Japanese encephalitis virus infection

Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 26

Japanese encephalitis virus infection MICHAEL J. GRIFFITHS1,2*, LANCE TURTLE1, AND TOM SOLOMON1,3,4 Institute of Infection and Global Health, University of Liverpool, Liverpool, UK

1

2

Alder Hey Children’s NHS Foundation Trust, Liverpool, UK 3

Walton Centre NHS Foundation Trust, Liverpool, UK

4

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK

INTRODUCTION Japanese encephalitis (JE) is numerically one of the most important causes of viral encephalitis worldwide, with an estimated 67 900 cases and 20 400 deaths annually (Campbell et al., 2011). Twenty-four countries are reported to be endemic for JE virus (JEV) within Asia and the Western Pacific rim, with outbreaks also reported outside these regions, such as in Northern Australia (Campbell et al., 2011). Although, only a minority of those infected with the virus develop JE, the impact of the disease is devastating. Typically 20–30% of patients with JE die, and 30–50% of survivors have severe and often persistent neurologic, cognitive, and/or behavioral problems (Solomon et al., 2002).

HISTORIC PERSPECTIVE Epidemics of encephalitis were described in Japan from the 1870 s onwards. The term type B encephalitis was used originally to distinguish these summer epidemics from von Economo’s encephalitis lethargica (sleeping sickness, and then known as type A encephalitis), but the “B” has since been dropped. In 1933 a filterable agent was transmitted from the brain of a fatal case of JE to cause encephalitis in monkeys; the prototype Nakayama strain of JEV was isolated from the brain of a fatal case in 1935. The virus was later classed as a member of the genus Flavivirus (family Flaviviridae), named after the prototype yellow fever virus (Latin; yellow ¼ flavi) (Solomon et al., 2000).

EPIDEMIOLOGY Molecular virologic studies have traced flaviviruses back to a common viral ancestor that evolved some

10 000–20 000 years ago (Gould et al., 1997). Although flaviviruses are genetically closely related, they are found in geographically different parts of the globe. JEV is transmitted by Culex mosquitoes. Being transmitted by mosquitoes, it is thus an arthropod-borne virus, or arbovirus; arthropods means insects or ticks. Examples of other mosquito-borne neurotropic flaviviruses include Murray Valley encephalitis virus in Australia, and St. Louis encephalitis virus in North America. West Nile virus was found in Africa and the Middle East, but in recent years has caused outbreaks of encephalitis in Southern Europe, and has reached America, where it rapidly spread across the continent (Solomon and Vaughn, 2002). In northern Europe and northern Asia, flaviviruses have evolved to use ticks as vectors. Far Eastern tick-borne encephalitis virus (also known as Russian spring–summer encephalitis virus) is endemic in the forests of central Europe and Russia. It is transmitted between small mammals by hard (Ixodid) ticks (Turtle et al., 2012). In the United Kingdom the tick-borne louping-ill virus is enzootic in sheep, and occasionally causes encephalitis in sheep and humans (Davidson et al., 1991).

Enzootic cycle JEV is zoonotic. The virus is naturally maintained and transmitted between a wide range of vertebrates by mosquitoes, primarily Culex tritaeniorhynchus in Asia. Animals which develop high viremias, such as herons and egrets, are important in maintaining a natural reservoir of virus during the enzootic cycle (Fig. 26.1). Rice fields are the preferred development sites for C. tritaeniorhynchus as well as the main foraging site for water birds; thus rice fields provide an important site

*Correspondence to: Michael J. Griffiths, Institute of Infection and Global Health University of Liverpool, 8 West Derby Street, Liverpool L69 7BE, UK. E-mail: [email protected]

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Fig. 26.1. The enzootic cycle and transmission of Japanese encephalitis virus (JEV). JEV is maintained in birds (particularly wading birds such as herons and egrets), transmitted by Culex mosquitoes. The virus can be transmitted to pigs, usually during the rainy season. In pigs there is sufficient viremia to act as a reservoir for transmission to humans, from where it is no longer transmitted any further. (Adapted from Solomon, 2004, with permission).

for birds and mosquitoes to meet. Pigs are a key host responsible for human transmission. Pigs are often kept close to humans, have prolonged and high viremias, and produce many offspring, thus providing a continuous supply of fresh uninfected new hosts. When mosquito populations become high, virus transmission can spill over from the mosquito–bird–pig cycle to humans living or traveling in close proximity to these host animals. In humans, viremias are usually brief and titers low; thus humans are a “dead end” for the virus’ enzootic cycle, from which further transmission does not normally occur. Two major risk factors of human infection are close proximity to rice fields and pigsties (Impoinvil et al., 2011).

Epidemiology of human disease JE is predominantly a disease of childhood, with 75% of cases being children under 14 years. Among unvaccinated populations in endemic areas, children are frequently affected, with the ratio between children and adult cases being typically 7:1 (Campbell et al., 2011). Most infections of humans are asymptomatic or cause a non-specific flu-like illness; estimates of the ratio of symptomatic to asymptomatic infection vary between 1 per 25 and 1 per 1000 (Huang, 1982). In the 1980s, prior to establishment of a JE control program, JE was endemic in Thailand, with 1500–2000 cases reported annually (Chunsuttiwat, 1989). The incidence was estimated to be up to 40 per 100 000 for ages 5–25, declining to almost zero for those over 35 in northern Thailand (Hoke et al., 1988; Solomon and Vaughn, 2002). The incidence was lower among young children

(<3 years old) than in older children, possibly reflecting behavioral factors, for example, playing outside after dusk (Vaughn and Hoke, 1992). Between 2005 and 2008, following 20 years of a national and multifaceted JE control program (involving education, vector control, and vaccination), the incidence of JE has fallen dramatically to 297–418 per year. Nevertheless, 10% of encephalitis patients enrolled in Bangkok hospitals are still reported to have JEV infection (Olsen et al., 2010). Broadly speaking, two epidemiologic patterns of JE are recognized. In northern areas (northern Vietnam, northern Thailand, Korea, Japan, Taiwan, China, Nepal, and northern India) huge epidemics occur during the summer months, whereas in southern areas (southern Vietnam, southern Thailand, Indonesia, Malaysia, Philippines, Sri Lanka, and southern India), JE tends to be endemic, and cases occur sporadically throughout the year, with a peak after the start of the rainy season (Vaughn and Hoke, 1992). Various explanations for these different epidemiologic patterns have been offered. Climatic variation is regarded as a key factor. Changes in both temperature and precipitation are capable of affecting JEV transmission. Changes in temperature act primarily through their influence on the development speed of immature mosquito stages (i.e., larvae and pupae), the mosquito population abundance, and the extrinsic incubation period of the virus in the mosquito (Reisen et al., 1976; Takahashi, 1976; Olson et al., 1983; Murty et al., 2010). Precipitation also influences development time of immature mosquito stages and may concentrate animal hosts around water sources. Studies of JE epidemiology in Japan demonstrated that transmission was associated with high temperature and low rainfall (Mogi, 1983). Studies in Nepal (Impoinvil et al., 2011), China (Bi et al., 2007), and Taiwan (Hsu et al., 2008) have also found significant temporal associations between climate and JEV transmission with differing lags between climatic changes and increased JE transmission.

Geographic distribution of JEV In the past 50 years the geographic area affected by JEV has expanded (Fig. 26.2). Differences in diagnostic capabilities and in reporting of encephalitis make it impossible to plot this expansion precisely. However, the timing of the first reported cases or new epidemics in each area gives an impression of the relentless spread of JE. In China outbreaks of summer encephalitis occurred from 1935, and the virus was first isolated there in 1940; there are currently 10 000–20 000 cases a year, although in the early 1970s it was over 80 000 cases annually . In the far eastern Russian states, JE first occurred in 1938. In 1949, large epidemics were reported from South Korea for the

JAPANESE ENCEPHALITIS VIRUS INFECTION

Fig. 26.2. Distribution of Japanese encephalitis virus (JEV). JEV is endemic to most of South and Southeast Asia, an area with a population of around 2.5 billion people. The historic spread of JE outbreaks from the first description in Japan in the 1870 s to the appearance in Northern Australia in the late 1990s is shown. (Adapted from Solomon and Winter, 2004, with permission.)

first time. Epidemics in northern Vietnam followed in 1965 and in Chiang Mai in northern Thailand in 1969 (Solomon et al., 2000). JE was recognized in southern India from 1955, but was confined to the south until the 1970s. Since then, large outbreaks (2000–7000 cases a year) have been reported from eastern and northeastern states. The fact that adults and children were equally affected in these Indian states strongly supports the idea that the virus was introduced here for the first time. The late 1970s also saw the first cases in Burma and Bangladesh, and large epidemics (up to 500 cases a year) in southwestern Nepal. In 1985 Sri Lanka experienced its first epidemic, with 410 cases and 75 deaths. JEV continues to spread west, with cases occurring in Pakistan (Igarashi et al., 1994) and new epidemics in the Kathmandu valley of Nepal (Zimmerman et al., 1997). Charting the progression of the disease southeast across Asia and the Pacific rim is harder because sporadic cases in endemic areas do not command the same attention as the massive epidemics that occur in temperate climates. The disease has occurred on the western Pacific islands, with outbreaks in Guam in 1947 and Saipan in 1990. In Malaysia the disease is endemic; the virus was first isolated in the 1960s and about 100 cases are recorded annually (Solomon et al., 2000). Occasionally outbreaks of encephalitis from other causes can be confused with JE. For example, in the late 1990s there was an epidemic of a previously unidentified encephalitic virus. This RNA paramyxovirus (named

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Nipah virus) is similar to the Australian Hendra virus and was transmitted to humans (especially abattoir workers and farmers) from the bodily fluids of pigs (Chua et al., 1999). JE is endemic in Indonesia, and 1000–2500 cases of encephalitis are reported annually, although in most, the etiologic agent is not confirmed (Wuryadi and Suroso, 1989). Further east, JE occurs sporadically in the Philippines and New Guinea. The first cases occurred in the Australian Torres Strait islands in 1995 (Hanna et al., 1996) and it was reported for the first time north of Cairns on the Australian mainland in 1998 (Hanna et al., 1999). The reasons for the geographic spread of JE are incompletely understood, but probably include changing agricultural practices, such as increased rice field planting and increased irrigation (which allows mosquito breeding), and animal husbandry (which provides host animals). In Indonesia, the lower prevalence of antibody to JEV in Borneo than neighboring Bali has been attributed to the lack of pigs in this predominantly Muslim culture (Wuryadi and Suroso, 1989). In developed countries such as Japan, Taiwan, and South Korea the number of cases has fallen, probably due to a combination of mass vaccination of children, spraying of pesticides, changing pig-rearing practices, separation of housing from farming, better housing with air conditioning, and less availability of mosquito-breeding pools (Innis, 1995).

VIROLOGY Akin to all flaviviruses, JEV has a small (50 nm) lipoprotein envelope surrounding a nucleocapsid comprising core protein and positive-sense single-stranded RNA This RNA strand is 11 kb in length in JEV (McMinn, 1997). The virion’s outer surface is comprised of a lipid membrane, derived from the host cell, in which are embedded the viral envelope (E) and pre-membrane (prM) proteins. During viral release from the cell, prM is cleaved to its mature membrane (M) protein form which yields the mature, infectious virus particle (Lindenbach et al., 2007). Packaged within the lipid and protein envelope is the viral genome which is complexed with the viral capsid (C) protein. For JEV, as for most flaviviruses, the E protein is responsible for virus attachment to and fusion with target cell membranes. Consequently, the E protein is the primary target for neutralizing antibodies and a critical component of any vaccine. The complete nucleotide sequence has been published, and includes 5’ and 3’ untranslated regions, and a single open reading frame encoding genes for the three structural proteins, C, PrM and E, as well as seven nonstructural proteins (NS1–7) (McMinn, 1997).

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Nucleotide sequencing and phylogenetic studies have defined four major genetic subtypes (genotypes) of JEV, with a fifth genotype represented by a single Muar strain (Huang, 1982; Vaughn and Hoke, 1992). The genotypes differ by approximately 10–20 and 2–6% at the nucleotide and amino acid sequence levels, respectively. In most endemic areas, multiple genotypes of JEV are present, although periodic changes in the dominant types have been reported (Pyke et al., 2001; Beasley et al., 2008). Antigenic differences have been reported to exist between JEV strains (Hasegawa et al., 1994), but it has also been suggested that the limited diversity at the amino acid level is consistent with them comprising a single serotype. Any JEV strain used as the basis for a vaccine antigen is expected to stimulate significant protection against all JEV genotypes. Existing JEV vaccines are based on genotype III strains, and neutralization assays against heterologous strains as well as passive immunization studies in mice have demonstrated that significant crossprotection probably does exist, although neutralizing antibody titers against heterologous strains are invariably lower (Monath et al., 2003; Beasley et al., 2004). Experimental studies in small animal models (mice) have demonstrated differences in the neurovirulence characteristics of various JEV strains, although at the present time there is no clear evidence to suggest enhanced virulence of strains in one genotype over another (Higgs and Gould, 1991; Ni and Barrett, 1996).

CLINICAL FEATURES Only about 1 in 25 to 1 in 1000 humans infected with JEV develop clinical features of infection (Halstead and Grosz, 1962; Huang, 1982; Vaughn and Hoke, 1992). These may range from a mild flu-like illness to a fatal meningoencephalomyelitis.

Encephalitis Patients with JE typically present after a few days of non-specific febrile illness, which may include coryza, diarrhea, and rigors. These non-specific features are followed by headache, vomiting, and a reduced level of consciousness, often heralded by a convulsion. In some patients, particularly older children and adults, abnormal behavior may be the only presenting feature, resulting in an initial diagnosis of mental illness (Solomon et al., 2000; Solomon and Vaughn, 2002). The classic description of JE includes a dull, flat, masklike facies with wide unblinking eyes, tremor, generalized hypertonia, and cogwheel rigidity. Opisthotonus and rigidity spasms, particularly on stimulation, occur in about 15% of patients and are associated with a poor prognosis. Other extrapyramidal features include head nodding and pill

Fig. 26.3. Dystonic posturing involving the left hand in an Indian child several months after acute Japanese encephalitis (JE). JE infection involves the extrapyramidal system, leading to parkinsonian features. (Courtesy of T. Solomon.)

rolling, dystonic posturing, opsoclonus-myoclonus, choreoathetosis, bizarre facial grimacing, and lip smacking (Kumar et al., 1990; Misra and Kalita, 1997; Solomon et al., 2000; Fig. 26.3). Upper motor neuron facial nerve palsies occur in around 10% of children and may be subtle, or intermittent. A proportion of patients make a rapid spontaneous recovery (so-called abortive encephalitis). Others may present with aseptic meningitis and have no encephalopathic features (Solomon et al., 2000). Changes of respiratory pattern, flexor and extensor posturing, and abnormalities of the pupillary and oculocephalic reflexes are poor prognostic signs (Kumar et al., 1990; Hoke et al., 1992; Solomon et al., 2002) and may reflect encephalitis in the brainstem (Innis, 1995). However in some patients a clear rostrocaudal progression of brainstem signs, an association with high cerebrospinal fluid (CSF) opening pressures, and a reversal of signs on aggressive management of raised intracranial pressure suggest that transtentorial herniation may also contribute (Solomon et al., 2002). Convulsions often occur in JE, and have been reported in up to 85% of children (Poneprasert, 1989; Kumar et al., 1990) and 10% of adults (Dickerson et al., 1952; Solomon et al., 2002). Generalized tonicclonic seizures occur more frequently than focal motor seizures, with up to a third of children exhibiting only subtle clinical manifestations with the seizures. Clinical manifestations of subtle seizures include: minimal intermittent clonic movements (twitching) of a digit, eyebrow, eyelid, or mouth; twitching plus nystagmus, eye deviation, excess salivation or irregular breathing; nystagmus and excess salivation; or isolated tonic eye deviation. Based on work in Vietnam, over half of the patients with generalized tonic-clonic seizures and all of those with subtle seizures were in status epilepticus.

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Given multiple or prolonged seizures and status epilepticus are all associated with higher rates of death and poor outcome, it is vital these seizures are recognized. However, without electroencephalographic monitoring these seizures can be difficult to identify (Solomon et al., 2002).

Acute flaccid paralysis We have previously identified a subgroup of patients infected with JEV who presented with a poliomyelitislike acute flaccid paralysis (Solomon et al., 1998a). After a short febrile illness there was a rapid onset of flaccid paralysis in one or more limbs, despite a normal level of consciousness. Weakness occurred more often in the legs than the arms, and was usually asymmetric. Thirty percent of such patients subsequently developed encephalitis, with reduced level of consciousness, and upper motor neuron signs, but in most acute flaccid paralysis was the only feature. At follow up (1–2 years later) there was persistent weakness and marked wasting in the affected limbs. Nerve conduction studies demonstrated markedly reduced motor amplitudes, and electromyogram showed a chronic partial denervation, suggesting anterior horn cell damage (Solomon et al., 1998a). Flaccid paralysis also occurs in comatose patients with “classic” JE, being reported in 5–20% (Dickerson et al., 1952; Kumar et al., 1991). Electrophysiologic studies have confirmed anterior horn cell damage, and magnetic resonance imaging (MRI) of the spinal cord showed abnormal signal intensity on T2-weighted images (Kumar et al., 1997). Occasionally respiratory muscle paralysis may be the presenting feature (Tzeng, 1989).

Fig. 26.4. Fixed flexion deformity of the upper limbs following Japanese encephalitis in a Malaysian boy. (Courtesy of T. Solomon.)

OUTCOME The global burden of disability secondary to JE is estimated at 709 000 disability-adjusted life years (DALY). In comparison, malaria has an estimated global burden of 46 000 000 DALY (Mathers et al., 2007; Campbell et al., 2011). This makes JE responsible for a higher burden of disability than any other arthropod-borne virus. About 30% of patients admitted to hospital with JE die, and around half of the survivors have severe neurologic sequelae. About 30% of survivors have frank motor deficits. These include a mixture of upper and lower motor neuron weakness, and cerebellar and extrapyramidal signs (Simpson and Meiklejohn, 1947; Richter and Shimojyo, 1961). Fixed flexion deformities of the arms and hyperextension of the legs with “equine feet” are common (Figs 26.4 and 26.5). Twenty percent of survivors have severe cognitive and language impairment (most with motor impairment also). Another 20% of survivors suffer seizures (Kumar

Fig. 26.5. Hyperextension of the ankles giving “equine” feet following Japanese encephalitis. (Courtesy of T. Solomon.)

et al., 1993; Huy et al., 1994). A higher rate of sequelae is reported for children than adults (Schneider et al., 1974). Follow-up studies have shown that the functional impact of JE continues to evolve following hospital discharge. Over a third of patients show functional improvement at follow-up (3 months or more after hospital discharge), whereas almost a fifth exhibit functional deterioration (Ooi et al., 2008; Griffiths

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Table 26.1 A simple 15-point scoring system for assessing disability after encephalitis* History from child/parents/carers Speech Feeding Can the child be left alone? Behavior Recognition (other than the main carer) School/work

Seizures in the last 2 months

Ability to dress Urinary and fecal continence Hearing Observation of the child Sitting Sitting to standing Observe the child walking for 5 meters Put both hands on your head; ask child to copy Pick up small object

The same as other children of this age (5) / Reduced (3) / Not speaking or communicating (2) The same as other children (5) / Occasionally needs help (3) / Always needs more help (2) Too young or yes (5) / Yes, briefly, in familiar environment (3) / No (2) Normal (5) / Gets angry easily (4) / Other behavioral problems (4) / Severely abnormal (2) Too young or yes (5) / Some (3) / None (2) Now back to normal at school or work (5) / Not doing as well (4) / Dropped a school grade or no longer attending school or work (3) If too young: Still able to do the same tasks at home and follow the same routine (5) / Not able to do as well as before (4) / Not able to do at all (3) No seizures and not on antiepileptic drugs (5) / No seizures and on antiepileptic drugs (4) / Yes, has had seizures (3) / Yes, seizures most days (2) The same as other children the same age (5) /Occasionally needs extra help (3) / Always needs more help than other children of the same age (2) The same as other children the same age (5) / Needs more help or is incontinent of bowel or bladder (2) Normal (5) / Reduced in one or both ears (4) / Cannot hear at all (3) Too young or yes, independently (5) / Needs help (3) / Not at all (2) Too young or yes, independently (5) / Needs help (3) / Not at all (2) Too young or normal (5) / Abnormal, but independently  crutches/stick (3) / Not able to walk (2) Too young (5) / Normal, both hands (5) / Abnormal, one or both hands (4) / Unable, one or both hands (3) Too young (5) / Normal pincer grasp both hands (5) / Unable, one hand (3) / Abnormal, one hand or both hands (3) / Unable, both hands (2)

*Specific scoring for each domain is shown. The overall score is the lowest score obtained for any question and therefore is scored from 5 (normal) to 1 (death). A score of 4 indicates mild disability such as behavioral problems, 3 indicates disability significant enough to affect function but leaves capacity for independent living, and 2 indicates disability severe enough to prevent independent living. The score is archived (at the time of writing) at http://www.webcitation.org/65R5BbmkF. Check http://www.liv.ac.uk/infection-and-global-health/research/brain-infections-group/education/ for updated information. Based on Lewthwaite et al. (2010a).

et al., 2013). Behavioral problems and a reduction in educational attainment are commonly reported at follow-up (Ooi et al., 2008; Hills et al., 2011). A simple scoring system, the Liverpool outcome score (Table 26.1; and available at http://www.webcitation.org/65R5BbmkF), has been developed to assess the degree of impairment after JE (or any other form of encephalitis). This score was developed in Asia and is specifically designed for use in children in low-resource settings and to be adaptable across different cultural settings (Lewthwaite et al., 2010a).

INVESTIGATIONS A neutrophil predominance is frequently seen in peripheral blood, and hyponatremia may occasionally occur as a consequence of inappropriate antidiuretic hormone secretion. The CSF opening pressure is increased in about 50% of patients. High pressures (>25 cm CSF)

are associated with a poor outcome. Typically there is a moderate CSF pleocytosis – median 53 (range 10–100) cells/mm3, with predominant lymphocytes, mildly increased protein – median 62 (range 13–168) mg/dL, and a normal glucose ratio. However, polymorphonuclear cells may predominate early in the disease, or there may be no CSF pleocytosis (Solomon et al., 2002). A range of imaging changes in JE have been described (Shoji et al., 1989, 1994; Kalita et al., 2003; Dung et al., 2009). The most commonly described imaging abnormalities are in the thalamus, where low-density lesions are seen on computed tomography, and high signal intensities are seen on T2-weighted MRI, as well as hemorrhagic changes. Other changes have been observed in the substantia nigra, the nucleus lentiformis of the basal ganglia, the caudate nucleus, the internal capsule, the midbrain, pons, cerebrum, and cerebellum (Misra et al., 1994; Kumar et al., 1997; Misra and Kalita, 1997).

JAPANESE ENCEPHALITIS VIRUS INFECTION Thalamic abnormalities, when seen, may assist in distinguishing JE from patients with acute encephalitis due to other causes. In one Vietnamese study, abnormalities in the thalamus were detected in 22% of serologically confirmed JE cases that underwent imaging. These abnormalities had a very high specificity (100%) but a low (22%) sensitivity for JE (Dung et al., 2009). Single photon emission tomography (SPECT) studies carried out acutely have shown hyperperfusion in the thalamus and putamen (Kimura et al., 1997). Follow-up imaging studies of JE patients have shown hypoperfusion in the same areas, as well as in the frontal lobes (Shoji et al., 1990). Various electroencephalographic abnormalities have been also reported in JE, including theta and delta coma, burst suppression, epileptiform activity, and occasionally alpha coma (Kalita and Misra, 1998; Solomon et al., 2002). Although not often confused, diffuse slowing may be useful in distinguishing JE from herpes simplex virus, in which changes are characteristically frontotemporal (Misra and Kalita, 1998). Measurement of evoked potentials shows delays of central motor conduction times consistent with widespread involvement at cortical and subcortical levels (Misra et al., 1994). The differential diagnosis of JE is broad and includes other viral encephalitides (arboviruses, herpesviruses, enteroviruses, and postinfectious and postvaccination encephalomyelitis), other central nervous system (CNS) infections (bacterial and fungal meningitis, tuberculosis, cerebral malaria, leptospirosis, tetanus, abscesses), other infectious diseases with CNS manifestations (typhoid encephalopathy, febrile convulsions), and non-infectious diseases (tumors, cerebrovascular accidents, Reye’s syndrome, toxic and alcoholic encephalopathies, and epilepsy). Where other flaviviruses circulate they should also be included in the differential (Innis, 1995; Solomon et al., 2000). Even viruses which are not traditionally considered as neurotropic may cause CNS disease, and only with appropriate diagnostic tests can viruses such as West Nile virus and dengue viruses be distinguished from JEV (Kedarnath et al., 1984; Solomon et al., 2000).

DIAGNOSIS There is no routine laboratory parameter that is specific for JE diagnosis. A definitive diagnosis is made by finding anti-JEV-specific immunoglobulin M (IgM) in the CSF of a patient in the context of acute encephalitis syndrome (Burke et al., 1985b). JEV is rarely isolated from clinical specimens. By the time encephalitis has developed, the viraemia is typically over (Sapkal et al., 2007). Virus is occasionally grown from CSF; such cases are more likely to be fatal (Burke et al., 1985a; Leake et al., 1986). Viral antigen–antibody complexes are detectable in the CSF

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in some patients (Desai et al., 1995). The virus may also be detected in the CSF by real-time reverse transcriptase polymerase chain reaction. However, its reliability as a routine diagnostic test has not been confirmed (Swami et al., 2008). If CSF is not available then the diagnosis can be supported by the finding of anti-JEV IgM in serum or a fourfold rise in neutralizing antibody titer between acute and convalescent samples; in practice the convalescent titer is seldom measured. Commercially manufactured kits are available for JEV serodiagnosis (Ravi et al., 2006, 2009; Lewthwaite et al., 2010b). These are all IgM capture enzyme-linked immunosorbent assays (ELISAs) and are validated variously for use in serum and CSF. A rapid filter paperbased test suitable for field use has also been developed (Solomon et al., 1998b). The IgM ELISAs are reasonably specific, though there are problems differentiating JEV from other flaviviruses in areas where different flaviviruses co-circulate, i.e., Asia. If a JE case is suspected in a non-endemic area the diagnostic laboratory should ideally be consulted prior to testing to ensure the appropriate tests are done and are interpreted correctly. In travelers who may have been vaccinated, a complete flavivirus vaccination history (JE, tick-borne encephalitis, yellow fever) is essential to allow the serology results to be correctly interpreted. In cases where samples are obtained after the acute phase, plaque reduction neutralization titers represent the most sensitive and specific tool for determining prior infection. However, such assays require the culture of live virus and take around a week to perform each assay so their use remains restricted to research. Anti-JEV neutralizing antibody is the standard endpoint for vaccine trials. IgG ELISA kits exist for some flaviviruses but again their specificity has not been fully evaluated.

PATHOGENESIS The pathogenesis of JE remains incompletely understood. Aspects of viral replication, CNS invasion, and the nature of the immune response are still being uncovered. Viral factors such as route of entry, titer, and genetic variation within the virus no doubt play an important role, but host factors such as pre-existing immunity, general health, age, and variations in the host immune responses are also likely to be critical determinants of clinical outcome.

Viral entry and replication Based on data from mice and macaque monkeys, following inoculation from the bite of an infected mosquito, virus is thought to undergo replication in the local tissues mainly in resident macrophages (Langerhans cells). Following replication, virus disseminates to the local lymph nodes where further replication in monocyte lineage

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cells takes place. This results in a viremia that is followed later by viral spread to the brain. In mice, high rates of JEV replication within dendritic cells are linked to higher overall mortality (Wang and Deubel, 2011). Similarly, stopping early viral replication in monocyte lineage cells using small-interfering RNAs prevents development of encephalitis in animal models of West Nile virus and St. Louis encephalitis virus. Autophagy (internal phagocytosis for recycling cell components), which is known to be important in dengue and hepatitis C virus replication, is also involved in early JEV replication. Enhancement of autophagy increased JEV replication and inhibition reduced JEV replication (Li et al., 2012). How the neurotropic flaviviruses gain access to the CNS remains unclear. In experimental studies with a hamster model of St. Louis encephalitis virus (a related flavivirus), the olfactory route was shown to be important (Monath et al., 1983). Intranasal spraying is also an effective means of experimentally inoculating monkeys (Myint et al., 1999). However immunohistochemical staining of human postmortem material has shown diffuse infection throughout the brain, indicating a hematogenous route of

entry (Johnson et al., 1985; Desai et al., 1995). Interactions at the blood–brain barrier (BBB) are probably critical. For example, clinical and pathologic studies have repeatedly observed that co-infection with neurocysticercosis (which compromises the BBB) increases the risk of developing encephalitis following infection with the virus (Desai et al., 1997). Passive transfer of the virus across the endothelial cells of the BBB (Dropulic and Masters, 1990; Liou and Hsu, 1998) or within leukocytes that migrate across the BBB has been the suggested mechanism of CNS entry for JEV. Based on experimental evidence in other flaviviruses, replication within the endothelial cells may also be an important mechanism.

Inflammatory changes Once in the CNS, there are many mechanisms by which JEV induces neuronal damage and cell death leading to the clinical manifestations of disease. Postmortem studies show a striking inflammatory response in the brain of patients who have died of JE (Zimmerman, 1946; Miyake, 1964; Johnson et al., 1985; German et al., 2006; Fig. 26.6A–E). The brain

Fig. 26.6. Characteristic brain histopathology in Japanese encephalitis. (A) Perivascular mononuclear cuffing and hemorrhage in human brain parenchyma (arrow). Hematoxylin and eosin (HE) stain; magnification  400. (B) Perivascular lymphocytic infiltrate around a vein containing a fibrin plug (HE stain  100). (C) Congested vessel centrally, surrounded by edema (white regions) and secondarily damaged myelin sheaths (arrow) in human brain parenchyma. Toluidine stain (200). (D) Human cerebellum, showing well-preserved Purkinje cells, compared with the granular cells. A focal, punched-out, acellular necrotic lesion is visible in the molecular layer, associated with an end vessel (HE stain  40); (E) Immunohistochemical stain for JE virus (JEV) antigen (red). Viral antigen is present in the human vascular endothelium (arrow) (100). (F) Immunohistochemical stain for JEV antigen present in neurons (red). Additional neurons were observed to be undergoing apoptosis (arrows) away from the infected neurons, possibly as part of “bystander” or indirect cell damage secondary to host immune responses triggered by the JEV infection. Brain tissue from macaque monkeys infected with JEV (400). (A–E adapted from German et al., 2006, with permission; F from K.S. Myint and T. Solomon, unpublished.)

JAPANESE ENCEPHALITIS VIRUS INFECTION parenchyma is congested with focal petechiae or hemorrhage. Punched-out necrotic lesions often close to blood vessels have also been observed. The white matter usually appears normal, although myelin degradation and an autoimmune pattern of demyelination have been reported (Tseng et al., 2011). In some patients, the gray matter of the spinal cord is confluently discolored, resembling that of poliomyelitis (Haymaker and Sabin, 1947). The thalamus, basal ganglia, and midbrain are heavily affected, providing anatomic correlates for the tremor and dystonias which characterize JE. Invasion of the CNS by JEV is associated with marked perivascular inflammatory cuffing. The cuff is predominantly composed of lymphocytes with some mononuclear cells (Fig. 26.6A, B). Microglial activation is also observed within the brain parenchyma. Interestingly, brain tissue regions where JEV antigen is detected do not always correspond with areas of inflammatory response or cell damage (German et al., 2006; Myint and Solomon, unpublished; Fig. 26.6 F). Indeed, in patients who die rapidly, there may be no histologic signs of inflammation, but immune histochemical studies disclose viral antigen in morphologically normal neurons (Johnson et al., 1985; Li et al., 1988). Such observations have led to speculation about how much of the brain damage is directly due to virus-induced cell death and how much is due to “by-stander” cell death secondary to host inflammation. In the case of West Nile virus there appears to be a fine balance whereby immune factors can mediate viral clearance (Shrestha and Diamond, 2004; Klein et al., 2005; Zhang et al., 2008), but can also cause damage within the CNS (Wang et al., 2003; Zhang et al., 2010). JEV-infected mouse peripheral macrophages release mediators that induce apoptosis of uninfected neurons in vitro (Nazmi et al., 2011). In mice models of JE, attenuating the host inflammatory response by using minocycline (an antibiotic with anti-inflammatory properties) resulted in reduced CNS damage and improved survival (Mishra and Basu, 2008; Das et al., 2011).

Innate immunity Interferon-a (IFN-a) and associated downstream mediators of innate immunity have been shown to limit JEV replication in in vitro and animal models. Evidence is now accumulating for several IFN-related mediators to influence flavivirus infection in humans. 2’-5’ oligoadenylate synthetases (2’-5’ OAS) promote degradation of human and viral RNA. Single-nucleotide polymorphisms in genes encoding for these proteins are associated with susceptibility to infection with West Nile virus in humans (Lim et al., 2009). More recently, OAS2 and OAS3 from the same gene family have been implicated

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in susceptibility to tick-borne encephalitis virus in humans (Barkhash et al., 2010). IFN-a has been detected in the plasma and CSF of humans with JE (Solomon et al., 2000). Transcripts encoding for multiple mediators involved in innate immunity, including the OAS pathways, have also been observed to be elevated in patients with JE (Griffiths and Solomon, unpublished).

Humoral immunity Antibody responses are readily detectable in humans, forming the basis for diagnostic tests (IgM) and vaccine trial endpoints (virus neutralization). When disease is due to primary infection (when JEV is the first flavivirus with which a person has been infected), a rapid and potent IgM response occurs in serum and CSF within days of infection. By day 7 most patients have raised titers (Burke et al., 1985a, b). The development of neutralizing antibody after vaccination parallels protection from disease (Hoke et al., 1988). However, the failure to mount an IgM response is associated with positive virus isolation and a fatal outcome (Burke et al., 1985a; Leake et al., 1986). Lower antibody levels are associated with poor outcome (Libraty et al., 2002; Winter et al., 2004). However, many patients with JE exhibit high neutralizing antibody titers, suggesting that other factors are also likely to be involved. In surviving patients immunoglobulin class switching occurs, and within 30 days most have IgG in the serum and CSF. Asymptomatic infection with JEV is also associated with raised IgM in the serum, but not CSF. In patients with secondary infection (those who have previously been infected with a different flavivirus; for example, dengue infection or yellow fever vaccination) there can be an anamnestic response to flavivirus group common antigen (Burke et al., 1985b). This secondary pattern of antibody activation is characterized by an early rise in IgG with a subsequent slow rise in IgM.

Cellular immunity In animal models of JE, the cellular immune response seems to contribute to the prevention of disease during acute infection (Larena et al., 2011); transfer of cells from mice immunized with live attenuated virus conveys protection against JEV infection (KimuraKuroda and Yasui, 1988; Biswas et al., 2009). In contrast, spider monkeys, which are normally unaffected by intracerebrally inoculated JEV, develop rapidly progressive encephalitis when T-cell function has been impaired by cyclophosphamide (Nathanson and Cole, 1970). T-cell responses are detectable in humans infected with JEV, though such responses are often small

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(Konishi et al., 1995; Kumar et al., 2003, 2004a, b). A mixture of CD4þ and CD8 þ T-cell responses are seen in humans who have been naturally exposed in JEV-endemic areas whereas generally only CD4 responses are seen in people who have been given inactivated JE vaccine. In a cohort of children who had recovered from JE, there was a correlation between low T-cell IFN-g production and poor clinical outcome (Kumar et al., 2004c).

MANAGEMENT Treatment Treatment for JE is supportive. Supportive measures can have a significant impact on outcome (Solomon et al., 2000; Tiroumourougane et al., 2003; Rayamajhi et al., 2011). Appropriate fluid provision and management of shock are important, with patients who are unconscious at risk of dehydration. However, fluid should be given carefully, with aspiration pneumonia a potentially fatal complication in patients who are unconscious or suffering dysphagia. Complications such as raised intracranial pressure, seizures, and hyponatremia should be actively sought out and treated. Overhydration should also be avoided, especially in the setting of raised intracranial pressure. Appropriate sedation may also enhance survival (Tiroumourougane et al., 2003). Nursing care and physiotherapy should aim to prevent the development of contractures (that lead to fixed flexion deformities) and bedsores. Corticosteroids have been, and still are, widely used in many endemic areas for the management of JE. There have also been reports of steroids being used in West Nile encephalitis, though comprehensive data are lacking (Pyrgos and Younus, 2004). A randomized controlled trial showed dexamethasone to be of no benefit in JE (Hoke et al., 1992). However, the trial was small and some researchers argue that the question as to whether corticosteroids are useful in JE remains unanswered. IFN-a inhibits JEV replication in vitro. Levels of IFNa are elevated in CSF of patients with JE and IFN-a has some efficacy in animal models. However, a randomized placebo-controlled trial in humans failed to show any benefit (Solomon et al., 2003). Similarly, the antiviral drug ribavirin, though theoretically promising, did not turn out to be effective in a randomized controlled trial (Kumar et al., 2009a). Previously, monoclonal antibodies were shown to be effective in animal models of JE (Kimura-Kuroda and Yasui, 1988; Zhang et al., 1989). A pilot trial of pooled human intravenous immunoglobulin containing anti-JEV antibodies, showed it was a feasible treatment for Nepali child patients with JE

(Rayamajhi et al., unpublished). A larger trial is required to show if intravenous immunoglobulin is of benefit.

Prevention Broadly speaking, measures to control JE include those which interfere with the enzootic cycle of the virus, and those which prevent disease in humans. Measures to control breeding of Culex mosquitoes, such as the application of larvicides to rice fields, and insecticide spraying have proved ineffectual. Vaccines have been used to protect swine against the virus; however, widespread vaccination is not feasible in most settings. Residents and travelers to endemic areas should take personal protection to reduce the number of Culex bites. These include minimizing outdoor exposure at dusk and dawn, wearing clothing that leaves a minimum of exposed skin, using insect repellents containing at least 30% DEET (N,N-diethyl-3 methlybenzamide) and sleeping under bed nets. While these measures may be possible for the short-term visitor, most are not practical for residents of endemic areas (Solomon et al., 2000).

VACCINES Vaccines against JE have been available for immunization for many decades. The earliest JE vaccines used formalin inactivated JEV propagated in mouse brain or via cell culture. A live attenuated vaccine based on the SA1414-2 strain of JEV became available in the 1980s. More recently, a formalin inactivated vaccine based on the SA14-14-2 strain was been developed. The World Health Organization (WHO) provides recommendations on production and quality control of vaccines to guide national regulatory agencies and in order for appropriate vaccines to be “prequalified” so that funding for their use can be supported by United Nations agencies. To date, no JE vaccines are prequalified (Ferguson et al., 2007; Beasley et al., 2008).

Mouse brain inactivated vaccines Historically JE vaccines used formalin inactivated JEV grown in mouse brain. The Biken JE vaccine, manufactured in Japan, and the Korean Green Cross vaccine were made widely available after clinical trials in Thailand and Korea (Hoke et al., 1988; Solomon, 2008). Up until recently, these were the only JE vaccines licenced for use in the United Kingdom, continental Europe, and the United States. These vaccines are relatively poorly immunogenic and require multiple vaccinations to induce protective immunity. Dosing regimens vary, but typically include a two- to threedose primary immunization course with a booster at

JAPANESE ENCEPHALITIS VIRUS INFECTION 1, 3, or 5 years. A sero-survey in the Torres Strait demonstrated that only 32% of individuals who had received either the primary three-dose JE vaccine course and/or a subsequent booster dose had detectable neutralizing antibodies 3 years after their final vaccination (Hanna et al., 2005). Longer duration of neutralizing antibodies among pediatric or adult vaccinees has been reported (Abe et al., 2007). However, these differences may be associated with boosting of antibody levels by natural infection in endemic areas. Local reactions following mouse brain-derived vaccination are common. Tenderness, redness, and swelling at the injection site are reported in 20% of vaccinees. A smaller number experience symptoms such as headache, myalgia, and gastrointestinal symptoms. Acute disseminated encephalomyelitis (ADEM) has been reported in 1 per 50 000–1 000 000 cases, although there are no definitive studies. The Global Advisory Committee on Vaccine Safety concluded there was no evidence to support the link with ADEM or to change current immunization recommendations with JE vaccines (WHO, 2005). Nevertheless, the use and production of the Biken vaccine in Japan were suspended in 2005 after a case of ADEM in a child that was temporally associated with JE vaccination (Beasley et al., 2008). The risk of developing ADEM is small and outweighed by the benefits of preventing JE among residents in endemic areas. However, for travelers, the risk of developing JE without vaccination is comparable to the risk of developing ADEM from inactivated vaccine.

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as ongoing postmarketing studies to ensure long-term safety (WHO, 2007). The vaccine is very cheap to manufacture, which is an important consideration for many countries endemic for JEV. It is not yet licenced for use internationally.

More recent vaccine developments In response to the need for a more suitable vaccine for travelers, where the risk of JE is low, a new killed vaccine based on the SA14-14-2 strain has been developed and is now widely licenced under the name Ixiaro (Jespect in Australia and New Zealand). This vaccine is derived from cell culture and is formalin-inactivated. This vaccine is effective (as shown by the development of neutralizing antibody against JEV) and is also very safe, making it an improvement on the mouse brain-derived vaccines (Tauber et al., 2007). Novel technologies have been applied to the JE vaccine field, for example Chimera-Vax uses genetically engineering viruses (YFV-17D-JEV) based on the yellow fever 17D vaccine backbone, with the addition of the envelope protein for JEV (Torresi et al., 2010). One product based on this strategy is now available in Australia under the trade name Imojev. All currently available JE vaccines are probably effective, and the choice between them will depend mostly on regional licencing arrangements and availability. In addition to these vaccines there are several other vaccines in development. Some of these are targeted at specific domestic markets and others are intended for international use (Beasley et al., 2008).

Live attenuated vaccine A live attenuated strain of JEV, SA14-14-2, was developed in China by serial passage in animals and in cell culture. This vaccine came into human use in China in the late 1980s and since then over 200 million doses have been administered in China. Studies from China have demonstrated that a single dose of SA14-14-2 provides 80–96% protection (Xin et al., 1988; Solomon et al., 2000) and 97.5% efficacy after two doses 1 year apart (Hennessy et al., 1996). Several studies outside China have also demonstrated both safety and efficacy of the vaccine (Bista et al., 2001; Ohrr et al., 2005; Tandan et al., 2007; Gatchalian et al., 2008; Kumar et al., 2009b). SA14-14-2 vaccine has now been introduced across many JE-endemic countries. There has been little evidence of significant toxicity (Liu et al., 1997; WHO, 2006), although by modern standards stricter monitoring has been recommended. A WHO working group has advised additional safety studies in selected high-risk groups (immune-compromised vaccinees, pregnant women, children aged < 1 year old) as well

Recommendations on who should be vaccinated JE vaccine is recommended for native and expatriate residents of endemic areas, laboratory workers potentially exposed to the virus, and travelers spending 30 days or more in endemic areas. For shorter visits, the vaccine is only recommended if there will be extensive outdoor activity in rural areas, or if visiting during known epidemics (CDC, 1993); considering the variable incidence of JE from year to year, its unpredictability, and the unreliability of some epidemiologic data, identifying areas of epidemic transmission is difficult. It has been argued that the benefit of immunization exceeds the risk of vaccine-related adverse effects, especially when the devastating impact of acquiring JE is contrasted with the lesser risk of an allergic reaction that can be aborted by drug therapy (Innis, 1995). Reports of travelers developing JE following short (<2 weeks) visits to Indonesia and of an 11-year-old girl who developed JE on returning from a visit to the relatively urban area of Manila in the

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Philippines with only day trips to more rural surrounding areas support the contention that all travelers to endemic countries should be vaccinated (Solomon et al., 2000; Anonymous, 2011).

FUTURE DIRECTIONS Since outbreaks of encephalitis were described in Japan nearly 150 years ago, JE has become a major cause of illness and death across Asia. Unlike smallpox and polio, for which humans are the only host and elimination by vaccination is feasible, the enzootic nature of JEV means that there is no possibility of global eradication. The area endemic for JEV has grown steadily since its first recognition; the effects of global climate change make it unlikely that this spread will halt any time soon. Highquality surveillance and rapid diagnostics are essential for identifying outbreaks, mapping the disease’s spread, and thus making maximal use of preventive vaccination. A better understanding of the host immune response and pathogenesis will guide future development of badly needed specific treatments against JE. In the interim, supportive care with effective management of complications remains imperative. Randomized controlled trials of supportive management may help standardize acute care for JE patients. Further long-term follow-up studies and review of JE patients’ integration back into school and the community will also be important, particularly as we better appreciate the subtle and long-term neurologic deficits caused by JE.

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