent, but they may be present. In Herpes simplex encephalitis, evidence of focal brain involvement (especially in the temporal lobes) is often obtained by clinical assessment and by using electroencephalography and imaging techniques (CT, MRI). These investigations may help differentiate between Herpes simplex encephalitis and arboviral encephalitis (95). In addition, detecting Herpes simplex virus DNA in the cerebrospinal fluid with polymerase chain reaction amplification is an important diagnostic test for Herpes simplex encephalitis. The mortality rate in untreated Herpes simplex virus encephalitis is about 70% (137).

Although enteroviruses more commonly cause aseptic meningitis, they may also cause encephalitis. Enteroviral infections also peak in the summer and early fall. They may be associated with a rash (72), and there may be a history of recent illness in the family. Enteroviral encephalitis is usually mild, with a good recovery.

Other viruses that cause encephalitis include mumps virus, lymphocytic choriomeningitis virus, Epstein-Barr virus, cytomegalovirus, adenovirus, and rabies virus. Nonviral infections include brain abscess, leptospirosis, Lyme disease, Rocky Mountain spotted fever, toxoplasmosis, and malaria. Postinfectious encephalomyelitis (67) and noninfectious diseases, including metabolic and septic encephalopathy (09), neurosarcoidosis, and neoplasms, should also be considered in the differential diagnosis.

Diagnostic workup

Routine laboratory studies are not usually helpful in establishing a diagnosis of arboviral encephalitis. Electroencephalograms often show generalized slowing, although epileptiform activity or periodic lateralizing epileptiform discharges (92) may be present. The results of imaging techniques, including CT and MRI scans, have not been reported frequently. Many patients with West Nile neuroinvasive disease have normal neuroimaging, but abnormalities may be demonstrated in the basal ganglia, thalamus, brainstem, and cerebellum (28; 08). CT or MRI scans have demonstrated lesions in the basal ganglia, thalamus, and brainstem in eastern equine encephalitis (30; 06). Powassan encephalitis may show cortical (107) or thalamic hemorrhages (25). In Japanese encephalitis, MRI scans show lesions in the thalami in most patients; lesions also occur in the basal ganglia, midbrain and pons, cerebral cortex, and cerebellum (78; 70; 51), and lesions may be hemorrhagic (112). T2 and fluid-attenuated inversion recovery (FLAIR) images are more sensitive (51). Temporal lobe lesions mainly involve the hippocampus and spare the rest of the temporal lobe and are associated with concurrent involvement of thalami and substantia nigra, which allows differentiation from Herpes simplex encephalitis (52). MRI lesions may be present in the thalamus, basal ganglia, and brainstem in tick-borne encephalitis (89). MR FLAIR axial imaging may show the “parenthesis sign” with marked linear hyperdensities in the external capsules and posterior parts of the internal capsules that have been observed in eastern equine encephalitis (119). A cerebellar-dominant MR imaging pattern has been recognized in Powassan encephalitis, which is associated with a 60% mortality rate (40). Imaging techniques are also useful because they may show temporal lobe lesions suggestive of Herpes simplex encephalitis, and they helpfexclude disorders that can mimic viral encephalitis.

A cerebrospinal fluid analysis is important in establishing a diagnosis of viral encephalitis, and a CT head scan (or MRI scan) should precede the lumbar puncture if there are focal neurologic signs or evidence of increased intracranial pressure. There is usually a cerebrospinal fluid pleocytosis with a modest number of leukocytes that are predominantly mononuclear cells. Cerebrospinal fluid protein is often elevated, and the cerebrospinal fluid glucose is usually normal. Viral cultures on cerebrospinal fluid for arboviruses are usually not positive, although Japanese encephalitis virus may be isolated from cerebrospinal fluid in up to one third of patients (84). However, enteroviruses, lymphocytic choriomeningitis virus, and mumps virus may be isolated from cerebrospinal fluid. Venezuelan equine encephalitis virus, tick-borne encephalitis viruses, and Colorado tick fever virus may be isolated from blood (47; 57). Arboviruses may be cultured from the brain and spinal cord in fatal cases. Rarely, a diagnosis may be made by using brain biopsy (91). Most arboviral infections are usually diagnosed serologically. A serologic diagnosis is commonly made on the basis of a 4-fold or greater rise (or fall) in the titer of viral antibodies (immunofluorescent, hemagglutination inhibition, complement fixation, or neutralizing) during the infection. Both acute and convalescent sera should be obtained, the latter 2 to 6 weeks later. A diagnosis may be made during hospital admission or soon afterward by demonstration of viral specific IgM in the cerebrospinal fluid by capture enzyme immunoassay (15; 58). Assays using polymerase chain reaction amplification are generally less reliable than detection of virus-specific immunoglobulin M in cerebrospinal fluid but may be useful in detecting viral RNA from arboviruses in the cerebrospinal fluid or brain tissues (128; 24; 60; 11). In immunosuppressed patients, serological tests in some cases may be negative, as in a patient with Powassan encephalitis on rituximab (120).

Management

No effective antiviral therapy is available for treating patients with arboviral encephalitis. Seizures should be treated with antiepileptic medications, but prophylactic therapy is not necessary. Corticosteroids are of unproven value, and a study did not demonstrate a benefit of high-dose dexamethasone in treating Japanese encephalitis (59). In tick-borne encephalitis, a retrospective study indicated that corticosteroids prolonged the disease duration and did not influence sequelae (76). Therapy with alpha-interferon was not found to improve outcomes in a clinical trial in Vietnamese children with Japanese encephalitis (123). A phase I/IIA trial of intravenous ribavirin therapy for La Crosse encephalitis showed poor penetration into the CSF at a moderate dose and adverse effects at an escalated dose (93); a randomized clinical trial was not recommended. A humanized monoclonal antibody (MGAWN1) has been developed against West Nile virus (100) and was evaluated in a large multicenter clinical trial, but few patients were enrolled and the study was not completed. Intravenous human immunoglobulin from donors in Israel has been used for therapy of West Nile encephalitis (97), but a multicenter, randomized, controlled clinical trial by the Collaborative Antiviral Study Group failed to show efficacy for the treatment of West Nile encephalitis. A small clinical trial showed therapy feasibility in children with suspected Japanese encephalitis using intravenous immunoglobulin (108). The therapeutic use of monoclonal antibodies for arboviral infections may be useful in the future (101). A small pilot study using interferon alpha-2b indicated possible efficacy in St Louis encephalitis, and a prospective, randomized, controlled trial might be warranted (106). However, no specific therapy is of proven benefit for West Nile encephalitis (61) or other arboviral encephalitis. Vigorous supportive therapy and avoidance of complications are important. Monitoring of intracranial pressure and therapy for intracranial hypertension may be necessary in some patients. Respiratory, metabolic, and septic complications may occur in severely ill patients with encephalitis, and patients should be closely monitored for these. Isolation procedures are not necessary; the possible exceptions to this are Venezuelan equine encephalitis and tick-borne encephalitis because of a concern about the potential for transmission by close direct contact (57; 20).

Outcomes

Neurologic sequelae are common in neuroinvasive arboviral infections. About one third of cases of eastern equine encephalitis are fatal, which has the highest mortality rate, and most cases have long-term sequelae. The mortality rate in Powassan virus infections is 19% in adults (69). The other neuroinvasive arboviral infections have lower mortality rates and fewer neurologic sequelae. Patients receiving rituximab therapy or other B-cell-depleting monoclonal antibodies may have a more severe or prolonged clinical course and also an absence of serological response to the infection (71).

Special considerations

Pregnancy

Information on arboviral infections during pregnancy is limited. There have been reports of transplacental transmission of western equine encephalitis virus (27), Venezuelan equine encephalitis (136), West Nile virus (23), Japanese encephalitis virus (90), Colorado tick fever virus (10), and La Crosse encephalitis virus (55). Zika virus infection in pregnant mothers can cause severe congenital abnormalities in fetuses, resulting in microcephaly and other severe CNS abnormalities (64; 118). Congenital infections due to arboviral infections may be much more common than recognized and be responsible for CNS malformations (129).

Anesthesia

There are no special considerations for anesthesia. However, there is evidence that inhalational anesthetics, including halothane and nitrous oxide, promote viral brain invasion and suppress the immune response in experimental West Nile virus infection in mice (73).