Flavivirus Encephalitis
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《新英格兰医药杂志》
During the summers of 2002 and 2003, North America was affected by its largest-ever outbreaks of arboviral encephalitis. West Nile virus caused 2942 cases of meningitis or encephalitis in 2002, with 276 deaths, and 2866 cases in 2003, with 246 deaths.1,2 West Nile virus, which in the United States was first detected in New York in 1999, is one of several mosquito-borne neurotropic members of the Japanese encephalitis (JE) serogroup of the genus flavivirus, family Flaviviridae, that cause similar disease patterns across the globe (Figure 1 and Table 1). These include St. Louis encephalitis virus in the United States, Rocio virus, which has caused encephalitis outbreaks in Brazil, and Murray Valley encephalitis virus in Australia, New Guinea, and New Zealand. Kunjin virus, which also circulates in Australia, recently has been reclassified as a subtype of West Nile virus. In terms of numbers, the most important member of the group is Japanese encephalitis virus, which causes an estimated 30,000 to 50,000 cases of encephalitis and 10,000 deaths in Asia every year.3 In addition to viruses of the JE serogroup, the flavivirus genus includes mosquito-borne causes of hemorrhagic fever (e.g., yellow fever and dengue viruses, which also occasionally cause encephalitis) and tick-borne viruses,4 which are not discussed here.
Figure 1. Approximate Global Distribution of Medically Important Members of the Japanese Encephalitis Serogroup of Flaviviruses.
This group consists of St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, and West Nile viruses (including Kunjin virus, which is a subtype of West Nile virus found in Australia).
Table 1. Epidemiologic Features of Flavivirus Encephalitis.
Flaviviruses are small RNA viruses, with an envelope protein that is important for viral attachment and entry into host cells.4 The recent outbreaks of West Nile encephalitis have raised questions about the epidemiology, clinical features, and management of the disease5,6 — which, to some extent, have already been answered for other members of the serogroup. In this article I will review the similarities and differences between West Nile virus and other flaviviruses of the JE serogroup and consider what we might expect for West Nile virus in terms of epidemiology, pathogenesis, and clinical features, given current knowledge about the other viruses.
Ecology and Epidemiology
The epidemiology of flavivirus encephalitis is governed by a complex interplay of climatic, entomologic, human behavioral, viral, and host factors that are not completely understood.6 Viruses are transmitted naturally among birds in enzootic cycles by bird-biting mosquitoes — especially the culex genus. Humans become infected inadvertently when they encroach on this cycle, but they are considered "dead-end" hosts because normally they do not have sufficiently high or prolonged viremia to transmit the virus further. However, during 2002 it became apparent that West Nile virus can be transmitted among humans through infected transplanted organs and blood products.7 In 2003 this finding prompted the screening of blood products, which appears to have been successful in limiting the spread of West Nile virus by this mechanism.8 Transplacental transmission occurs with Japanese encephalitis virus9 and recently has been described for West Nile virus as well.10,11 Ultrasonographic examination of the fetus is now recommended if maternal illness due to West Nile virus occurs during pregnancy.12
In Asia, pigs as well as birds are important natural hosts for Japanese encephalitis virus, and because these animals are often kept close to human dwellings, they serve as amplifying or bridging hosts that transmit the virus to humans. In the United States, the death of corvid birds (such as crows and blue jays) may serve as a warning that human disease is imminent.13,14
Japanese encephalitis is mostly a disease of children, whereas in the United States, West Nile encephalitis and St. Louis encephalitis are more likely to affect adults (Figure 2). This apparent paradox is probably explained, to some extent, by differences in the intensity of transmission and by acquired immunity. In rural Asia, where exposure to infected mosquitoes is unavoidable, serologic surveys show that almost everyone is exposed to Japanese encephalitis virus during childhood. However, fever develops in only a small proportion (about 1 in 300) of those exposed, and neurologic disease develops in even fewer persons.18 Thus, Japanese encephalitis does not often occur in adults because, in most cases, they are already immune to the virus. Recent work has examined the role of the virus's nonstructural proteins in eliciting this protective immunity.19 However, when previously unexposed adults become infected — for example, when Japanese encephalitis virus spreads to new areas, or when travelers visit Asia — they, too, are at risk for the disease.3
Figure 2. Age-Specific Incidence and Seroprevalence of Japanese Encephalitis in Endemic Areas of Asia and West Nile Encephalitis in Nonendemic Areas of Europe.
Adapted from Tsai et al.,15 Monath and Tsai,16 and Grossman et al.17
The epidemiology of Murray Valley encephalitis in Australia and West Nile virus in Africa follows a pattern similar to that of Japanese encephalitis in Asia, despite the fact that far fewer cases of encephalitis occur in these areas. On both continents, disease tends to be seen more commonly in children or in visitors to areas of endemic disease than in resident adults, who have preexisting immunity.20 Whereas the febrile syndrome caused by Murray Valley encephalitis virus is usually not diagnosed, West Nile virus can cause large outbreaks of a characteristic syndrome of fever, arthralgia, and rash known as West Nile fever21 — though in recent outbreaks, rash and arthralgia have been less common. However, when West Nile virus has spread to new areas (e.g., to North America or parts of Europe), the infection of large numbers of previously unexposed adults has resulted in large outbreaks of encephalitis (Figure 2).
St. Louis encephalitis virus is already endemic in the southern United States, but most of the population does not have preexisting immunity because the rates of transmission of the virus to humans have been relatively low. When environmental conditions have favored substantial viral amplification in the bird–mosquito–bird cycle, however, large numbers of cases have occurred; for example, there were approximately 2000 cases of St. Louis encephalitis in 1975.22 It is unclear whether the epidemiology of West Nile encephalitis in North America will follow that of St. Louis encephalitis or will be more like that of Japanese encephalitis in Asia, with thousands of cases every year, though the large number of North American cases of West Nile disease two years in succession seems ominous.
Pathogenesis
The factors that govern which persons will become ill with neurologic disease, and how severely, are not completely understood. The host immune response is important to control replication of the virus in the skin, lymph nodes, and blood before the virus enters the brain. Thus, it has been shown that for Japanese encephalitis virus, the failure of the host to produce antibodies to the virus is associated with an increased likelihood that the virus will be isolated and with an increased risk of death.23 For West Nile virus, chronic illness and immunosuppression also appear to be risk factors for severe disease and death7,14,24,25,26,27; in an animal model, production of antibody is known to be important.28,29 In mice, the production of interferon is protective,30 and a host gene for susceptibility to infection with flavivirus has recently been identified.31,32 Advanced age is associated with a greater severity of disease in West Nile encephalitis, St. Louis encephalitis, and Japanese encephalitis (for which there is a second peak of incidence in the elderly).24,33 The reason for the more severe illness in older persons is not known, but impaired integrity of the blood–brain barrier due to cerebrovascular disease has been postulated. Disruption of the blood–brain barrier is also thought to explain why cysticercosis is a risk factor for Japanese encephalitis.34
When a person has been exposed to one flavivirus, cross-reacting antibodies may affect the outcome of infection with a second flavivirus. Thus, for patients with Japanese encephalitis, prior infection with dengue virus, which circulates through much of Asia, appears to protect against severe disease.35 Prior exposure to dengue may also explain why, during the 1962 epidemic of St. Louis encephalitis in Florida, longtime inhabitants of the area were mostly spared.36 In contrast, serial infection with different serotypes of dengue virus appears to be associated with more severe disease (e.g., dengue hemorrhagic fever), possibly because of an antibody-dependent enhancement of infection,37 though the strain of dengue virus may also be important.38 These questions of reduced or increased severity in secondary flavivirus infections may be important in the parts of the United States and Central America where West Nile virus may circulate with St. Louis encephalitis or dengue virus. Determinants of the virulence of a virus may also be important. For both Japanese encephalitis and West Nile viruses, certain lineages or genotypes of virus appear to be associated with large encephalitis outbreaks, which suggests that these genotypes may have greater virulence.39,40 However, a recent detailed molecular analysis of the distribution of genotypes of Japanese encephalitis virus suggests that such interpretations may be overly simplistic.41 Nevertheless, in rodent models of infection with a flavivirus, the ability to enter the nervous system may be affected by a small number of changes in the amino acids in critical regions of the virus's envelope protein.42,43 Whether such subtle changes could be responsible for altered virulence in birds, and thus could explain the rapid spread of West Nile virus across North America, is under investigation.
Clinical Features
Neurologic disease typically develops in patients after an incubation period of 5 to 15 days (though this period can be as brief as 2 to 3 days) and a short, nonspecific febrile prodrome. The neurologic manifestations depend on which part of the nervous system is infected — the meninges (to cause meningitis), the parenchyma of the brain (encephalitis), or the spinal cord (myelitis).44 Aseptic meningitis is less common than encephalitis (Table 1). The more important presentations (which often overlap) include a reduced level of consciousness, which may be associated with seizures, a flaccid paralysis resembling that of poliomyelitis, and parkinsonian movement disorders.
Seizures
Seizures are common in children with flavivirus encephalitis — they occur in approximately 85 percent of children with Japanese encephalitis or Murray Valley encephalitis45,46,47 — and in up to 10 percent of adults with West Nile encephalitis. An association between seizures — especially multiple seizures and status epilepticus — and poor outcome has been shown for Japanese encephalitis and for St. Louis encephalitis.46,48 In addition to clinically obvious status epilepticus, subtle convulsive status, of which the only manifestation is the twitching of a digit, an eyebrow, or the mouth, has been described in Japanese encephalitis and St. Louis encephalitis46,49 and is associated with a grave prognosis. The importance of subtle convulsive status in West Nile encephalitis has yet to be established, although in one study it was not seen.50 Electroencephalograms may also reveal periodic lateralized epileptiform discharges,46,49 which are often encountered in herpes simplex encephalitis. Multiple uncontrolled seizures may be associated with raised intracranial pressure and with clinical signs of brain-stem herniation syndromes.46
Approximately 50 percent of patients with Japanese encephalitis and 30 percent of patients with St. Louis encephalitis have elevated cerebrospinal fluid opening pressures. Brain swelling is seen at autopsy, although herniation is not often reported.7,33,51 Distinguishing the clinical signs of brain-stem herniation from those of direct viral damage in the brain stem may be difficult, but the possibility of this reversible complication should not be overlooked. Severe brain-stem encephalitis may result in the locked-in syndrome.27
Poliomyelitis-Like Paralysis
Motor weakness is common in patients with flavivirus encephalitis. In addition to weakness of the upper motor neurons, which is reported in 30 to 50 percent of patients, flaccid weakness of the limbs, with reduced or absent reflexes, is also common. This weakness is associated with respiratory or bulbar paralysis and is reported in approximately 20 to 60 percent of patients.24,27,45,52 In addition to causing flaccid weakness in comatose patients who have encephalitis, flaviviruses can also cause an acute flaccid paralysis similar to that of poliomyelitis in fully conscious patients. The earliest outbreaks of Murray Valley encephalitis were thought to be an aberrant form of poliomyelitis,53 and illness that resembles poliomyelitis has been described in patients infected with Japanese encephalitis virus54 and those with West Nile viruses.55,56,57,58
Nerve-conduction studies typically show reduced or absent compound muscle action potentials, with preserved sensory-nerve action potentials and normal conduction velocities.54,57,58 Although initially ascribed by some to the Guillain–Barré syndrome, in most cases these responses probably indicate damage to the lower motor neurons in the anterior horns of the spinal cord (i.e., anterior myelitis), as seen at autopsy53,58,59,60,61,62 and on imaging of the spinal cord.52,57 However, demyelination, involvement of the sensory nerves, and radiculitis also occur occasionally.27,63,64 Electromyography typically shows positive sharp waves and spontaneous fibrillations, which are consistent with denervation. Acute retention of urine owing to an atonic bladder may be an early clue that paralysis is the result of a flavivirus.44,54 In some patients, damage to both upper and lower motor neurons can lead to bizarre mixtures of clinical signs, which may change hourly during the acute stages of infection.
Parkinsonian Movement Disorders
In Japanese encephalitis, movement disorders are common, both in the acute stages of infection and as part of the sequelae. In one recent series of cases, one quarter of patients had acute manifestations.46 A characteristic "parkinsonian syndrome" includes mask-like facies, tremors, and cogwheel rigidity. Other movement disorders include generalized rigidity, jaw dystonia, opisthotonos, choreoathetosis, orofacial dyskinesias (e.g., involuntary tongue protrusions), myoclonic jerks, and opsoclonus myoclonus.46,65 Similar movement disorders have been reported for Murray Valley encephalitis, St. Louis encephalitis, and, more recently, West Nile encephalitis27,66,67 and are thought to be the clinical correlate of the inflammation often seen in the basal ganglia — particularly the thalamus and substantia nigra — on magnetic resonance imaging and at autopsy (Figure 3).33,44,46,59,65,66,68,69,70,71,72 In some patients, intention tremors and ataxia may suggest cerebellar involvement.27
Figure 3. T2-Weighted Magnetic Resonance Images Showing High Signal Intensity and Swelling in the Thalamus (Arrows) of Patients with Japanese Encephalitis (Panel A), West Nile Encephalitis (Panel B), and Murray Valley Encephalitis (Panel C).
Panel B is adapted from Solomon et al.,66 and Panel C is adapted from Kienzle and Boyes.68
Diagnosis and Treatment
Attempts to isolate virus from the blood of patients with flavivirus encephalitis are usually unsuccessful because viremia is transient and titers are low. Virus is occasionally isolated from the cerebrospinal fluid of patients who do not yet have antibody, particularly those who subsequently die,23,26 and from postmortem brain tissue.7,23,73 Viral ribonucleic acid occasionally may be detected in the cerebrospinal fluid by the reverse transcriptase polymerase chain reaction (PCR)74,75; for West Nile virus, real-time PCR has proved more useful.76 However, the accepted standard for diagnosing flavivirus encephalitis is the IgM capture enzyme-linked immunosorbent assay (ELISA). This assay will often detect antibody on a single cerebrospinal fluid or serum sample.1,3 Not all patients have antibody on admission to the hospital, and the test should be repeated if it is initially negative. False positive results can occur in patients who live in areas where more than one flavivirus circulates or in patients who have received a flavivirus vaccine, but this problem can be minimized by parallel testing for antibody against various flaviviruses.77,78,79 Assays for neutralizing antibodies are more specific than ELISAs but can be performed only in specialized laboratories that can grow dangerous viruses. Antibody may persist in the serum for many months after infection.80,81
There is no established antiviral treatment for any flavivirus infection. The most promising compound was interferon alfa. This is produced naturally in patients with flavivirus infections, and recombinant interferon alfa has efficacy in some animal models. Interferon alfa was reported to have shown promise in open clinical trials against Japanese encephalitis82 and St. Louis encephalitis83 and, on that basis, was given empirically to patients with West Nile encephalitis during 2002. However, a randomized, double-blind, placebo-controlled trial of interferon alfa in Vietnamese children with Japanese encephalitis showed that it had no effect on the outcome.84 Ribavirin and intravenous immune globulin also have been given empirically to patients with West Nile encephalitis.85,86 There are supportive data from animal models for the use of immune globulin,87 and a clinical trial has been set up by the National Institute of Allergy and Infectious Diseases. Treatment of flavivirus encephalitis currently consists of managing the complications of infection and, with good nursing care and physical therapy, avoiding bedsores and contractures. Even with intensive therapy, severe neuropsychiatric sequelae are common in survivors (Table 1).
Future Prospects
Formalin-inactivated and live attenuated vaccines against Japanese encephalitis exist, but because of costs and logistics, they are not available to much of the population of rural Asia that needs them.88 The inactivated vaccine is licensed in the United States, but there is some controversy about which travelers to Asia should receive it.89 A three-dose regimen (administered on days 0, 7, and 30) is recommended for travelers who spend prolonged periods (i.e., more than one month) in the rural parts of Asia where Japanese encephalitis is endemic or epidemic.90 However, because Japanese encephalitis has appeared in short-term travelers, some physicians recommend more liberal use of the vaccine.91 Approximately 20 percent of vaccine recipients have local cutaneous or mild systemic reactions. More serious allergic reactions occur in about 0.6 percent of recipients. Vaccines against St. Louis encephalitis have never been fully developed because the disease burden has not been considered great enough. A crude formalin-inactivated vaccine against West Nile virus is being used to protect horses (in which encephalitis can also develop). Newer vaccines that are being developed for flavivirus encephalitis include DNA vaccines and chimeric vaccines.88,92 Further research is needed to understand the pathogenesis of flavivirus encephalitis and thus to provide a rational approach to new treatments.
Supported by grants from the Wellcome Trust. Dr. Solomon is a Wellcome Trust Career Development Fellow.
I am indebted to my many colleagues and friends in Asia, Africa, the United States, and the United Kingdom whose data and insights have helped to shape this review.
Source Information
From the Departments of Neurological Science and Medical Microbiology, University of Liverpool, Liverpool, United Kingdom.
Address reprint requests to Dr. Solomon at the Department of Neurological Science, University of Liverpool, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, United Kingdom, or at tsolomon@liv.ac.uk.
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Solomon T, Dung NM, Wills B, et al. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet 2003;361:821-826.
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Haley M, Retter AS, Fowler D, Gea-Banacloche J, O'Grady NP. The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis. Clin Infect Dis 2003;37:e88-e90.
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Monath TP. Japanese encephalitis vaccines: current vaccines and future prospects. Curr Top Microbiol Immunol 2002;267:105-138.
Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis 2002;35:183-188.
Inactivated Japanese encephalitis virus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1993;42:1-15.
Solomon T. Vaccines against Japanese encephalitis. In: Jong EC, Zuckerman JN, eds. Travelers' vaccines. Hamilton, Ont., Canada: B.C. Decker, 2004:219-56.
Monath TP. Prospects for development of a vaccine against the West Nile virus. Ann N Y Acad Sci 2001;951:1-12.(Tom Solomon, M.D., Ph.D.)
Figure 1. Approximate Global Distribution of Medically Important Members of the Japanese Encephalitis Serogroup of Flaviviruses.
This group consists of St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, and West Nile viruses (including Kunjin virus, which is a subtype of West Nile virus found in Australia).
Table 1. Epidemiologic Features of Flavivirus Encephalitis.
Flaviviruses are small RNA viruses, with an envelope protein that is important for viral attachment and entry into host cells.4 The recent outbreaks of West Nile encephalitis have raised questions about the epidemiology, clinical features, and management of the disease5,6 — which, to some extent, have already been answered for other members of the serogroup. In this article I will review the similarities and differences between West Nile virus and other flaviviruses of the JE serogroup and consider what we might expect for West Nile virus in terms of epidemiology, pathogenesis, and clinical features, given current knowledge about the other viruses.
Ecology and Epidemiology
The epidemiology of flavivirus encephalitis is governed by a complex interplay of climatic, entomologic, human behavioral, viral, and host factors that are not completely understood.6 Viruses are transmitted naturally among birds in enzootic cycles by bird-biting mosquitoes — especially the culex genus. Humans become infected inadvertently when they encroach on this cycle, but they are considered "dead-end" hosts because normally they do not have sufficiently high or prolonged viremia to transmit the virus further. However, during 2002 it became apparent that West Nile virus can be transmitted among humans through infected transplanted organs and blood products.7 In 2003 this finding prompted the screening of blood products, which appears to have been successful in limiting the spread of West Nile virus by this mechanism.8 Transplacental transmission occurs with Japanese encephalitis virus9 and recently has been described for West Nile virus as well.10,11 Ultrasonographic examination of the fetus is now recommended if maternal illness due to West Nile virus occurs during pregnancy.12
In Asia, pigs as well as birds are important natural hosts for Japanese encephalitis virus, and because these animals are often kept close to human dwellings, they serve as amplifying or bridging hosts that transmit the virus to humans. In the United States, the death of corvid birds (such as crows and blue jays) may serve as a warning that human disease is imminent.13,14
Japanese encephalitis is mostly a disease of children, whereas in the United States, West Nile encephalitis and St. Louis encephalitis are more likely to affect adults (Figure 2). This apparent paradox is probably explained, to some extent, by differences in the intensity of transmission and by acquired immunity. In rural Asia, where exposure to infected mosquitoes is unavoidable, serologic surveys show that almost everyone is exposed to Japanese encephalitis virus during childhood. However, fever develops in only a small proportion (about 1 in 300) of those exposed, and neurologic disease develops in even fewer persons.18 Thus, Japanese encephalitis does not often occur in adults because, in most cases, they are already immune to the virus. Recent work has examined the role of the virus's nonstructural proteins in eliciting this protective immunity.19 However, when previously unexposed adults become infected — for example, when Japanese encephalitis virus spreads to new areas, or when travelers visit Asia — they, too, are at risk for the disease.3
Figure 2. Age-Specific Incidence and Seroprevalence of Japanese Encephalitis in Endemic Areas of Asia and West Nile Encephalitis in Nonendemic Areas of Europe.
Adapted from Tsai et al.,15 Monath and Tsai,16 and Grossman et al.17
The epidemiology of Murray Valley encephalitis in Australia and West Nile virus in Africa follows a pattern similar to that of Japanese encephalitis in Asia, despite the fact that far fewer cases of encephalitis occur in these areas. On both continents, disease tends to be seen more commonly in children or in visitors to areas of endemic disease than in resident adults, who have preexisting immunity.20 Whereas the febrile syndrome caused by Murray Valley encephalitis virus is usually not diagnosed, West Nile virus can cause large outbreaks of a characteristic syndrome of fever, arthralgia, and rash known as West Nile fever21 — though in recent outbreaks, rash and arthralgia have been less common. However, when West Nile virus has spread to new areas (e.g., to North America or parts of Europe), the infection of large numbers of previously unexposed adults has resulted in large outbreaks of encephalitis (Figure 2).
St. Louis encephalitis virus is already endemic in the southern United States, but most of the population does not have preexisting immunity because the rates of transmission of the virus to humans have been relatively low. When environmental conditions have favored substantial viral amplification in the bird–mosquito–bird cycle, however, large numbers of cases have occurred; for example, there were approximately 2000 cases of St. Louis encephalitis in 1975.22 It is unclear whether the epidemiology of West Nile encephalitis in North America will follow that of St. Louis encephalitis or will be more like that of Japanese encephalitis in Asia, with thousands of cases every year, though the large number of North American cases of West Nile disease two years in succession seems ominous.
Pathogenesis
The factors that govern which persons will become ill with neurologic disease, and how severely, are not completely understood. The host immune response is important to control replication of the virus in the skin, lymph nodes, and blood before the virus enters the brain. Thus, it has been shown that for Japanese encephalitis virus, the failure of the host to produce antibodies to the virus is associated with an increased likelihood that the virus will be isolated and with an increased risk of death.23 For West Nile virus, chronic illness and immunosuppression also appear to be risk factors for severe disease and death7,14,24,25,26,27; in an animal model, production of antibody is known to be important.28,29 In mice, the production of interferon is protective,30 and a host gene for susceptibility to infection with flavivirus has recently been identified.31,32 Advanced age is associated with a greater severity of disease in West Nile encephalitis, St. Louis encephalitis, and Japanese encephalitis (for which there is a second peak of incidence in the elderly).24,33 The reason for the more severe illness in older persons is not known, but impaired integrity of the blood–brain barrier due to cerebrovascular disease has been postulated. Disruption of the blood–brain barrier is also thought to explain why cysticercosis is a risk factor for Japanese encephalitis.34
When a person has been exposed to one flavivirus, cross-reacting antibodies may affect the outcome of infection with a second flavivirus. Thus, for patients with Japanese encephalitis, prior infection with dengue virus, which circulates through much of Asia, appears to protect against severe disease.35 Prior exposure to dengue may also explain why, during the 1962 epidemic of St. Louis encephalitis in Florida, longtime inhabitants of the area were mostly spared.36 In contrast, serial infection with different serotypes of dengue virus appears to be associated with more severe disease (e.g., dengue hemorrhagic fever), possibly because of an antibody-dependent enhancement of infection,37 though the strain of dengue virus may also be important.38 These questions of reduced or increased severity in secondary flavivirus infections may be important in the parts of the United States and Central America where West Nile virus may circulate with St. Louis encephalitis or dengue virus. Determinants of the virulence of a virus may also be important. For both Japanese encephalitis and West Nile viruses, certain lineages or genotypes of virus appear to be associated with large encephalitis outbreaks, which suggests that these genotypes may have greater virulence.39,40 However, a recent detailed molecular analysis of the distribution of genotypes of Japanese encephalitis virus suggests that such interpretations may be overly simplistic.41 Nevertheless, in rodent models of infection with a flavivirus, the ability to enter the nervous system may be affected by a small number of changes in the amino acids in critical regions of the virus's envelope protein.42,43 Whether such subtle changes could be responsible for altered virulence in birds, and thus could explain the rapid spread of West Nile virus across North America, is under investigation.
Clinical Features
Neurologic disease typically develops in patients after an incubation period of 5 to 15 days (though this period can be as brief as 2 to 3 days) and a short, nonspecific febrile prodrome. The neurologic manifestations depend on which part of the nervous system is infected — the meninges (to cause meningitis), the parenchyma of the brain (encephalitis), or the spinal cord (myelitis).44 Aseptic meningitis is less common than encephalitis (Table 1). The more important presentations (which often overlap) include a reduced level of consciousness, which may be associated with seizures, a flaccid paralysis resembling that of poliomyelitis, and parkinsonian movement disorders.
Seizures
Seizures are common in children with flavivirus encephalitis — they occur in approximately 85 percent of children with Japanese encephalitis or Murray Valley encephalitis45,46,47 — and in up to 10 percent of adults with West Nile encephalitis. An association between seizures — especially multiple seizures and status epilepticus — and poor outcome has been shown for Japanese encephalitis and for St. Louis encephalitis.46,48 In addition to clinically obvious status epilepticus, subtle convulsive status, of which the only manifestation is the twitching of a digit, an eyebrow, or the mouth, has been described in Japanese encephalitis and St. Louis encephalitis46,49 and is associated with a grave prognosis. The importance of subtle convulsive status in West Nile encephalitis has yet to be established, although in one study it was not seen.50 Electroencephalograms may also reveal periodic lateralized epileptiform discharges,46,49 which are often encountered in herpes simplex encephalitis. Multiple uncontrolled seizures may be associated with raised intracranial pressure and with clinical signs of brain-stem herniation syndromes.46
Approximately 50 percent of patients with Japanese encephalitis and 30 percent of patients with St. Louis encephalitis have elevated cerebrospinal fluid opening pressures. Brain swelling is seen at autopsy, although herniation is not often reported.7,33,51 Distinguishing the clinical signs of brain-stem herniation from those of direct viral damage in the brain stem may be difficult, but the possibility of this reversible complication should not be overlooked. Severe brain-stem encephalitis may result in the locked-in syndrome.27
Poliomyelitis-Like Paralysis
Motor weakness is common in patients with flavivirus encephalitis. In addition to weakness of the upper motor neurons, which is reported in 30 to 50 percent of patients, flaccid weakness of the limbs, with reduced or absent reflexes, is also common. This weakness is associated with respiratory or bulbar paralysis and is reported in approximately 20 to 60 percent of patients.24,27,45,52 In addition to causing flaccid weakness in comatose patients who have encephalitis, flaviviruses can also cause an acute flaccid paralysis similar to that of poliomyelitis in fully conscious patients. The earliest outbreaks of Murray Valley encephalitis were thought to be an aberrant form of poliomyelitis,53 and illness that resembles poliomyelitis has been described in patients infected with Japanese encephalitis virus54 and those with West Nile viruses.55,56,57,58
Nerve-conduction studies typically show reduced or absent compound muscle action potentials, with preserved sensory-nerve action potentials and normal conduction velocities.54,57,58 Although initially ascribed by some to the Guillain–Barré syndrome, in most cases these responses probably indicate damage to the lower motor neurons in the anterior horns of the spinal cord (i.e., anterior myelitis), as seen at autopsy53,58,59,60,61,62 and on imaging of the spinal cord.52,57 However, demyelination, involvement of the sensory nerves, and radiculitis also occur occasionally.27,63,64 Electromyography typically shows positive sharp waves and spontaneous fibrillations, which are consistent with denervation. Acute retention of urine owing to an atonic bladder may be an early clue that paralysis is the result of a flavivirus.44,54 In some patients, damage to both upper and lower motor neurons can lead to bizarre mixtures of clinical signs, which may change hourly during the acute stages of infection.
Parkinsonian Movement Disorders
In Japanese encephalitis, movement disorders are common, both in the acute stages of infection and as part of the sequelae. In one recent series of cases, one quarter of patients had acute manifestations.46 A characteristic "parkinsonian syndrome" includes mask-like facies, tremors, and cogwheel rigidity. Other movement disorders include generalized rigidity, jaw dystonia, opisthotonos, choreoathetosis, orofacial dyskinesias (e.g., involuntary tongue protrusions), myoclonic jerks, and opsoclonus myoclonus.46,65 Similar movement disorders have been reported for Murray Valley encephalitis, St. Louis encephalitis, and, more recently, West Nile encephalitis27,66,67 and are thought to be the clinical correlate of the inflammation often seen in the basal ganglia — particularly the thalamus and substantia nigra — on magnetic resonance imaging and at autopsy (Figure 3).33,44,46,59,65,66,68,69,70,71,72 In some patients, intention tremors and ataxia may suggest cerebellar involvement.27
Figure 3. T2-Weighted Magnetic Resonance Images Showing High Signal Intensity and Swelling in the Thalamus (Arrows) of Patients with Japanese Encephalitis (Panel A), West Nile Encephalitis (Panel B), and Murray Valley Encephalitis (Panel C).
Panel B is adapted from Solomon et al.,66 and Panel C is adapted from Kienzle and Boyes.68
Diagnosis and Treatment
Attempts to isolate virus from the blood of patients with flavivirus encephalitis are usually unsuccessful because viremia is transient and titers are low. Virus is occasionally isolated from the cerebrospinal fluid of patients who do not yet have antibody, particularly those who subsequently die,23,26 and from postmortem brain tissue.7,23,73 Viral ribonucleic acid occasionally may be detected in the cerebrospinal fluid by the reverse transcriptase polymerase chain reaction (PCR)74,75; for West Nile virus, real-time PCR has proved more useful.76 However, the accepted standard for diagnosing flavivirus encephalitis is the IgM capture enzyme-linked immunosorbent assay (ELISA). This assay will often detect antibody on a single cerebrospinal fluid or serum sample.1,3 Not all patients have antibody on admission to the hospital, and the test should be repeated if it is initially negative. False positive results can occur in patients who live in areas where more than one flavivirus circulates or in patients who have received a flavivirus vaccine, but this problem can be minimized by parallel testing for antibody against various flaviviruses.77,78,79 Assays for neutralizing antibodies are more specific than ELISAs but can be performed only in specialized laboratories that can grow dangerous viruses. Antibody may persist in the serum for many months after infection.80,81
There is no established antiviral treatment for any flavivirus infection. The most promising compound was interferon alfa. This is produced naturally in patients with flavivirus infections, and recombinant interferon alfa has efficacy in some animal models. Interferon alfa was reported to have shown promise in open clinical trials against Japanese encephalitis82 and St. Louis encephalitis83 and, on that basis, was given empirically to patients with West Nile encephalitis during 2002. However, a randomized, double-blind, placebo-controlled trial of interferon alfa in Vietnamese children with Japanese encephalitis showed that it had no effect on the outcome.84 Ribavirin and intravenous immune globulin also have been given empirically to patients with West Nile encephalitis.85,86 There are supportive data from animal models for the use of immune globulin,87 and a clinical trial has been set up by the National Institute of Allergy and Infectious Diseases. Treatment of flavivirus encephalitis currently consists of managing the complications of infection and, with good nursing care and physical therapy, avoiding bedsores and contractures. Even with intensive therapy, severe neuropsychiatric sequelae are common in survivors (Table 1).
Future Prospects
Formalin-inactivated and live attenuated vaccines against Japanese encephalitis exist, but because of costs and logistics, they are not available to much of the population of rural Asia that needs them.88 The inactivated vaccine is licensed in the United States, but there is some controversy about which travelers to Asia should receive it.89 A three-dose regimen (administered on days 0, 7, and 30) is recommended for travelers who spend prolonged periods (i.e., more than one month) in the rural parts of Asia where Japanese encephalitis is endemic or epidemic.90 However, because Japanese encephalitis has appeared in short-term travelers, some physicians recommend more liberal use of the vaccine.91 Approximately 20 percent of vaccine recipients have local cutaneous or mild systemic reactions. More serious allergic reactions occur in about 0.6 percent of recipients. Vaccines against St. Louis encephalitis have never been fully developed because the disease burden has not been considered great enough. A crude formalin-inactivated vaccine against West Nile virus is being used to protect horses (in which encephalitis can also develop). Newer vaccines that are being developed for flavivirus encephalitis include DNA vaccines and chimeric vaccines.88,92 Further research is needed to understand the pathogenesis of flavivirus encephalitis and thus to provide a rational approach to new treatments.
Supported by grants from the Wellcome Trust. Dr. Solomon is a Wellcome Trust Career Development Fellow.
I am indebted to my many colleagues and friends in Asia, Africa, the United States, and the United Kingdom whose data and insights have helped to shape this review.
Source Information
From the Departments of Neurological Science and Medical Microbiology, University of Liverpool, Liverpool, United Kingdom.
Address reprint requests to Dr. Solomon at the Department of Neurological Science, University of Liverpool, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, United Kingdom, or at tsolomon@liv.ac.uk.
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