Encephalitis Seizures

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Seizures in encephalitis

Usha Kant Misra DM, *C T Tan MD, Jayantee Kalita DM

Department of Neurology, Sanjay Gandhi PGIMS, Lucknow, India; *Department of Medicine, University

of Malaya, Kuala Lumpur, Malaysia

Abstract

A large number of viruses can result in encephalitis. However, certain viruses are more prevalent in

certain geographical regions. For example, Japanese encephalitis (JE) and dengue in South East Asia

and West Nile in Middle East whereas Herpes simplex encephalitis (HSE) occurs all over the world

without any seasonal or regional variation. Encephalitis can result in acute symptomatic seizures

and remote symptomatic epilepsy. Risk of seizures after 20 years is 22% following encephalitis and

3% after meningitis with early seizures. Amongst the viruses, HSE is associated with most frequentand severe epilepsy. Seizures may be presenting feature in 50% because of involvement of highly

epileptogenic frontotemporal cortex. Presence of seizures in HSE is associated with poor prognosis.

HSE can also result in chronic and relapsing form of encephalitis and may be an aetiology factor in

drug resistant epilepsy. Amongst the Flaviviruses, Japanese encephalitis is the most common and is

associated with seizures especially in children. The frequency of seizures in JE is reported to be 6.9% to

46%. Associated neurocysticercosis in JE patients may aggravate the frequency and severity of seizures.

Other aviviruses such as equine, St Louis, and West Nile encephalitis can also produce seizures. In

Nipah encephalitis, seizures are commoner in relapsed and late-onset encephalitis as compared to acute

encephalitis (50% vs 24%). Other viruses like measles, varicella, mumps, inuenza and enteroviruses

may result in encephalitis and seizures. Status epilepticus can also occur in encephalitis. It may be

refractory to medication and require aggressive treatment. Single or discrete seizures in encephalitis

should be treated as any other acute symptomatic seizures.

Neurology Asia 2008; 13 : 1 13

Address for correspondence:U K Misra, Professor and Head, Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences,Raebareily Road, Lucknow- 226014, India. FAX: 091-0522-2668017, Email: [email protected], [email protected]

INTRODUCTION

Encephalitis refers to acute inammatory process

affecting the brain. Viral infections are the most

important cause of encephalitis. There are over

00 viruses that can result in encephalitis. The

patients present with fever and varying degree of

alteration in sensorium which may be associated

with focal neurological signs or seizures. In such

patients, malaria, bacterial meningitis and non

infectious causes of encephalopathy must becarefully excluded. Viral encephalitis generally

results in nonspecic clinical picture with some

specic features of anatomical involvement

such as behavioral changes, aphasia or partial

complex seizure in herpes simplex encephalitis

(HSE) because of characteristic frontotemporal

involvement.

There are numerous viruses responsible

for viral encephalitis. While precise estimates

about the incidence of encephalitis following

these viral infections are not available; there

are estimates that HSE is the most important

cause of treatable viral encephalitis with an

incidence of case/million population/year.

Certain viruses are prevalent in certain regions.

Japanese encephalitis (JE) in South East Asia,

West Nile encephalitis is Middle East, St. Luis

encephalitis and equine encephalitis in America

are some examples. Lately West Nile encephalitis

from USA and Nipah virus encephalitis from

Malaysia have been reported. The incidence ofclinically diagnosable encephalitis is between

3.5-7.4/00,000 population/year; however

in children the incidence is much higher.

Encephalitis may occur in sporadic or epidemic

form. Establishing the diagnosis of viral

encephalitis may be challenging. The likelihood

of a virus depends upon the geographical location,

timing of the epoch studied and method or rigor

of investigation. In a recent study in Finland,

cerebrospinal fluid (CSF) polymerase chain

reaction (PCR) was used to diagnose over 3,000

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patients with CNS infections, such as encephalitis,

meningitis and myelitis. In this study, Vericella

zoster was the most common infection (29%),

followed by herpes and entero viruses in %

each, and inuenza A virus in 7% of patients.2

This study suggests that HSV is probably over

estimated and Varicella zoster underestimated.HSE however, remains a critical diagnosis because

specic treatment is available for this encephalitis.

In USA, the most important encephalitides are

HSE and arbovirus encephalitides, but 73%

encephalitis is of undetermined etiology.3

Encephalitis and meningoencephalitis are

important causes of acute symptomatic seizures

and remote symptomatic epilepsy. Long-term risk

of seizures following CNS infection was studied

in a large population based study. Twenty year

risk of unprovoked seizures was 6.8%; 22% for

encephalitis with early seizures, and 3% for

bacterial meningitis with early seizures.4 In the

present review, the seizures in HSE, Flavivirus

(Japanese encephalitis, eastern equine and western

equine, dengue), and other viruses including Nipah

virus encephalitis will be discussed.

HERPES SIMPLEX ENCEPHALITIS

Herpes simplex virus is a neurotropic virus

and is the most important cause of sporadic

encephalitis in children above 6 months and in

adults.5 No seasonal or gender related preference

occurs in HSE. It has a high mortality of 70% if

untreated and prognosis is poor. Only a minority

of patients return to normal functions. There is

a bimodal distribution of HSE with one third

cases occurring before 20 years of age and half

in those above 50 year of age. In a recent PCR

study on 56 patients with clinical evidence of

encephalitis, 7.4% patients were due to HSE and

most of these HSE patients were above 40 year

of age.6 The bimodal distribution of HSE may

reect primary HSV infection in younger agegroup and reactivation of latent HSV infection

in older patients. In immunocompetent patients,

more than 90% of HSE occurs due to infection

with HSV- and the remainder due to HSV-2.7

More than two-third cases of HSE due to HSV

infection appears to result from reactivation

of endogenous latent HSV- infection in the

individuals previously exposed to the virus.

HSV- has remarkable capability for producing

latency, persistent infection and for reactivation.8

Primary HSV infection results in axoplasmic

transport to the trigeminal sensory ganglionwhere it establishes latency. Latent HSV1 virus

is detectable in trigeminal ganglia of nearly all

seropositive individuals.8 Reactivation results in

retrograde transport of virus resulting in herpes

labialis amongst other clinical manifestations.

However the pathway by which HSV reaches the

CNS in humans to produce encephalitis remains

unknown. In Primary infection, virus could invade

the olfactory bulbs through the nose and spreadvia olfactory pathway to orbitofrontal and medial

temporal lobes.9 Afnity of HSV-1 for basi-

frontal and medial temporal (limbic) cortex and

sparing of the most other cortices, grey matter,

nuclear masses and white matter is interesting and

mysterious. The afnity for the specialized areas

is attributed to intranasal inoculation and spread

via olfactory nerve of HSV.9 Proximity of dural

nerves to basifrontal and temporal lobes, virus

lies dormant in anterior and middle cranial fossa

which renders these areas more susceptible to

HSV. The virus may travel by cell to cell contact

across the meninges into adjacent cortices. The

structures involved in HSE are part of limbic

system and these boundaries are respected by

HSV.0 This afnity is attributed to distinctive

anatomical, neurochemical and immunological

properties of these cortices.

Clinical spectrum

The clinical manifestations of HSE in older

children and adults are indicative of area of

pathology in the brain. These include focal

encephalitis with fever, altered sensorium, bizarre

behavior and focal neurological signs. The focal

neurological signs are related to fronto-temporal

involvement including aphasia, personality

change and focal seizures. Such focality however

may be minimal in the acute stage and may not

be diagnostic of a particular viral cause. It has

recently been reported that about 20% HSE cases

may be relatively mild and atypical without any

focal feature.

The EEG and MRI ndings in HSE areconsistent with frontotemporal involvement

(Figure ). However there are no characteristic

series of findings pathognomonic of HSE.

Seizures in HSE can be acute symptomatic or

remote symptomatic. In a study on 29 survivors

of 34 biopsy proven HSE patients with acyclovir

therapy, who were evaluated 6 months to year

after HSE, the most common long term symptom

was behavioral abnormality in 45% followed by

seizures in 24.7%.2 Seizures were the presenting

feature in 50% patients in the acute stage. Seizures

are not only common in HSE but also haveprognostic signicance. In a study on children


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with HSE where 47 patients were evaluated,

26 (65%) had good outcome and 4 (35%) had

poor outcome. Seizures occurred at the time of

presentation in 63% and 7% of them had poor

outcome. Abnormal neuroimaging (79%) and EEG

(92%) were more prevalent in patients with poor

outcome group.3 Temporal and frontal corticesare highly epileptogenic compared to parietal

and occipital cortex. Change in excitability of

hippocampal A3 neuronal network and HSV

induced neuronal loss results in mossy ber

reorganization which may play an important role

in the generation of epileptiform activity.4

Clinical characteristics and prognosis of post

encephalitic epilepsy in children were evaluated

in 44 patients aged 2 mo to 7 year (mean 8.

years) who were selected from 798 epilepsy

children. Twenty had favorable and 24 poor

outcome. Factors predicting a poor outcome in

post encephalitic epilepsy were status epilepticus

occurring during the rst stage, slow background

activity, multifocal spikes and HSE.5

Figure 1A: Cranial MRI, T2 sequence of a patient with

herpes simplex encephalitis shows hyper

intensity in temporal lobes.

Figure B: EEG of the same patients showing rhythmic slow waves both sides, and periodic lateralized epileptiformdischarges (PLEDs) on the right.


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Although HSE typically produces a monophasic

illness, chronic encephalitis and relapsing

encephalitis have also been reported rarely. A

66 year old immunocompetent man developed

status epilepticus and died of pneumonia in the

course of progressive hemiparesis, cognitive

decline and brain atrophy over 9.5 year periodafter HSE. Autopsy conrmed active encephalitis

consisting of necrosis and lymphocytic inltration

with intranuclear inclusions in neurons and glia

and markedly edematous parenchyma of frontal

and parietal lobes. HSV antigen was detected

by immunohistochemistry, HSV-1 DNA by in situ

hybridization and herpes virus nucleocapsid by

electron microscopy. These ndings suggest that

direct viral reactivation might result in relapse of

HSE causing progressive clinical deterioration

associated with persistence of HSV in brain.6 In

a long term follow up study of cognitive sequelae

of HSE, out of 8 adult patients with HSE

experienced progressive clinical deterioration.7

In children with HSE progressive cognitive and

behavioral deterioration for many years has

also been reported.8,9 Most of these patients

develop intractable seizures, slowly progressive

hemiparesis and cognitive decline some years

after contacting the disease. The histopathological

changes are consistent with chronic active

encephalitis.

Intractable seizure disorders associated withchronic herpes infection are being reported when

the pharmaco-resistant epilepsy patients were

subjected to epilepsy surgery and resected brain

tissue was subjected to histopathology and PCR.

Three patients who developed HSV encephalitis

diagnosed 6 months, 3 years and 7 months back,

underwent surgical reaction 8.5 years, 6 years and

3 years respectively. Pathological examination

conrmed chronic encephalitis in all 3 patients

and PCR revealed HSV genome. These cases

represent example of chronic herpes encephalitis

manifesting with seizure disorder and presenceof viral genome in brain long after initial episode

of treated HSE.8

There was a case report of chronic persistent

temporal lobe encephalitis following genital

herpes by HSV-2 resulted in intractable partial

complex seizure which necessitated temporal

lobectomy. Immunohistochemistry of resected

temporal lobe conrmed HSV2 infection. Post

operative exacerbation of seizures was resistant

to drugs and could be controlled after acyclovir

therapy.20

Complicated febrile convulsions may also be

the initial manifestation of HSV-1 encephalitis. In

a study on 5 children with febrile convulsions;

5 children with complicated febrile convulsion

did not have HSV antibodies in serum and CSF,

but CSF was positive for HSV PCR. The authors

suggested that any patient with complicated febrile

convulsion should be investigated for HSV PCR,

to look for HSV encephalitis.2 These preliminaryresults do need further studies.

Experimental studies on hippocampal excitability

in herpes simplex encephalitis

Corneal inoculation of mice with HSV-

induces acute spontaneous behavioral and

electroencephalographic seizures because of

increased hippocampal excitability and seizure

susceptibility. In slices from infected mice, the

surviving hippocampal CA3 pyramidal neurons

exhibited a more depolarizing resting membranepotential concomitant with an increase in

membrane input resistance. They also had lower

threshold for generating synchronized bursts and

a decrease in amplitude after hyperpolarization

(AHP) compared to controls. These results

suggest that a direct change in the excitability

of hippocampal CA3 neuronal network could

play an important role in the development of

acute seizure and subsequent epilepsy in HSV

infection.22 Similar results were reported in

another experimental study in which hippocampal

cell culture on treatment with HSV- virus resulted

in epileptiform activity, neuronal loss and increase

in mossy ber sprouting. Intracellular recording

of CA3 pyramidal neurons revealed more

depolarizing resting membrane potential, reduced

threshold for generating synchronized burst

and decreased amplitude of hyperpolarization

compared to controls. These results show increase

in CA3 neuronal excitability, neuronal loss and

mossy ber reorganization which may have a

role in seizures and epilepsy following HSV

infection.4

HSV strains vary with respect to their neuro-

virulence, +GC strains of HSV replicate to

higher titers and expressed more abundant viral

antigens then GC strain. +GC strains spread

more completely through out the brain to involve

amygdela, nucleus accumbens, brainstem nuclei

and locus ceruleus. +GC antigens has also been

found in cerebral cortex layer of animals that

developed seizures.

FLAVIVIRUS ENCEPHALITIS

Several mosquito born neurotropic members of

genus avi virus family cause similar disease


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pattern across the globe. These viruses include St.

Louis and equine encephalitis in USA, Rocio virus

encephalitis in Brazil, Murray Valley encephalitis

in Australia, New Guinea, and New Zealand. JE is

the most important avirus, which causes 30,000

to 50,000 cases of encephalitis and 0,000 deaths

in Asia every year. West Nile virus is prevalentin Middle East and recently outbreaks have been

reported from USA. Flavivirus genus also includes

mosquito born virus that causes hemorrhagic fever

(yellow fever, dengue fever and tick borne virus).

Flavivirus is a small RNA virus with an envelop

protein which is important for viral attachment

and entry into the host.

Epidemiology

Epidemiology of flavivirus is governed by

complex interplay between entomologic (vector),climatic, human behavior and viral factors that

are not completely understood.23 Humans are dead

end host because they dont have sufciently

prolonged viremia to transmit the virus. However,

West Nile virus can be transmitted to humans

through blood products and organ transplantation

because of relatively prolonged viremia. In Asia,

pigs and birds are important natural hosts for JE

virus because these animals are often kept close

to human habitat. They serve as amplifying host

and transmit virus to humans. In USA death of

crows and blue jays may serve as warning that

human disease is imminent.24,25

JE is mostly a disease of children where as

West Nile encephalitis and St Louis encephalitis

in USA affect adults. This paradox is attributed

to intensity of viral transmission and to acquired

immunity. Serological surveys reveal that in

endemic areas almost everyone is infected by

JE virus during childhood, however fever occurs

in a minority ( in 300) of the exposed persons

and encephalitis occurs in even fewer. Thus JEdoes not occur in adults in endemic areas because

adults are already immune to JE virus. However in

a newly invaded JE virus area all the age groups

are at risk of developing JE. Travelers to endemic

area are also at risk of developing JE.

Epidemiology of Murray valley encephalitis

in Australia and West Nile in Africa follows a

pattern similar to JE in Asia, though fewer cases

of encephalitis occur in these areas. A pure febrile

syndrome caused by Murray valley encephalitis

virus is not seen. West Nile virus results in large

out breaks of fever, arthralgia and rash but whenit spread to new areas, it results in outbreaks of

encephalitis. St Louis encephalitis is endemic in

southern USA, but most of the population does

not have pre-existing immunity because of low

rate of transmission of virus to humans. However

occasionally there has been outbreak of St Louis

encephalitis as in 975.26

Advance age is associated with greater severity

of West Nile, St Louis and JE27,28, in which thereis a second peak in the elderly. The exact reason

for more severe disease in elderly though not

known but impaired integrity of blood brain

barrier (BBB) due to cerebrovascular disease or

neurocysticercosis may be responsible.29 Prior

infection with a avivirus and cross reacting

antibodies may affect the outcome of infection

with a second avivirus. For example, in JE,

prior infection with dengue may protect against

a severe illness.30 However, serial infection with

different serotypes of dengue virus is associated

with more severe illness; e.g. dengue hemorrhagic

fever. The strain variation may also be important

determinant of the severity of clinical picture in

endemic area.

Clinical features

The neurological disease typically develops

in patients after an incubation period of 3-5

days and a short nonspecic febrile illness. The

neurological symptoms and signs depend on

which part of the nervous system is predominantly

affected. The involvement of meninges cause

meningitis, brain parenchyma causes encephalitis

and spinal cord causes myelitis. The most

important manifestation which often overlap

are impairment of consciousness and seizures

occurring in about 85% patients with JE and

Murray Valley encephalitis, and up to 0% in

West Nile encephalitis.

Japanese encephalitis

JE is a severe form of endemic flavivirus

encephalitis manifesting with features ofencephalitis or encephalomyelitis. In a study on

radiological changes in JE, CT scan was done in

38 and MRI in 31 patients. Thalamic involvement

was present in 93.5% (Figure 2), basal ganglia in

35%, mid brain in 58%, pons in 26% and cerebral

cortex in 9.4% of patients.3 Similar ndings

have been reported in earlier autopsy studies.32,33

Anterior horn cell involvement in JE has also been

reported based on clinical, neurophysiological34,35

and neuropathological ndings.32 Thalamus and

basal ganglia involvement in JE is associated withhigh frequency of movement disorders, which

may appear as transient form of parkinsonism


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Figure 2A: Cranial MRI T1 sequence of a child

with Japanese encephalitis and status

epilepticus shows hyperintense lesion

in thalamus bilaterally and frontopari-

etal cortical involvement.

Figure 2B: EEG of the same child shows epileptiform discharges on the left side, some of which spread

to right.

and varying types of dystonia. Severe dystonia

simulating status dystonicus have also been

reported.34,36,37

Neurocysticercosis and JE coinfection has

been reported from China and India.38,39,40 In a

study on 63 JE patients, 37.4% had evidence

of neurocysticercosis conrmed by antibodies inCSF, CT scan or autopsy.29 In MRI studies, similar

observations have also been reported (Misra

UK and Kalita J, Unpublished observation).

The coexistence of JE and neurocysticercosis

is attributed to the pivotal role of pig in the

transmission of JE virus and Tenia solium. Pig is

amplifying host of JE virus and intermediate host in

the life cycle of Tenia solium. Neurocysticercosis

may enhance the susceptibility of host to JE virus

infection and could add to the seizure burden in

JE patients.

Seizures in Japanese encephalitis

Seizures in JE have been noted by a number of

investigators. These are partial motor or secondary

generalized and appear at the onset or during

the course of disease occurring more frequently

in children. In a study, seizure was documented

in 6.7% patients.4 Isolated case report of

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diencephalic seizure has been reported in JE and

are of interest because of involvement of thalamus

and brain stem.42 In JE, seizures are less intractable

then HSE.43 In a study, 30 out of 65 JE patients

had seizures in the rst week of encephalitis. The

seizures were generalized tonic clinic in 7 and

partial motor with secondary generalization in3. Eleven patients had single seizure, 8 had two

seizures and 11 had multiple seizures. Interictal

EEG in the patients with seizure revealed theta to

delta slowing in all and epileptiform discharges

in 4 patients only. MRI carried out in 26 patients

revealed bilateral thalamic lesion in 24, cortical in

7, basal ganglia in 8 and brainstem involvement

in 3. In the seizure group, 3 patients died, 9 had

poor, 8 partial and 9 complete recovery by 3

months. Presence of seizure in JE correlated with

GCS score, focal weakness, EEG abnormality and

cortical lesion on CT or MRI, though seizure was

not associated with poor prognosis.44 Although

seizure has been reported to be commoner in

children4, in a comparative study of JE in adults

and children, seizures were present 67.2% of

adults and 56.7% of children, but this difference

was not statically signicant.46 The seizure was

generally infrequent and easily controlled with

phenytoin or carbamazepine monotherapy.44

The experience of JE in children from Vietnam

however was different. In a study on 144 JE

patients, 34 children and 0 adults, 29% hadseizures and 2% died. Of the 40 patients with

witnessed seizures, 60% died or had severe

sequelae compared to only 26% of 04 with no

witnessed seizures. Patients with seizures were

more likely to have elevated CSF opening pressure

and signs of brain herniation.47 High frequency

of seizure in Vietnamese study could be due to

difference in the herd immunity as well as referral

bias. The Indian study was from a tertiary care

referral center where very sick patients with

seizures could not have been referred.44,45

EEG changes in JE are nonspecic. In a studyon 27 patients with JE, diffuse slowing of theta to

delta range was the commonest (24), lateralized

spike or spike wave discharges and alpha coma

in 3 patients each. High frequency of slowing is

attributed for thalamic involvement, lateralized

epileptic discharges to cortical and alpha coma

to the involvement of thalamus and brainstem,

which is sufcient to produce loss consciousness

but not enough to block the alpha activity. Alpha

coma in JE may be common but its prognosis is

not as bad as hypoxic coma or cardiac arrest. In3 JE patients with alpha coma, patient died and

one each had partial and complete recovery.48 In

another study on EEG in 56 patients revealed

slowing of background activity in 35, unreactive

slowing in 9, low amplitude in , burst suppression

pattern in and normal in patient. Patients

with grade b had poor outcome compared to

less severe EEG abnormality. Asymmetrical EEG

pattern was not related to outcome. Seizures weredocumented in 20% of patients.47

Dengue

Dengue is an important avivirus with nearly

50 million cases occurring world wide mostly in

Asia, Africa and South America. Most patients

present with fever but some may have dengue

hemorrhagic fever, dengue shock syndrome

and dengue encephalopathy or encephalitis.

Though dengue is regarded as a non neurotropic

virus, a variety of neurological manifestationsfollowing dengue virus infection have been

reported. Encephalopathy in dengue may be due

to metabolic alterations, hypotension, hypoxia,

hepatic or renal failure. Recently evidence of CNS

invasion of dengue virus based on experimental,

CSF antibody and PCR studies have been

suggested.49,50 In a study on 24 dengue patients

with neurological manifestations, 50% had altered

sensorium; 5 of whom had seizures (generalized

in 3, focal in one). In another study, 11 out of

7 patients had encephalopathy and 6 had acute

accid paralysis (myositis). In the encephalopathy

group 3 had seizures and one had myoclonus. CSF

pleocytosis and EEG changes were present in 8

patients each. In the myositis group, creatinine

kinase was raised in 5, electromyography

(EMG) and muscle biopsy were consistent with

myositis in one patient each. The patients with

myositis improved completely within one month

but in encephalopathy group 3 died and had

poor outcome. Dengue patients presenting with

encephalopathy had more severe illness and worse

outcome than those with myositis only. Denguemyositis may be an early or mild form of disease

whereas encephalopathy may be a more severe

form and some patients may have an overlapping

clinical picture.5,52 The EEG changes in dengue

virus infection are nonspecic; slowing occurs in

55% patients in a study on 24 dengue patients with

neurological involvement. The EEG abnormality

correlates with level of consciousness.5

St. Louis encephalitis

St Louis encephalitis is one of the most commonarboviral disease in USA in earlier series. It is

spread by at least 3 different mosquitoes which


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breed in stagnant water or irrigated fields,

explaining both urban and rural distribution.

It manifests with u like illness followed by

meningoencephalitis. Severity of disease and

propensity of virus to infect the CNS increases

with age.53 The disease often occurs in outbreaks

and clinical manifestations are similar to West Nileencephalitis. Neurological sequelae are present in

5% of surviving patients.

West Nile encephalitis

West Nile encephalitis occurs in summer months.

The most common neurological syndromes

caused by West Nile Virus in New York city

epidemic included encephalitis with muscle

weakness (39%), aseptic meningitis (32%),

encephalitis without muscle weakness (22%)

and milder illness with fever and headache only(7%).54 Neuromuscular manifestations include

polyradiculitis, axonal polyneuropathy simulating

poliomyelitis or occasionally Guillain-Barre

syndrome.55 Seizures is said to be uncommon in

West Nile encephalitis..56

Eastern equine encephalitis

Eastern equine encephalitis is a life threatening

mosquito borne arboviral infection found mainly

along the east and gulf coast of USA. Cases occur

sporadically in small epidemics. Two hundredand twenty three cases were reported to Centers

for Disease Control and Prevention during 1955

to 1993. It results in nonspecic clinical picture

and diagnosis is based on CSF serology, PCR and

brain tissue. The radiological ndings are similar

to JE. In a study on eastern equine encephalitis,

MRI revealed thalamic and basal ganglia

involvement in 7% each and brainstem in 43%

patients. Cortical lesions, white matter changes

and meningeal enlargement were less common.

Seizures were reported in 8 patients (25%); 5

had generalized seizure; 3 had focal seizures with

one secondary generalized and one had complex

partial seizure. EEG revealed slowing except in

6 patients who had focal epileptiform discharges

and periodic lateralized epileptiform discharges

(PLEDs). Thirty six percent of patients died and

35% had moderate to severe sequelae.57

Nipah virus encephalitis

Nipah virus is closely related to Hendra virus.

Hendra virus was discovered in an outbreak in

Australia in 1994. Nipah virus was rst isolated

in 998-999, where it resulted in an outbreak

of encephalitis in pig farmers of Malaysia and

Singapore affecting about 300 patients.58 Nipah

virus has high infection rate because half the

patients have affected family members and for

every 3 patients there was one asymptomatic

infections. The reservoir of Nipah virus is fruit bat

ofPteropus species. Half eaten fruits by bats mayinfect the pigs.59 Pig to pig transmission nally

affects the human being working in pig farms.

Outbreaks of Nipah virus encephalitis have also

been reported from Siliguri, India and Bangladesh.

The pathogenesis of Nipah virus encephalitis

is thought to be due to vasculitis of medium

and small sized vessels causing thrombosis and

microinfarcts, and direct neuronal invasion.58

Nipah encephalitis affects all age groups; its

incubation period is less than 2 weeks. The clinical

manifestations are fever, headache, vomiting

and altered sensorium. Brain stem involvement

results in distinctive clinical features such as

myoclonus, hypotonia, ataxia and autonomic

changes. Segmental myoclonus occurs in one-

third cases mostly in diaphragm and anterior neck

muscles which is associated with high mortality.

Nipah encephalitis has an unusual tendency for

recurrence. About 0% patients suffer a second or

even third episode months or years after recovery

form the rst attack (relapsed Nipah encephalitis).

About 5% patients who either were asymptomatic

or had a mild nonencephalitic illness may alsodevelop late-onset Nipah encephalitis.60 Seizure

is commoner in relapsed or late-onset Nipah

encephalitis occurring in half the patients;

however myoclonus is uncommon. The autopsy

studies have revealed that relapsed / late-onset

encephalitis is associated with presence of Nipah

virus antigen detected by immuno-localization in

brain with out vasculitis.6,62 In a study on 137

patients with Nipah encephalitis, 2.2% developed

epilepsy in 8 years follow up. Risk of epilepsy

is .8% in acute and 4% in late-onset Nipah

encephalitis (Tan CT, unpublished observation).Cerebrospinal uid shows pleocytosis and

protein rise in 75% patients. IgM antibodies

are present in all by 12 weeks and IgG by 4

weeks. Brain MRI in acute stage shows multiple

disseminated small discrete hyperintense lesions

best seen in FLAIR sequence particularly in

sub-cortical and deep white matter suggesting

microinfarct, which has been confirmed in

postmortem studies.63 EEG abnormalities have

been reported in 97% patients. It is commonly

seen as continuous, diffuse symmetrical slowingof background with or without focal changes.

The slowing corresponds to severity of illness.


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Bilateral periodic lateralized epileptiform

discharges (BiPLEDs) are seen in 25% patients

with acute encephalitis and correlated with coma

and high mortality (all patients with BiPLEDs died

by day 5).64 The mortality of Nipah encephalitis

seems to be reduced by ribavirin.65

MISCELLANEOUS VIRUSES

A number of other viruses can result in encephalitis

and seizures. Some important viruses are briey

mentioned in the following section.

Varicella zoster

Chickenpox is a common self-limiting childhood

infection. Sometimes in adults, chickenpox may

be associated with encephalitis. Varicella zoster

is also associated with uni-focal and multi-focal

vasculopathy. Uni-focal large vessel vasculopathy

usually affects elderly immuno-competent patients

whereas muiti-focal vasculopathy affects elderly

immuno-compromised patients. In the former,

zoster is followed several weeks later by ipsilateral

middle cerebral artery infarction due to retrograde

spread of Varicella zoster via trigeminal system.

Less typical presentation includes cerebral

vasculopathy following remote site of infection

e.g. sacral, progressive leucoencephalopathy or

vasculitic optic neuropathy.66 Seizure is a feature

of zoster encephalitis-vasculitis.67 The prognosisis good following acyclovir therapy.

Mumps

Mumps virus is a paramyxovirus and causes self-

limiting febrile illness with parotitis. Neurological

complications are common in mumps. CSF

pleocytosis was present in 50% patients with

uncomplicated parotitis who underwent lumbar

puncture.68 Aseptic meningitis in mumps is

self limiting and may persist up to one month.

Before mumps vaccination, mumps encephalitisconstituted 20-30% of encephalitis.69 Encephalitis

generally occurs -2 weeks after the parotitis and

manifests with fever, altered sensorium, seizures,

focal weakness, abnormal movements and

aphasia. Mumps encephalitis usually resolves by

-2 weeks. The sequelae include focal weakness

and seizures.69,70 Death occurs in 1-2% cases.

Orchitis, parotitis and pancreatitis may or may

not accompany CNS disease.

Influenza

Encephalitis is a rare complication of inuenza

A infection and is associated with mortality

rate of 25%. Systemic manifestations such

as coagulopathy and hepatic dysfunction are

associated with high mortality. Inuenza B

is associated with seizures, PLEDs and focal

temporal lobe abnormalities on MRI.7

Enteroviruses

Enteroviruses cause 40-60% of viral meningitis,

most cases of acute flaccid paralytic and

a small number of cases of encephalitis in

children. With nearly successful eradication

of poliovirus by vaccination, coxsackie and

echo viruses are the responsible enteroviruses.

Most enterovirus infections are asymptomatic.

However, systemic manifestations include rash,

respiratory symptoms, pleurodynia, carditis

and diarrhea. Group A coxsackie virus causes

herpengina. Coxsackie and echo virus is commoncause of aseptic meningitis but occasionally causes

encephalitis, cerebellitis, opsoclonus myoclonus

syndrome and focal encephalitis.72 Rarely bilateral

hippocampal lesions on MRI mimicking HSE have

been reported.73 Enteroviruses can cause severe

spinal and brainstem encephalitis in children.74

Seizure has been described in enterovirus 7

encephalitis.75

Measles

Measles is infrequently associated with encephalitisalthough subclinical form of CNS involvement

demonstrated by EEG abnormalities in 50%

cases.76 Measles encephalitis is usually nonfocal

and presents during convalescence. Patients

present with fever, seizures and altered mental

state. Following measles encephalitis, although

most patients survive, neurological sequelae

are common. Diagnosis is usually on clinical

grounds but can be conrmed serologically.

Measles can also cause progressive sub-acute

encephalitis in immune compromised patients77,

acute disseminated encephalomyelitis (ADEM)

and subacute sclerosing panencephalitis, which

can also be associated with seizures.

ACUTE DISSEMINATED

ENCEPHALOMYELITIS (ADEM)

Acute disseminated encephalomyelitis (ADEM)

is a monophasic complication characterized by

rapid onset of neurologic symptoms and signs

following viral encephalitis in children and adults.

ADEM occurs in 1 in 1000 measles infection

with mortality as high as 25% and neurological

sequelae in 25-40% of survivors.78 On the


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0

other hand, the incidence of ADEM following

varicella zoster and rubella infections are in

0,000 and in 20,000 respectively with lower

occurrence of neurological sequelae compared to

measles. In the tropical countries because of poor

vaccination coverage, ADEM continues to be a

common health problem. The important pathogensassociated with ADEM include measles, herpes

simplex, HIV, human herpes virus, mumps,

inuenza, Epstein Barr and coxsackie viruses.

The frequency and severity of ADEM following

viral infection is highly variable. ADEM has also

been reported following Mycoplasma pneumoniae

and Legionella, Cincinnatiensis. The neurologic

signs and symptoms include paresthesia, pain,

weakness, spasticity, incoordination, dysarthria

and dysphagia. Seizure may occur in severe

cases and its incidence ranges between 4% and

35%.79,80 Seizures in ADEM following measles

infection may be as high as 50%. Some studies

have reported high incidence (35%) of partial

seizures and status epilepticus in ADEM.76 The

management of seizures in ADEM is same as

encephalitis.

STATUS EPILEPTICUS IN ENCEPHALITIS

Encephalitis is an important cause of refractory

seizures and status epilepticus. There is paucity

of systemic prospective study of status epilepticus

in encephalitis. Herpes simplex, JE, West Nile,

inuenza, Papova virus have been reported to

result in status epilepticus. In last 3 years, our

studies on status epilepticus revealed 3 out

of 0 cases (30%) were due to encephalitis,

another 25% were from other CNS infection.

The etiologies of the encephalitis were JE in

9, HSE in , dengue in , and in 7 patients no

etiology agent could be established. Generalized

convulsive status epilepticus was the commonest

(2), followed by partial status epilepticus with

secondary generalization (5) and nonconvulsivestatus epilepticus in 4 patients. The seizures

were difcult to control. Nine of our patients had

refractory status epilepticus, and 10 died. MRI

changes and Glasgow Coma Scale were related

to outcome. We concluded that status epilepticus

in encephalitis requires aggressive therapy. (Misra

UK, Kalita J, unpublished observations)

MANAGEMENT OF SEIZURES IN VIRALENCEPHALITIS

Seizures can occur at any stage of encephalitis,from being the presenting feature to late sequelae.

Their severity, frequency and response to

treatment are variable according to the etiology

and other factors. There are limited large-scale

studies on management of seizures in encephalitis.

The recommendations on management of seizures

related to encephalitis, including the section

below are largely based on clinical experience,

and experience from other causes of acutesymptomatic seizures.

General management

Other than the use of antiepileptic drugs to arrest

the seizures, other general measures including the

use of antibiotic and antiviral drugs, electrolyte

and uid management, blood pressure monitoring,

respiratory and other aspects of intensive care are

equally important. Many antibiotics often used in

co-existent infections such as quinolones, third or

fourth generation cephalosporins and meropenemmay precipitate or aggravateseizures.

Urgency of seizure control and choice of

antiepileptic drugs

The signicance of single seizure in encephalitis

is obviously dependant on the type of infection,

and the clinical status of the individual patient.

Seizures are common in HSE and is associated

with poor outcome.3 In a Vietnamese study on JE,

seizures were again common, had high mortality,

poor sequele as well as brain herniation.47

Thesearguefor urgent measures even after rst seizure

in encephalitis. We have found in majority of JE,

the seizures are easily controlled by phenytoin

or carbamazepine monotherapy.44 However,

when intravenous antiepileptic drugs are used,

one should be aware of the potential deleterious

effect of respiratory suppression, and lowering of

blood pressure on the brain with high intracranial

pressure.

Management of status epilepticus

As mentioned above, encephalitis is an important

cause of status epilepticus, and is associated with

high mortality. Diagnosis of convulsive seizures

is easy, but subtle seizures and nonconvulsive

seizures require EEG. The subtle seizures manifest

with eye deviation, nystagmus, hyperventilation

and subtle tremulousmovement of ngers, chin,

and eyelids. Management of status epilepticus in

encephalitis is similar to status epilepticus from

other causes.

Prophylactic antiepileptic drug treatment

In encephalitis from HSV and JE, where there is


11/13

high incidence of seizures, which may contribute

to the high mortality and morbidity, one may argue

for the routine use of prophylactic antiepileptic

drugs during acute encephalitis, without clinical

seizures. However, the benet of such a practice

awaits conrmation from further studies.

Duration of use of antiepileptic drug treatment

In encephalitis with seizures that is easily

controlled by antiepileptic drugs, there is no study

to address the issue of the duration to continue

the antiepileptic drugs. Based on the consideration

that the seizures is related to acute pathology, the

antiepileptic drugs should thus cover the duration

of active pathology, which in most cases, is less

than 3 months.

ACKNOWLEDGEMENT

We acknowledge Rakesh Kumar Nigam for

secretarial help.

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