Viral encephalitis of public health significance in India: Current status

Symposium : Tropical Ped ia t r i c s -Par t I Indian J Pediatr 1999; 66 : 73-83 i

Viral Encephalitis of Public Health Significance in India : Current Status

Rashmi Kumar

Department ofPediatrics, King George's Medical College, Lucknow

Abstract : Japanese encephalitis (JE) and rabies are 2 viral encephalitis that are of public health importance in India. JE is a zoonosis with the primary cycle occurring in arthropods (mosquito vectors) and vertebrate animals (primarily the pig), man being only an incidental 'dead end' host. Out- breaks have been seen in most parts of India except the north west. The disease presents with a prodromal stage, an acute encephalitic stage with coma, convulsions and variable deficits and a convalescent stage. Diagnosis can be made by viral isolation from CSF or brain, or serologic tests such as haemagglutination inhibition test and IgM antibody capture ELISA in CSF and blood. There is no specific treatment. Mortality ranges from 20-50% and almost half the survivors have sequelae. The most effective control measure besides control of mosquitos is vaccination. A killed mouse brain vaccine is being prepared in India and is safe and effective but expensive. Rabies is a highly fatal encephalomyelitis primarily occurring in urban dogs and wild animals especially canines. It is endemic in India and affects an estimated 3 per 100,000 persons annually. The patient initially may display bizarre combative behaviour. The disease can be effectively prevented by post exposure vaccination. The nervous tissue vaccine is no longer recommended because of unac- ceptable neurotoxicity. Three cell culture vaccines are presently available with about equal efficacy (Indian J Pediatr 1999; 66 : 73-83)

Key words : Japanese encephalitis; Rabies; Viral encephalitis.

Viral encephalitis is an important cause of hospital admissions, mortality and perma- nent neurologic sequelae in children in In- dia. A wide variety of viruses may cause encephalitis but only 2 types of viral encephalitis can be said to be of public health importance in India - Japanese encephalitis and rabies.

JAPANESE ENCEPHALITIS (JE)

thropod borne) virus of the type B (flavivirus) subgroup of the Togaviridae. This RNA virus is 40-50 nm in diameter with marked neurotropism. JE is a zoonotic disease having its natural cycle in wild or domestic animals and hematophagus arthropods, man being only the incidental 'dead end' host. Under specific ecologic condi- tions it may cause focaI outbreaks. The incubation period is 7-14 days I.

Originally known as Japanese B encephalitis, this disease is caused by an arbo (ar-

Reprint requests : Rashmi Kumar, Department of Pediatrics, King George's Medical College, Lucknow-226 003, U.P.

History

The disease was first recognised in Ja- pan. It remained a major health problem in Japan, Korea and Taiwan till the mid 1960's after which it declined dramaticallv

24 RASHMI KUMAR Vol. 66, No. 1, 19q9

in these countries 1. It affected hundreds of American soldiers stationed in Korea and Vietnam 2,3,4. JE now mainly occurs in India, Nepal, China, Srilanka, Thailand and Viet- nam, and sporadically in Indonesia, Singa- pore and Malaysia s.

In India, the disease was first reported in the mid 1950's from Vellore in Tamil Nadu state, where cases of an encephalitis like illness were seen and serologically proven to be due to JE or a closely related virus. Over the next decade, 52 cases of encephalitis presenting to the Christian Medi- cal College Hospital, Vellore were identified to be JE. Around the same time, exten- sive serological surveys in South India revealed widespread flavivirus activity%

The first major epidemic of JE from In- dia was reported in the Bankura and Burdwan districts of West Bengal in 19738. Since then, repeated annual outbreaks have occurred especially in the post monsoon high mosquito season in West BengaP, Bihar 1~ Assam n and the North East 12, Uttar Pradesh 13,14 and the 3 southern states of Tamilnadu, Karnataka and Andhra PradeshlS, lL These annual epidemics are superimposed on an year round occur- rence or endemicity. The first JE epidemic from the west coast was reported from Goa in 199317. An outbreak of JE was reported from Haryana in 199018 and the disease was also seen in OrissML Kerala experi- enced the first epidemic of JE in 19962~ Thus it is clear that the disease is highly prevalent in southern and eastern parts of the country and is also making inroads to newer areas. Presently, it may be found anywhere except the North West. The total number of reported JE cases in India have been roughly 7500 in epidemic years. The estimated morbidi ty rate is 1.5 - 0.3 per 10,000 population 21. However, the true inci-

dence is probably much higher because a large proportion of cases may never reach hospital and even in those that reach, diagnosis may be difficult in a rural out reach hospital.

Epidemiology

JE may affect all age groups, but children between 5 - 15 years of age bear the brunt of the disease. In non immune areas, epidemics have affected all age groups. Males are usually more commonly affected than females with a male : female ratio of 2.1 : 1.56 . It is seen mostly in the lower socio-economic class in rural rice growing areas - a population least equipped to with- stand this scourge that kills and maims so may people. Very high incidence is seen in extensively irrigated low lying areas. How- ever, the true magnitude of the infection can be gauged by serological surveys only as the estimated ratio of overt to inapparent infection is 1 : 300 to I : 1000L There is a scattered pattern of incidence - only 1-2 cases occurring per village with some villages completely spared.

A community based study in a cohort of children aged between 5-9 years in a highly endemic district in Tamil Nadu showed thai an average of 4000 subclinical infections occurred per 10,000 children while concurrently an average of 15 cases of JE were reported, giving an apparent : inapparent ratio of 1 : 270. Forty four to 77% of children originally negative for haemagglutination inhibiting antibodies serocon- verted during the transmission season. Six to 8 months later, the antibodies dropped to undetectable levels in about half these children 23. A lower ratio has been noted in other areas. The seasonal incidence varies slightly in different regions of the country.

Vol. 66, No. 1, 1999 VIRAL ENCEPHALITIS IN INDIA 75

in West Bengal, the disease is seen mostly from May to October. In Uttar Pradesh, South India and Assam, epidemics have mainly occurred in the post monsoon months of September to December, but some epidemics have occurred between December and April in relation to abnor- mally heavy rainfalF 2. Ecological studies implicate Culex tritaeniorrhynchus - a mosquito that breeds in paddy fields as the ma- jo r vector in many South East Asian countries including India. However , JE virus has been isolated from 10 other species of Culex, 2 species of Anopheles and 3 of Mansonii suggesting that other mosquitoes also play a role in transmission of the disease. In a recent s tudy in Tamilnadu, of 91 isolations from mosquitos, 58 were from Culex tritaeniorrhynchus, 22 from C. vishnui, 6 from C. fuscocephata and 5 from C. gelid- us 24. Man is not involved until a high densi-

of infected mosquitos is reached. More than 40 mosquitos per man per hour are re- quired to maintain the cycle a.

Pigs are considered the major vertebrate hosts of the virus in all countries where the disease occurs. These animals do not them- selves develop the illness but act as 'ampli- fiers' as the virus multiplies and circulates in them 6. Studies from different JE activity areas of the country have shown that 30- 80% of pigs had antibodies to JE. A signifi- cantly higher number of cases are seen in pig rearing communities. Man is only an occasional and "dead end ' host as the viremia is too low and short lasting in man. It was postulated that cattle too may act as reservoirs of the infection, but viremia has not been demonst ra ted in cattle. On the other hand, cattle may attract a large number of infected mosquitos and serve to 'dampen' the disease. Studies also suggest that birds of the family Ardeidae (which in-

cludes cattle egret and herons) develop viremia and are effective in transmitting the infection 6.

Pathogenesis and Pathology

After the virus gets inoculated into the skin by the bite of an infected mosquito, it is quickly disseminated in the body and proliferates in the reticuloendothelial system. There is a transient period of viremia and the virus then localises in the central

�9 nervous system. Autopsy specimen of the brain revealed cerebral edema and focal capillary congestion. Punched out necrolyt- ic areas were seen in the grey matter. Mi- croscopicall)~ there is perivascular cuffing by lymphocytes, perivascular hemorrhag- es, formation of gliomesenchymal nodules and discrefe and confluent areas of cystic necrosis 25. Pos tmortem examination of brain showed evidence of neurocystecerco- sis (NCC) in 33% of patients dying with JE, but in only 1% of patients dying due to other causes, suggesting that NCC may some- how predispose to JE 2~'27. A high level of tumour necrosis factor correlated with adverse outcome in JE 28.

Clinical Features

The course of the disease can be divided into 3 stages - a prodromal stage with fever, an encephalitic stage with central nervous system manifestations such as convulsions and coma and a convalescent stage marked by gradual recovery and sequelae. A hospital based s tudy in children in Lucknow 29 done on 92 laboratory proven cases revealed a high incidence of fever (94.5%), coma (100%), and convulsions (84.7%). Focal neurological signs were seen in 29.3%, meningeal signs in 13% an d

76 RASHMI KUMAR Vol. 66, No. 1, 1999

extrapyramida! signs in 21.3%. The mortality rate was 37%. Many other illnesses can mimic JE even during epidemics. A de- tailed multivariate analysis of clinical features showed that presence of 2 clinical signs viz. central neurogenic hyperventila- tion and extrapyramidal signs in a child with an acute encephalitis like illness were significant predictors of the diagnosis of JE 3~

Laboratory Findings : A peripheral blood leucocytosis and relative neutrophilia is usually found. CSF usually shows pleocytosis of upto 200 cells/cu mm (range (MOO0). CSF proteins may be mildly el- evated and sugar is within normal limits. EEG shows diffuse delta wave activity or alpha coma2L

Imaging : Computed tomography and magnetiC resonance studies show distinct changes in the thalamus, basal ganglia (in.- cluding putamen) and even brain stem 3~-32.

Diagnosis

Viral isolation may be at tempted from CSF or brain b iopsy specimen. Conven- tionally, intracerebral inoculation of infant mice followed by identification using quick complement fixation test or neutralisation test was used for isolation of ]E virus. Re- cently, mosquito derived cell lines are described as very sensitive for the virus 22. Demonstration of JE virus antigen in CSF by monoclonal ant ibody based immuno- flourescence has been shown to be a rapid method of diagnosis taking only 2-3 hrs, with 58% sensitivity 33.

.Serology : Conventionally, a 4 fold or greater rise in ant ibody titres by

haemagglutination (HI) test or complement fixation (CF) test in acute and convalescent phase sera is considered suggestive of the infection. Antibody response may be either primary (monotypic) or secondary. A primary response is said to be present when there is no previous exposure to flaviviruses and antibody response only to JE is seen. However, previous exposure to flaviviruses produces an anamnestic response to West Nile and dengue viruses also. In this situation, JE can be diagnosed if titres to the other viruses are lower by at least 4 fold or if 2-mercaptoethanol sensitive IgM type of antibodies can be demon- stratedL Detection of IgM type of JE specific antibodies in acute phase CSF or serum specimen by antibody capture ELISA (MAC ELISA) is a widely used test which is sensitive and specific and differentiates JE from related infections 4.

Neutralisation test and Agar gel diffu- sion tests are more specific than HI or CF tests. A single radial hemolysis test has been developed which is rapid, specific, less expensive and positive even during the acute stage 622.

Treatment

So far, no specific antiviral agent is recommended for ]E. Treatment is essentially symptomatic and includes control of pyrexia, control of seizures, proper nutri- tion and nursing of the comatose patient and measures to reduce cerebral edema with mannitol. High dose dexamethasone therapy in a double blind randomised trial in Thailand did not reveal any significant benef i t .

Mortality and Sequelae

Mortality rate in different series has been


reported as 20 - 50% 36. In a follow up study of 55 proven cases who survived the illness, major sequelae (frank mental retarda- tion, frank motor deficits or epilepsy) were seen in 45% while minor sequelae (subtle neurological signs, scholastic backward- ness or behavioural problems) were found in another 25% 37. JE can result in lower motor neuron type of flaccid paralysis also, suggesting involvement of the spinal cord in some cases aS,ag.

Control

Control measures for JE may be aimed at the vector, the vertebrate animal host or the susceptible human population.

1. The usual methods for reducing mosquito breeding which include drain- ing out of stagnant water, residual in- door spraying with insecticides, out- door fogging with malathion and chemical larviciding of rice fields are well known 4~ but difficult to achieve in far flung rural areas. Pyrethrum group of insecticides is the most effective one. In a recent s tudy in Karnataka, deltamethrin was the most effective adulticide which killed 100% of the vectors within 15 min- utes. C. tritaeniorrhynchus was found to be more tolerant to insecticides compared to other species 4l. In another s tudy from Rajasthan, C. tritaeniorrhynchus was susceptible to permethrin but resistant to DDT, dieldrin and fenitrothion 42.

2. Control of transmission in the vertebrate host involves keeping pig sties away from residential areas, regular insecticide spraying, and vaccination of pigs.

. Control of transmission of the infection to human subjects can be achieved to some extent by use of bed nets, insect repellents and neem cake powder which has also been shown to repel mosquitos. However , the mainstay of control of JE is vaccination of susceptible human populations. A killed vaccine prepared by injection of the Nakayama strain of the virus into mouse brain is in use in Japan since the 1960's and was effective in practically eliminat- ing the disease there. This vaccine is being manufactured at the Central Research Institute, Kasauli, Himachal Pradesh. Two doses (1 ml in adults and 0.5 ml in children below 3 years) are recommended 10-14 days apart, with a booster 12 months later. The efficacy of this vaccine in field trials has been 80-880/043 . The generation of neutralising antibodies of 1 : 10 titre or higher correlates well with protection, and side effects are few 44. H o w - ever, the vaccine is expensive and in short supply. Further, there are many logistic problems in administering it to such a large susceptible population in inaccessible rural areas, and these problems have prevented the proper implementation of a JE vaccination policy in India. Intradermal administration of the vaccine in 2 sites was shown to be as effective as the intra- muscular dose 4s. Recently, an inex- pensive live attenuated vaccine developed from baby hamster kidney cell line (SAI4-14-2) was tried in China. The efficacy of 2 doses of this vaccine given a year apart was 98% 46. Its safety with respect to common adverse effects has been established and


studies of long term and rare side effects are underway.

RABIES

Rabies or hydrophobia is a severe, highly fatal viral encephalomyelitis caused by a lyssavirus type I or rhabdovirus. It is primarily a zoonotic disease of warm blooded animals especially the canines - dogs, cats, wolves and jackals, which account for 99% of human rabies4L

The disease is of worldwide importance and continues to exist in 87 countries. It ranks 12th on WHO's list of major mortality causing diseases 48. The human death toll due to rabies is about 30,000 cases in Asia, 5000 in Africa and 300 in Latin America. Globally each year, about 10 million people receive post exposure immunisation. However , many countries are "rabies free' either because of vigorous cam- paigns or because the disease was never in- troduced there. The most effective natural barriers to rabies are geographical bounda- ries especially water. Australia, Taiwan, United Kingdom, Cyprus, Japan, Malta, New Zealand, Iceland, Ireland and the islands of the Western Pacific are free of the disease as are Sweden, Norway and Fin- land. A rabies free area is defined as one in which no case of indiginously acquired rabies has occurred in man or any animal species for 2 years 47.

In India, rabies continues to occur with considerable magnitude with an estimated 3 per 100,000 cases per year as compared to 1 per 100,000 in other Asian countries. The annual human mortality rate is 25,000 with 3 million people receiving post exposure prophylaxis. Except for the islands of Lakshadweep, Andamans and Nicobar, all other parts of the country are endemic for

rabies4L

Epidemiology and Transmission

Rabies can exist in 3 epidemiological forms : urban, wild life and bat rabies. Ur- ban dogs are infected by bite Of wild animals thus maintaining the urban cycle. A single rabied dog may transmit the infection to a large number of humans and animals over a considerable area. Cats may also transmit the infection*L Wild life rabies represents the ultimate and inestima- ble reservoir of infection, and is perpetu- ated mainly by the jackal, fox, hyena and wolf. The animals maintain the cycle in na- ture and occasionally transmit the infection to dogs and domestic animalS. Bat rabies is also an important reservoir of infection in some countries, and is responsible for the loss of thousands of cattle. Rabies virus is probably transmitted be tween vampire bats either by bite or aerosol. Bats may be infected for long periods without showing symptoms s~

Man is infected by the bite or lick of a rabied animal. Scratches may also be dan- gerous because animals lick their claws. Dogs may have the virus in their saliva for 2-4 days before symptoms appear. How- ever, not all rabid animals with rabies have virus in their saliva and even when it is present, the amount is variable. This ac- counts for rabies resulting in less than half of untreated bites by proven rabid animals. Saliva applied tO mucosal surfaces such as conjunctiva may also be infectious. Cases of rabies from human bite are on record and transmission through corneal trans- plant has also occurred s~ In general, if a biting animal does not die within 10 days, rabies is unlikely. Rare cases of terrestial animals recovering from rabies have been

VoI. 66, No. 1, 1999 VIRAL ENCEPHALITIS IN INDIA 7~

reported.

Pathogenesis and Pathology

There are 3 critical steps involved. The first is the introduction of rabies virus into a wound or mucosa. Second, the entry of the virus into a fibroblastic or muscle cell. The virus multiplies here for several gen- erations, after which it gains access to a nerve ending. This is the third critical step. Thereafter the virus travels along the nerve into the central nervous system sl. The basic lesion is neuronal destruction and glial in- filtrates in the brain stem and medulla. The cerebral cortex appears relatively normal. The Negri body-the pathological hallmark ~ of rabies - is a cytoplasmic inclusion con- sisting of clumped viral nucleocapsid. Its absence does not exclude rabies and flourescent antibody stains of brain section may be positive in its absence. Antibodies to the nucleocapsid can be detected in infected animals, but only antibodies to the surface glycoproteins are neutralising and protective 50.

Clinical Manifestations

Rabies is characterised by an extremely variable and long incubation period. The usual incubation period is 30-60 days but periods as short as 9 days and as long as 7 years have been described s~

A prodromal stage lasting 2 - 10 days is characterised by nonspecific symptoms including fever, malaise, headache, anorexia vomiting and ill defined anxiety. Pain, pruritis and parasthesias at the wound site may be felt.

The acute neurologic stage again lasts for 2-10 days. In this stage the patient has bursts of hyperactivity, disorientation and

bizarre combative behaviour alternating with periods of lucidity. Meningismus and ophisthotonus may be present. Hydropho- bia oi'aerophobia may be prominent. These symptoms seem to be due to neuronal dys- function in certain areas of the brain stem. Seizures may occur. CSF examination may show lymphocytic pleocytosis with mild elevation of protein or may be normal. As the disease advances the patient may develop a flaccid paralysis and slip into coma ~.

In about a fifth of patients, the illness presents as an ascending symmetric flaccid paralysis. Myocarditis with hypotension and arrythmias is also an important com- plication. Prognosis is extremely bleak with almost 100% morality 5~

Differential Diagnosis

Any encephalitis illness such as arboviral or herpes simplex encephalitis may initially be difficult to differentiate. In rabies however, sensorium is initially dear despite presence of brain stern signs. Para- lytic rabies has to be differentiated from Guillian Barre syndrome, poliomyelitis, post rabies vaccination encephalomyelitis and botulinism. The spasms of tetanus also may cause diagnostic confusion. One most difficult differential diagnosis is hysteria in a person who thinks she has rabies :*'.

Laboratory Diagnosis

The virus may be demonstra ted by flourescent antibody stain of corneal smears or sections of skin at the nape of the neck at the hairline. Autopsies of brains are positive for Negri bodies and flourescent antibody stain. If the patient survives the acute stage, neutralising antibodies at ex-


tremely high levels (> 100 IU) develop in the serum and CSF. Vaccination even with potent vaccines does not raise titres beyond 20 IU s2.

Management of Dog Bite

Washing and tetanus irnmunisation should be carried out after all bites. The first critical procedure against rabies is thorough washing of the wound with soap and water. This removes the virus me- chanically. Soap also dissolves the lipid en- velope of the virus and removes virus par- ticles by detergent action. Application of 70% alcohol and povidone iodine to the wound site causes chemical disruption of the glycoprotein coat of the virusSL

Pass ive I m m u n i s a t i o n : This is indicated for bites where nerve endings are more widely distributed - the face, scalp, neck, palms and genitalia - so as to have anti: body protection as soon as possible. It should also be given irrespective of site of the bite if the animal is presumed rabied. Human antirabies immune globulin (HRIG) in a dose of 20 IU/kg body weight is given. Half the amount is injected around the site of the bite. This prevents multiplication of the virus at the wound site and its entry into nerve endings. The rest is given intramuscularly. If HRIG is not available, horse antirabies serum (40 IU/ kg) may be given after doing a skin test for hypersensitivity a9~1.

Act ive Immun i sa t i on : Great strides have been made in anti-rabies immunisat ion ever since Louis Pasteur performed the first successful human post exposure immunisat ion in 1885. Rabies vaccine is unique in being the only vaccine given af-

ter exposure to infection. Post exposure vaccination aims at building up the immune status in the host as early as possible, before the virus establishes itselfin the peripheral nerve. Serum antibodies appear about 7 days after vaccine administration. Immunity is not absolute especially when exposure is very severe.

Nervous tissue vaccine : This vaccine is still widely used in India because of its low cost but is beset with the problem of neuroparalysis which occurs in 1 in 3000- 5000 persons and may be fatal. This occurs due to an immune mediated demyelination induced by myelin protein in the vaccine.

Ceil culture vaccines : There are 3 different cell culture vaccines available in India. These are the human diploid cell vaccine, the purified chick embryo cell vaccine and vero cell vaccine. Although the cell culture substrates are different, the final result is a suspension of purified, inactivated rabies virus. Contaminating proteins or nucleic acids from the substrate are so low that they are undetectable. Thus, these 3 vaccines are nearly identical in antigenicity and quality sl. These vaccines are more expensive than the nervous tissue vaccine. The dose schedule is the same for all age groups and is given on days, 0, 3, 7, 14 and 30. Another dose at day 90 is recommended if post exposure passive immunisation was given. These vaccines are given intramuscularly. Adverse reactions include local pain and erythema in 25% recipients along with mild systemic symptoms. Neurologic illness resembling Guillian Barre syndrome has been reported with an incidence of 1 in 150,000 s2. Intradermal route of administration of these vaccines has been found to be equally immunogenic, requires less vaccine and


may reduce the cost of vaccination. How- ever, seroconversion is found to be poor if antimalarial treatment is also given at the same time. The intradermal route has not yet been passed for use in our country s2.

Indications for post exposure antirabies immunisation are :

1. If the animal shows signs of rabies or dies within 10 days of the bite.

2. If the biting animal cannot be traced or identified.

3. Unprovoked bites.

4. Laboratory tests (eg. flourescent rabies antibody test or test for Negri bodies) in the brain of the biting animal are postive.

5. All bites by wild animals.

However, when the animal is apparently healthy, decision for and design of post exposure immunisation is made individually for each patient after careful consideration of several factors such as immunisation status of the animal, site and severity of bite and presence of animal rabies in the lo- cality.

According to WHO recommendations for management of animal bites s3' category I contact consists of touching or feeding of animals and licks on intact skin. No prophylaxis is neccessary in such cases if a reliable history is available. Category II contact consists of nibbling of uncovered skin, minor scratches or abrasions without bleeding and licks on broken skin. In such cases, vaccination should be commenced immediately. Category III contact consists of single or multiple transdermal bites or scratches, or contamination of mucus membrane or saliva. Here, vaccine should be administered immediately along with rabies immunoglobulin. Whenever possible, the animal should be observed for 10

days. If at the end of this period, the animal remains well, further doses may be omit- ted. There is no longer any rationale for witholding treatment while observing the animal.

Control

Since dog is the most common source of infection, the most logical method of control would be elimination of stray and ownerless dogs and immunisation of at least 80% of the total dog population of the area. Other methods include registration of all domestic dogs, restraint of dogs in public places, health education of families with pet dogs about prevention of rabies, immediate destruction of dogs or cats known to be infected and quarantine of imported animals for 6 months. An oral vaccine administered through baits has been intro- duced for immunisation of foxes. This has been very successful in controlling wild life rabies in certain European countries and may be useful in dogs too s2.

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Viral encephalitis of public health significance in India: Current status