Seizures in encephalitis

Neurology Asia 2008; 13 : 1 – 13
REVIEW ARTICLES
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
13% after meningitis with early seizures. Amongst the viruses, HSE is associated with most frequent
and 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 flaviviruses 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, influenza 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.
INTRODUCTION
Encephalitis refers to acute inflammatory process
affecting the brain. Viral infections are the most
important cause of encephalitis. There are over
100 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 be
carefully excluded. Viral encephalitis generally
results in nonspecific clinical picture with some
specific 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 1 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 of
clinically diagnosable encephalitis is between
3.5-7.4/100,000 population/year; however
in children the incidence is much higher. 1
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
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: ukmisra@sgpgi.ac.in, drukmisra@rediffmail.com
Neurology Asia
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 11%
each, and influenza 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
specific 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 13% 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 516 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
reflect primary HSV infection in younger age
group and reactivation of latent HSV infection
in older patients. In immunocompetent patients,
more than 90% of HSE occurs due to infection
with HSV-1 and the remainder due to HSV-2.7
More than two-third cases of HSE due to HSV1
infection appears to result from reactivation
of endogenous latent HSV-1 infection in the
individuals previously exposed to the virus.
HSV-1 has remarkable capability for producing
latency, persistent infection and for reactivation.8
Primary HSV1 infection results in axoplasmic
transport to the trigeminal sensory ganglion
where it establishes latency. Latent HSV1 virus
is detectable in trigeminal ganglia of nearly all
June 2008
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 spread
via olfactory pathway to orbitofrontal and medial
temporal lobes.9 Affinity of HSV-1 for basifrontal and medial temporal (limbic) cortex and
sparing of the most other cortices, grey matter,
nuclear masses and white matter is interesting and
mysterious. The affinity 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
HSV1.10 This affinity 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.11
The EEG and MRI findings in HSE are
consistent with frontotemporal involvement
(Figure 1). 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 11 year
after HSE, the most common long term symptom
was behavioral abnormality in 45% followed by
seizures in 24.7%.12 Seizures were the presenting
feature in 50% patients in the acute stage. Seizures
are not only common in HSE but also have
prognostic significance. In a study on children
Figure 1A: Cranial MRI, T2 sequence of a patient with
herpes simplex encephalitis shows hyper
intensity in temporal lobes.
with HSE where 47 patients were evaluated,
26 (65%) had good outcome and 14 (35%) had
poor outcome. Seizures occurred at the time of
presentation in 63% and 71% of them had poor
outcome. Abnormal neuroimaging (79%) and EEG
(92%) were more prevalent in patients with poor
outcome group.13 Temporal and frontal cortices
are highly epileptogenic compared to parietal
and occipital cortex. Change in excitability of
hippocampal A3 neuronal network and HSV1
induced neuronal loss results in mossy fiber
reorganization which may play an important role
in the generation of epileptiform activity.14
Clinical characteristics and prognosis of post
encephalitic epilepsy in children were evaluated
in 44 patients aged 21 mo to 17 year (mean 8.1
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 first stage, slow background
activity, multifocal spikes and HSE.15
Figure 1B: EEG of the same patients showing rhythmic slow waves both sides, and periodic lateralized epileptiform
discharges (PLEDs) on the right.
Neurology Asia
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 period
after HSE. Autopsy confirmed active encephalitis
consisting of necrosis and lymphocytic infiltration
with intranuclear inclusions in neurons and glia
and markedly edematous parenchyma of frontal
and parietal lobes. HSV1 antigen was detected
by immunohistochemistry, HSV-1 DNA by in situ
hybridization and herpes virus nucleocapsid by
electron microscopy. These findings suggest that
direct viral reactivation might result in relapse of
HSE causing progressive clinical deterioration
associated with persistence of HSV1 in brain.16 In
a long term follow up study of cognitive sequelae
of HSE, 1 out of 8 adult patients with HSE
experienced progressive clinical deterioration.17
In children with HSE progressive cognitive and
behavioral deterioration for many years has
also been reported.18,19 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 with
chronic 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 HSV1 encephalitis
diagnosed 6 months, 3 years and 7 months back,
underwent surgical reaction 8.5 years, 6 years and
3 years respectively. Pathological examination
confirmed chronic encephalitis in all 3 patients
and PCR revealed HSV1 genome. These cases
represent example of chronic herpes encephalitis
manifesting with seizure disorder and presence
of viral genome in brain long after initial episode
of treated HSE.18
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 confirmed 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
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a study on 151 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.21 These preliminary
results do need further studies.
Experimental studies on hippocampal excitability
in herpes simplex encephalitis
Corneal inoculation of mice with HSV-1
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 membrane
potential 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-1 virus resulted
in epileptiform activity, neuronal loss and increase
in mossy fiber 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 fiber reorganization which may have a
role in seizures and epilepsy following HSV
infection.14
HSV strains vary with respect to their neurovirulence, +GC strains of HSV1 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 1 of animals that
developed seizures.
FLAVIVIRUS ENCEPHALITIS
Several mosquito born neurotropic members of
genus flavi virus family cause similar disease
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 flavirus, which causes 30,000
to 50,000 cases of encephalitis and 10,000 deaths
in Asia every year. West Nile virus is prevalent
in 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 don’t have sufficiently
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 (1 in 300) of the exposed persons
and encephalitis occurs in even fewer. Thus JE
does 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 when
it 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 1975.26
Advance age is associated with greater severity
of West Nile, St Louis and JE27,28, in which there
is 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 flavivirus and cross reacting
antibodies may affect the outcome of infection
with a second flavivirus. 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 3-15
days and a short nonspecific 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 10% in
West Nile encephalitis.
Japanese encephalitis
JE is a severe form of endemic flavivirus
encephalitis manifesting with features of
encephalitis 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 19.4% of patients.31 Similar findings
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 findings.32 Thalamus and
basal ganglia involvement in JE is associated with
high frequency of movement disorders, which
may appear as transient form of parkinsonism
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June 2008
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 163 JE patients, 37.4% had evidence
of neurocysticercosis confirmed by antibodies in
CSF, 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
Figure 2A: Cranial MRI T1 sequence of a child
with Japanese encephalitis and status
epilepticus shows hyperintense lesion
in thalamus bilaterally and frontoparietal cortical involvement.
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. 41 Isolated case report of
Day 90
Figure 2B: EEG of the same child shows epileptiform discharges on the left side, some of which spread
to right.
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 first week of encephalitis. The
seizures were generalized tonic clinic in 17 and
partial motor with secondary generalization in
13. 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
children41, 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 significant.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, 134 children and 10 adults, 29% had
seizures and 12% died. Of the 40 patients with
witnessed seizures, 60% died or had severe
sequelae compared to only 26% of 104 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 nonspecific. In a study
on 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 sufficient 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. In
3 JE patients with alpha coma, 1 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 1, burst suppression
pattern in 1 and normal in 1 patient. Patients
with grade 1 b had poor outcome compared to
less severe EEG abnormality. Asymmetrical EEG
pattern was not related to outcome. Seizures were
documented in 20% of patients.47
Dengue
Dengue is an important flavivirus 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 manifestations
following 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
17 patients had encephalopathy and 6 had acute
flaccid 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 1 had
poor outcome. Dengue patients presenting with
encephalopathy had more severe illness and worse
outcome than those with myositis only. Dengue
myositis 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.51,52 The EEG changes in dengue
virus infection are nonspecific; slowing occurs in
55% patients in a study on 24 dengue patients with
neurological involvement. The EEG abnormality
correlates with level of consciousness.51
St. Louis encephalitis
St Louis encephalitis is one of the most common
arboviral 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 flu 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 Nile
encephalitis. 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 hundred
and twenty three cases were reported to Centers
for Disease Control and Prevention during 1955
to 1993. It results in nonspecific clinical picture
and diagnosis is based on CSF serology, PCR and
brain tissue. The radiological findings are similar
to JE. In a study on eastern equine encephalitis,
MRI revealed thalamic and basal ganglia
involvement in 71% each and brainstem in 43%
patients. Cortical lesions, white matter changes
and meningeal enlargement were less common.
Seizures were reported in 18 patients (25%); 15
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 first isolated
in 1998-1999, where it resulted in an outbreak
June 2008
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
of Pteropus species. Half eaten fruits by bats may
infect the pigs.59 Pig to pig transmission finally
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 onethird cases mostly in diaphragm and anterior neck
muscles which is associated with high mortality.
Nipah encephalitis has an unusual tendency for
recurrence. About 10% patients suffer a second or
even third episode months or years after recovery
form the first attack (relapsed Nipah encephalitis).
About 5% patients who either were asymptomatic
or had a mild nonencephalitic illness may also
develop 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.61,62 In a study on 137
patients with Nipah encephalitis, 2.2% developed
epilepsy in 8 years follow up. Risk of epilepsy
is 1.8% in acute and 4% in late-onset Nipah
encephalitis (Tan CT, unpublished observation).
Cerebrospinal fluid 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 slowing
of background with or without focal changes.
The slowing corresponds to severity of illness.
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
rate of 25%. Systemic manifestations such
as coagulopathy and hepatic dysfunction are
associated with high mortality. Influenza B
is associated with seizures, PLEDs and focal
temporal lobe abnormalities on MRI.71
MISCELLANEOUS VIRUSES
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 common
cause 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 71
encephalitis.75
A number of other viruses can result in encephalitis
and seizures. Some important viruses are briefly
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 prognosis
is good following acyclovir therapy.
Mumps
Mumps virus is a paramyxovirus and causes selflimiting 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 encephalitis
constituted 20-30% of encephalitis.69 Encephalitis
generally occurs 1-2 weeks after the parotitis and
manifests with fever, altered sensorium, seizures,
focal weakness, abnormal movements and
aphasia. Mumps encephalitis usually resolves by
1-2 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 influenza
A infection and is associated with mortality
Enteroviruses
Measles
Measles is infrequently associated with encephalitis
although 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 confirmed 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
Neurology Asia
other hand, the incidence of ADEM following
varicella zoster and rubella infections are 1 in
10,000 and 1 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 pathogens
associated with ADEM include measles, herpes
simplex, HIV, human herpes virus, mumps,
influenza, 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,
influenza, Papova virus have been reported to
result in status epilepticus. In last 3 years, our
studies on status epilepticus revealed 31 out
of 101 cases (30%) were due to encephalitis,
another 25% were from other CNS infection.
The etiologies of the encephalitis were JE in
9, HSE in 1, dengue in 1, and in 17 patients no
etiology agent could be established. Generalized
convulsive status epilepticus was the commonest
(21), followed by partial status epilepticus with
secondary generalization (5) and nonconvulsive
status epilepticus in 4 patients. The seizures
were difficult 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 VIRAL
ENCEPHALITIS
Seizures can occur at any stage of encephalitis,
from being the presenting feature to late sequelae.
Their severity, frequency and response to
10
June 2008
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 acute
symptomatic 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 fluid 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 meropenem
may precipitate or aggravate seizures.
Urgency of seizure control and choice of
antiepileptic drugs
The significance 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.13 In a Vietnamese study on JE,
seizures were again common, had high mortality,
poor sequele as well as brain herniation.47 These
argue for urgent measures even after first 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 tremulous movement of fingers, 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
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 benefit of such a practice
awaits confirmation 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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