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Home , 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 , Sanjay Gandhi PGIMS, Lucknow, India; *Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Abstract

A large number of can result in encephalitis. However, certain viruses are more prevalent in certain geographical regions. For example, (JE) and dengue in South East Asia and West Nile in Middle East whereas encephalitis (HSE) occurs all over the world without any seasonal or regional variation. Encephalitis can result in acute symptomatic and remote symptomatic . Risk of seizures after 20 years is 22% following encephalitis and 13% after 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 . HSE can also result in chronic and relapsing form of encephalitis and may be an aetiology factor in drug resistant epilepsy. Amongst the , 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 , varicella, , and may result in encephalitis and seizures. 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 are estimates that HSE is the most important Encephalitis refers to acute inflammatory process cause of treatable with an affecting the brain. Viral are the most of 1 case/million population/year. important cause of encephalitis. There are over Certain viruses are prevalent in certain regions. 100 viruses that can result in encephalitis. The Japanese encephalitis (JE) in South East Asia, patients present with and varying degree of West Nile encephalitis is Middle East, St. Luis alteration in sensorium which may be associated encephalitis and equine encephalitis in America with focal neurological signs or seizures. In such are some examples. Lately West Nile encephalitis patients, , bacterial meningitis and non from USA and Nipah encephalitis from infectious causes of must be Malaysia have been reported. The incidence of carefully excluded. Viral encephalitis generally clinically diagnosable encephalitis is between results in nonspecific clinical picture with some 3.5-7.4/100,000 population/year; however specific features of anatomical involvement in children the incidence is much higher.1 such as behavioral changes, aphasia or partial Encephalitis may occur in sporadic or epidemic complex in herpes simplex encephalitis form. Establishing the diagnosis of viral (HSE) because of characteristic frontotemporal encephalitis may be challenging. The likelihood involvement. of a virus depends upon the geographical location, There are numerous viruses responsible timing of the epoch studied and method or rigor for viral encephalitis. While precise estimates of investigation. In a recent study in Finland, about the incidence of encephalitis following (CSF) polymerase chain these viral infections are not available; there 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: [email protected], [email protected]

 Neurology Asia June 2008 patients with CNS infections, such as encephalitis, seropositive individuals.8 Reactivation results in meningitis and . In this study, Vericella retrograde transport of virus resulting in herpes zoster was the most common (29%), labialis amongst other clinical manifestations. followed by herpes and entero viruses in 11% However the pathway by which HSV reaches the each, and influenza A virus in 7% of patients.2 CNS in humans to produce encephalitis remains This study suggests that HSV is probably over unknown. In Primary infection, virus could invade estimated and Varicella zoster underestimated. the olfactory bulbs through the nose and spread HSE however, remains a critical diagnosis because via olfactory pathway to orbitofrontal and medial specific treatment is available for this encephalitis. temporal lobes.9 Affinity of HSV-1 for basi- In USA, the most important encephalitides are frontal and medial temporal (limbic) cortex and HSE and encephalitides, but 73% sparing of the most other cortices, grey matter, encephalitis is of undetermined etiology.3 nuclear masses and white matter is interesting and Encephalitis and are mysterious. The affinity for the specialized areas important causes of acute symptomatic seizures is attributed to intranasal inoculation and spread and remote symptomatic epilepsy. Long-term risk via olfactory nerve of HSV.9 Proximity of dural of seizures following CNS infection was studied nerves to basifrontal and temporal lobes, virus in a large population based study. Twenty year lies dormant in anterior and middle cranial fossa risk of unprovoked seizures was 6.8%; 22% for which renders these areas more susceptible to encephalitis with early seizures, and 13% for HSV. The virus may travel by cell to cell contact bacterial meningitis with early seizures.4 In the across the into adjacent cortices. The present review, the seizures in HSE, structures involved in HSE are part of limbic (Japanese encephalitis, eastern equine and western system and these boundaries are respected by equine, dengue), and other viruses including Nipah HSV1.10 This affinity is attributed to distinctive virus encephalitis will be discussed. anatomical, neurochemical and immunological properties of these cortices. HERPES SIMPLEX ENCEPHALITIS Clinical spectrum is a neurotropic virus and is the most important cause of sporadic The clinical manifestations of HSE in older encephalitis in children above 6 months and in children and adults are indicative of area of adults.5 No seasonal or gender related preference pathology in the brain. These include focal occurs in HSE. It has a high mortality of 70% if encephalitis with fever, altered sensorium, bizarre untreated and prognosis is poor. Only a minority behavior and focal neurological signs. The focal of patients return to normal functions. There is neurological signs are related to fronto-temporal a bimodal distribution of HSE with one third involvement including aphasia, personality cases occurring before 20 years of age and half change and focal seizures. Such focality however in those above 50 year of age. In a recent PCR may be minimal in the acute stage and may not study on 516 patients with clinical evidence of be diagnostic of a particular viral cause. It has encephalitis, 7.4% patients were due to HSE and recently been reported that about 20% HSE cases most of these HSE patients were above 40 year may be relatively mild and atypical without any of age.6 The bimodal distribution of HSE may focal feature.11 reflect primary HSV infection in younger age The EEG and MRI findings in HSE are group and reactivation of latent HSV infection consistent with frontotemporal involvement in older patients. In immunocompetent patients, (Figure 1). However there are no characteristic more than 90% of HSE occurs due to infection series of findings pathognomonic of HSE. with HSV-1 and the remainder due to HSV-2.7 Seizures in HSE can be acute symptomatic or More than two-third cases of HSE due to HSV1 remote symptomatic. In a study on 29 survivors infection appears to result from reactivation of 34 biopsy proven HSE patients with acyclovir of endogenous latent HSV-1 infection in the therapy, who were evaluated 6 months to 11 year individuals previously exposed to the virus. after HSE, the most common long term symptom HSV-1 has remarkable capability for producing was behavioral abnormality in 45% followed by latency, persistent infection and for reactivation.8 seizures in 24.7%.12 Seizures were the presenting Primary HSV1 infection results in axoplasmic feature in 50% patients in the acute stage. Seizures transport to the trigeminal sensory ganglion are not only common in HSE but also have where it establishes latency. Latent HSV1 virus prognostic significance. In a study on children is detectable in trigeminal ganglia of nearly all

 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 Figure 1A: Cranial MRI, T2 sequence of a patient with post encephalitic epilepsy were status epilepticus herpes simplex encephalitis shows hyper occurring during the first stage, slow background intensity in temporal lobes. 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.

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Although HSE typically produces a monophasic a study on 151 children with febrile ; illness, chronic encephalitis and relapsing 5 children with complicated febrile encephalitis have also been reported rarely. A did not have HSV in serum and CSF, 66 year old immunocompetent man developed but CSF was positive for HSV PCR. The authors status epilepticus and died of pneumonia in the suggested that any patient with complicated febrile course of progressive , cognitive convulsion should be investigated for HSV PCR, decline and brain atrophy over 9.5 year period to look for HSV encephalitis.21 These preliminary after HSE. Autopsy confirmed active encephalitis results do need further studies. consisting of necrosis and lymphocytic infiltration with intranuclear inclusions in neurons and glia Experimental studies on hippocampal excitability and markedly edematous parenchyma of frontal in herpes simplex encephalitis and parietal lobes. HSV1 antigen was detected Corneal inoculation of mice with HSV-1 by immunohistochemistry, HSV-1 DNA by in situ induces acute spontaneous behavioral and hybridization and herpes virus nucleocapsid by electroencephalographic seizures because of electron microscopy. These findings suggest that increased hippocampal excitability and seizure direct viral reactivation might result in relapse of susceptibility. In slices from infected mice, the HSE causing progressive clinical deterioration surviving hippocampal CA3 pyramidal neurons associated with persistence of HSV1 in brain.16 In exhibited a more depolarizing resting membrane a long term follow up study of cognitive sequelae potential concomitant with an increase in of HSE, 1 out of 8 adult patients with HSE membrane input resistance. They also had lower experienced progressive clinical deterioration.17 threshold for generating synchronized bursts and In children with HSE progressive cognitive and a decrease in amplitude after hyperpolarization behavioral deterioration for many years has (AHP) compared to controls. These results also been reported.18,19 Most of these patients suggest that a direct change in the excitability develop intractable seizures, slowly progressive of hippocampal CA3 neuronal network could hemiparesis and cognitive decline some years play an important role in the development of after contacting the disease. The histopathological acute seizure and subsequent epilepsy in HSV changes are consistent with chronic active infection.22 Similar results were reported in encephalitis. another experimental study in which hippocampal Intractable seizure disorders associated with cell culture on treatment with HSV-1 virus resulted chronic herpes infection are being reported when in epileptiform activity, neuronal loss and increase the pharmaco-resistant epilepsy patients were in mossy fiber sprouting. Intracellular recording subjected to epilepsy surgery and resected brain of CA3 pyramidal neurons revealed more tissue was subjected to histopathology and PCR. depolarizing resting membrane potential, reduced Three patients who developed HSV1 encephalitis threshold for generating synchronized burst diagnosed 6 months, 3 years and 7 months back, and decreased amplitude of hyperpolarization underwent surgical reaction 8.5 years, 6 years and compared to controls. These results show increase 3 years respectively. Pathological examination in CA3 neuronal excitability, neuronal loss and confirmed chronic encephalitis in all 3 patients mossy fiber reorganization which may have a and PCR revealed HSV1 genome. These cases role in seizures and epilepsy following HSV represent example of chronic herpes encephalitis infection.14 manifesting with seizure disorder and presence HSV strains vary with respect to their neuro- of viral genome in brain long after initial episode virulence, +GC strains of HSV1 replicate to of treated HSE.18 higher titers and expressed more abundant viral There was a case report of chronic persistent antigens then –GC strain. +GC strains spread temporal lobe encephalitis following genital more completely through out the brain to involve herpes by HSV-2 resulted in intractable partial amygdela, nucleus accumbens, brainstem nuclei complex seizure which necessitated temporal and locus ceruleus. +GC antigens has also been lobectomy. Immunohistochemistry of resected found in cerebral cortex layer 1 of animals that temporal lobe confirmed HSV2 infection. Post developed seizures. operative exacerbation of seizures was resistant to drugs and could be controlled after acyclovir FLAVIVIRUS ENCEPHALITIS therapy.20 Complicated febrile convulsions may also be Several mosquito born neurotropic members of the initial manifestation of HSV-1 encephalitis. In genus flavi virus family cause similar disease

 pattern across the globe. These viruses include St. southern USA, but most of the population does Louis and equine encephalitis in USA, Rocio virus not have pre-existing immunity because of low encephalitis in Brazil, Murray Valley encephalitis rate of transmission of virus to humans. However in Australia, New Guinea, and New Zealand. JE is occasionally there has been outbreak of St Louis the most important flavirus, which causes 30,000 encephalitis as in 1975.26 to 50,000 cases of encephalitis and 10,000 deaths Advance age is associated with greater severity in Asia every year. is prevalent of West Nile, St Louis and JE27,28, in which there in Middle East and recently outbreaks have been is a second peak in the elderly. The exact reason reported from USA. Flavivirus genus also includes for more severe disease in elderly though not mosquito born virus that causes hemorrhagic fever known but impaired integrity of blood brain (yellow fever, and tick borne virus). barrier (BBB) due to or Flavivirus is a small RNA virus with an envelop neurocysticercosis may be responsible.29 Prior protein which is important for viral attachment infection with a flavivirus and cross reacting and entry into the host. antibodies may affect the outcome of infection with a second flavivirus. For example, in JE, Epidemiology prior infection with dengue may protect against a severe illness.30 However, serial infection with Epidemiology of flavivirus is governed by different serotypes of dengue virus is associated complex interplay between entomologic (vector), with more severe illness; e.g. dengue hemorrhagic climatic, human behavior and viral factors that fever. The strain variation may also be important are not completely understood.23 Humans are dead determinant of the severity of clinical picture in end host because they don’t have sufficiently endemic area. prolonged viremia to transmit the virus. However, West Nile virus can be transmitted to humans Clinical features through blood products and organ transplantation because of relatively prolonged viremia. In Asia, The neurological disease typically develops pigs and birds are important natural hosts for JE in patients after an incubation period of 3-15 virus because these animals are often kept close days and a short nonspecific febrile illness. The to human habitat. They serve as amplifying host neurological symptoms and signs depend on and transmit virus to humans. In USA death of which part of the is predominantly crows and blue jays may serve as warning that affected. The involvement of meninges cause human disease is imminent.24,25 meningitis, brain parenchyma causes encephalitis and causes myelitis. The most JE is mostly a disease of children where as important manifestation which often overlap West Nile encephalitis and St Louis encephalitis are impairment of consciousness and seizures in USA affect adults. This paradox is attributed occurring in about 85% patients with JE and to intensity of viral transmission and to acquired Murray Valley encephalitis, and up to 10% in immunity. Serological surveys reveal that in West Nile encephalitis. endemic areas almost everyone is infected by JE virus during childhood, however fever occurs Japanese encephalitis in a minority (1 in 300) of the exposed persons and encephalitis occurs in even fewer. Thus JE JE is a severe form of endemic flavivirus does not occur in adults in endemic areas because encephalitis manifesting with features of adults are already immune to JE virus. However in encephalitis or . In a study on a newly invaded JE virus area all the age groups radiological changes in JE, CT scan was done in are at risk of developing JE. Travelers to endemic 38 and MRI in 31 patients. Thalamic involvement area are also at risk of developing JE. was present in 93.5% (Figure 2), basal ganglia in Epidemiology of Murray valley encephalitis 35%, mid brain in 58%, pons in 26% and cerebral cortex in 19.4% of patients.31 Similar findings in Australia and West Nile in Africa follows a 32,33 pattern similar to JE in Asia, though fewer cases have been reported in earlier autopsy studies. of encephalitis occur in these areas. A pure febrile Anterior horn cell involvement in JE has also been reported based on clinical, neurophysiological34,35 caused by Murray valley encephalitis 32 virus is not seen. West Nile virus results in large and neuropathological findings. Thalamus and out breaks of fever, arthralgia and rash but when basal ganglia involvement in JE is associated with it spread to new areas, it results in outbreaks of high frequency of movement disorders, which encephalitis. St Louis encephalitis is endemic in may appear as transient form of

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and varying types of . Severe dystonia simulating 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 Seizures in JE have been noted by a number of with Japanese encephalitis and status investigators. These are partial motor or secondary epilepticus shows hyperintense lesion generalized and appear at the onset or during in thalamus bilaterally and frontopari- the course of disease occurring more frequently etal cortical involvement. 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 another study on EEG in 56 patients revealed are of interest because of involvement of thalamus slowing of background activity in 35, unreactive and brain stem.42 In JE, seizures are less intractable slowing in 9, low amplitude in 1, burst suppression then HSE.43 In a study, 30 out of 65 JE patients pattern in 1 and normal in 1 patient. Patients had seizures in the first week of encephalitis. The with grade 1 b had poor outcome compared to seizures were generalized tonic clinic in 17 and less severe EEG abnormality. Asymmetrical EEG partial motor with secondary generalization in pattern was not related to outcome. Seizures were 13. Eleven patients had single seizure, 8 had two documented in 20% of patients.47 seizures and 11 had multiple seizures. Interictal EEG in the patients with seizure revealed theta to Dengue delta slowing in all and epileptiform discharges in 4 patients only. MRI carried out in 26 patients Dengue is an important flavivirus with nearly revealed bilateral thalamic lesion in 24, cortical in 50 million cases occurring world wide mostly in 7, basal ganglia in 8 and brainstem involvement Asia, Africa and South America. Most patients in 3. In the seizure group, 3 patients died, 9 had present with fever but some may have dengue poor, 8 partial and 9 complete recovery by 3 hemorrhagic fever, dengue shock syndrome months. Presence of seizure in JE correlated with and dengue encephalopathy or encephalitis. GCS score, focal , EEG abnormality and Though dengue is regarded as a non neurotropic cortical lesion on CT or MRI, though seizure was virus, a variety of neurological manifestations not associated with poor prognosis.44 Although following dengue virus infection have been seizure has been reported to be commoner in reported. Encephalopathy in dengue may be due children41, in a comparative study of JE in adults to metabolic alterations, hypotension, hypoxia, and children, seizures were present 67.2% of hepatic or renal failure. Recently evidence of CNS adults and 56.7% of children, but this difference invasion of dengue virus based on experimental, 46 CSF and PCR studies have been was not statically significant. The seizure was 49,50 generally infrequent and easily controlled with suggested. In a study on 24 dengue patients phenytoin or carbamazepine monotherapy.44 with neurological manifestations, 50% had altered The experience of JE in children from Vietnam sensorium; 5 of whom had seizures (generalized however was different. In a study on 144 JE in 3, focal in one). In another study, 11 out of patients, 134 children and 10 adults, 29% had 17 patients had encephalopathy and 6 had acute seizures and 12% died. Of the 40 patients with flaccid paralysis (myositis). In the encephalopathy witnessed seizures, 60% died or had severe group 3 had seizures and one had . CSF sequelae compared to only 26% of 104 with no pleocytosis and EEG changes were present in 8 witnessed seizures. Patients with seizures were patients each. In the myositis group, creatinine more likely to have elevated CSF opening pressure kinase was raised in 5, electromyography and signs of .47 High frequency (EMG) and muscle biopsy were consistent with of seizure in Vietnamese study could be due to myositis in one patient each. The patients with difference in the herd immunity as well as referral myositis improved completely within one month but in encephalopathy group 3 died and 1 had bias. The Indian study was from a tertiary care referral center where very sick patients with poor outcome. Dengue patients presenting with seizures could not have been referred.44,45 encephalopathy had more severe illness and worse EEG changes in JE are nonspecific. In a study outcome than those with myositis only. Dengue on 27 patients with JE, diffuse slowing of theta to myositis may be an early or mild form of disease delta range was the commonest (24), lateralized whereas encephalopathy may be a more severe form and some patients may have an overlapping spike or spike wave discharges and alpha coma 51,52 in 3 patients each. High frequency of slowing is clinical picture. The EEG changes in dengue attributed for thalamic involvement, lateralized virus infection are nonspecific; slowing occurs in epileptic discharges to cortical and alpha coma 55% patients in a study on 24 dengue patients with to the involvement of thalamus and brainstem, neurological involvement. The EEG abnormality correlates with level of consciousness.51 which is sufficient to produce loss consciousness but not enough to block the alpha activity. Alpha St. Louis encephalitis coma in JE may be common but its prognosis is not as bad as hypoxic coma or cardiac arrest. In St Louis encephalitis is one of the most common 3 JE patients with alpha coma, 1 patient died and arboviral disease in USA in earlier series. It is one each had partial and complete recovery.48 In spread by at least 3 different mosquitoes which

 Neurology Asia June 2008 breed in stagnant water or irrigated fields, of encephalitis in pig farmers of Malaysia and explaining both urban and rural distribution. Singapore affecting about 300 patients.58 Nipah It manifests with flu like illness followed by virus has high infection rate because half the meningoencephalitis. Severity of disease and patients have affected family members and for propensity of virus to infect the CNS increases every 3 patients there was one asymptomatic with age.53 The disease often occurs in outbreaks infections. The reservoir of Nipah virus is fruit bat and clinical manifestations are similar to West Nile of Pteropus species. Half eaten fruits by bats may encephalitis. Neurological sequelae are present in infect the pigs.59 Pig to pig transmission finally 5% of surviving patients. affects the human being working in pig farms. Outbreaks of Nipah virus encephalitis have also West Nile encephalitis been reported from Siliguri, India and Bangladesh. The pathogenesis of Nipah virus encephalitis West Nile encephalitis occurs in summer months. is thought to be due to vasculitis of medium The most common neurological and small sized vessels causing thrombosis and caused by West Nile Virus in New York city microinfarcts, and direct neuronal invasion.58 epidemic included encephalitis with muscle Nipah encephalitis affects all age groups; its weakness (39%), aseptic meningitis (32%), incubation period is less than 2 weeks. The clinical encephalitis without muscle weakness (22%) manifestations are fever, , and milder illness with fever and headache only 54 and altered sensorium. Brain stem involvement (7%). Neuromuscular manifestations include results in distinctive clinical features such as polyradiculitis, axonal polyneuropathy simulating myoclonus, , ataxia and autonomic poliomyelitis or occasionally Guillain-Barre changes. Segmental myoclonus occurs in one- syndrome.55 Seizures is said to be uncommon in .56 third cases mostly in diaphragm and anterior neck West Nile encephalitis. muscles which is associated with high mortality. Eastern equine encephalitis Nipah encephalitis has an unusual tendency for recurrence. About 10% patients suffer a second or Eastern equine encephalitis is a life threatening even third episode months or years after recovery mosquito borne arboviral infection found mainly form the first attack (relapsed Nipah encephalitis). along the east and gulf coast of USA. Cases occur About 5% patients who either were asymptomatic sporadically in small epidemics. Two hundred or had a mild nonencephalitic illness may also and twenty three cases were reported to Centers develop late-onset Nipah encephalitis.60 Seizure for Disease Control and Prevention during 1955 is commoner in relapsed or late-onset Nipah to 1993. It results in nonspecific clinical picture encephalitis occurring in half the patients; and diagnosis is based on CSF serology, PCR and however myoclonus is uncommon. The autopsy brain tissue. The radiological findings are similar studies have revealed that relapsed / late-onset to JE. In a study on eastern equine encephalitis, encephalitis is associated with presence of Nipah MRI revealed thalamic and basal ganglia virus antigen detected by immuno-localization in involvement in 71% each and brainstem in 43% brain with out vasculitis.61,62 In a study on 137 patients. Cortical lesions, white matter changes patients with Nipah encephalitis, 2.2% developed and meningeal enlargement were less common. epilepsy in 8 years follow up. Risk of epilepsy Seizures were reported in 18 patients (25%); 15 is 1.8% in acute and 4% in late-onset Nipah had generalized seizure; 3 had focal seizures with encephalitis (Tan CT, unpublished observation). one secondary generalized and one had complex Cerebrospinal fluid shows pleocytosis and partial seizure. EEG revealed slowing except in protein rise in 75% patients. IgM antibodies 6 patients who had focal epileptiform discharges are present in all by 12 weeks and IgG by 4 and periodic lateralized epileptiform discharges weeks. Brain MRI in acute stage shows multiple (PLEDs). Thirty six percent of patients died and disseminated small discrete hyperintense lesions 35% had moderate to severe sequelae.57 best seen in FLAIR sequence particularly in sub-cortical and deep white matter suggesting Nipah virus encephalitis microinfarct, which has been confirmed in postmortem studies.63 EEG abnormalities have Nipah virus is closely related to Hendra virus. been reported in 97% patients. It is commonly Hendra virus was discovered in an outbreak in seen as continuous, diffuse symmetrical slowing Australia in 1994. Nipah virus was first isolated of background with or without focal changes. in 1998-1999, where it resulted in an outbreak The slowing corresponds to severity of illness.

 Bilateral periodic lateralized epileptiform rate of 25%. Systemic manifestations such discharges (BiPLEDs) are seen in 25% patients as coagulopathy and hepatic dysfunction are with acute encephalitis and correlated with coma associated with high mortality. Influenza B and high mortality (all patients with BiPLEDs died is associated with seizures, PLEDs and focal by day 5).64 The mortality of Nipah encephalitis temporal lobe abnormalities on MRI.71 seems to be reduced by ribavirin.65 Enteroviruses MISCELLANEOUS VIRUSES Enteroviruses cause 40-60% of , A number of other viruses can result in encephalitis most cases of acute flaccid paralytic and and seizures. Some important viruses are briefly a small number of cases of encephalitis in mentioned in the following section. children. With nearly successful eradication of by vaccination, coxsackie and Varicella zoster echo viruses are the responsible enteroviruses. Most infections are asymptomatic. is a common self-limiting childhood However, systemic manifestations include rash, infection. Sometimes in adults, chickenpox may respiratory symptoms, pleurodynia, carditis be associated with encephalitis. Varicella zoster and diarrhea. Group A coxsackie virus causes is also associated with uni-focal and multi-focal herpengina. Coxsackie and echo virus is common vasculopathy. Uni-focal large vessel vasculopathy cause of aseptic meningitis but occasionally causes usually affects elderly immuno-competent patients encephalitis, cerebellitis, myoclonus whereas muiti-focal vasculopathy affects elderly syndrome and focal encephalitis.72 Rarely bilateral immuno-compromised patients. In the former, hippocampal lesions on MRI mimicking HSE have zoster is followed several weeks later by ipsilateral been reported.73 Enteroviruses can cause severe middle cerebral artery infarction due to retrograde spinal and brainstem encephalitis in children.74 spread of Varicella zoster via trigeminal system. Seizure has been described in enterovirus 71 Less typical presentation includes cerebral encephalitis.75 vasculopathy following remote site of infection e.g. sacral, progressive leucoencephalopathy or Measles vasculitic optic neuropathy.66 Seizure is a feature of zoster encephalitis-vasculitis.67 The prognosis Measles is infrequently associated with encephalitis is good following acyclovir therapy. although subclinical form of CNS involvement demonstrated by EEG abnormalities in 50% Mumps cases.76 Measles encephalitis is usually nonfocal and presents during convalescence. Patients is a paramyxovirus and causes self- present with fever, seizures and altered mental limiting febrile illness with parotitis. Neurological state. Following measles encephalitis, although complications are common in mumps. CSF most patients survive, neurological sequelae pleocytosis was present in 50% patients with are common. Diagnosis is usually on clinical uncomplicated parotitis who underwent lumbar 68 grounds but can be confirmed serologically. puncture. Aseptic meningitis in mumps is Measles can also cause progressive sub-acute self limiting and may persist up to one month. encephalitis in immune compromised patients77, Before mumps vaccination, mumps encephalitis 69 acute disseminated encephalomyelitis (ADEM) constituted 20-30% of encephalitis. Encephalitis and subacute sclerosing panencephalitis, which generally occurs 1-2 weeks after the parotitis and can also be associated with seizures. manifests with fever, altered sensorium, seizures, focal weakness, abnormal movements and ACUTE DISSEMINATED aphasia. Mumps encephalitis usually resolves by ENCEPHALOMYELITIS (ADEM) 1-2 weeks. The sequelae include focal weakness and seizures.69,70 Death occurs in 1-2% cases. Acute disseminated encephalomyelitis (ADEM) Orchitis, parotitis and pancreatitis may or may is a monophasic characterized by not accompany CNS disease. rapid onset of neurologic symptoms and signs following viral encephalitis in children and adults. Influenza ADEM occurs in 1 in 1000 measles infection with mortality as high as 25% and neurological Encephalitis is a rare complication of influenza sequelae in 25-40% of survivors.78 On the A infection and is associated with mortality

 Neurology Asia June 2008 other hand, the incidence of ADEM following treatment are variable according to the etiology varicella zoster and infections are 1 in and other factors. There are limited large-scale 10,000 and 1 in 20,000 respectively with lower studies on management of seizures in encephalitis. occurrence of neurological sequelae compared to The recommendations on management of seizures measles. In the tropical countries because of poor related to encephalitis, including the section vaccination coverage, ADEM continues to be a below are largely based on clinical experience, common health problem. The important pathogens and experience from other causes of acute associated with ADEM include measles, herpes symptomatic seizures. simplex, HIV, human herpes virus, mumps, influenza, Epstein Barr and coxsackie viruses. General management The frequency and severity of ADEM following Other than the use of antiepileptic drugs to arrest viral infection is highly variable. ADEM has also the seizures, other general measures including the been reported following pneumoniae use of and antiviral drugs, electrolyte and Legionella, Cincinnatiensis. The neurologic and fluid management, blood pressure monitoring, include paresthesia, pain, respiratory and other aspects of intensive care are weakness, spasticity, incoordination, dysarthria equally important. Many often used in and dysphagia. Seizure may occur in severe co-existent infections such as quinolones, third or cases and its incidence ranges between 4% and fourth generation cephalosporins and meropenem 35%.79,80 Seizures in ADEM following measles may precipitate or aggravate seizures. infection may be as high as 50%. Some studies have reported high incidence (35%) of partial Urgency of seizure control and choice of seizures and status epilepticus in ADEM.76 The antiepileptic drugs management of seizures in ADEM is same as encephalitis. The significance of single seizure in encephalitis is obviously dependant on the type of infection, STATUS EPILEPTICUS IN ENCEPHALITIS and the clinical status of the individual patient. Seizures are common in HSE and is associated Encephalitis is an important cause of refractory with poor outcome.13 In a Vietnamese study on JE, seizures and status epilepticus. There is paucity seizures were again common, had high mortality, of systemic prospective study of status epilepticus poor sequele as well as brain herniation.47 These in encephalitis. Herpes simplex, JE, West Nile, argue for urgent measures even after first seizure influenza, Papova virus have been reported to in encephalitis. We have found in majority of JE, result in status epilepticus. In last 3 years, our the seizures are easily controlled by phenytoin studies on status epilepticus revealed 31 out 44 or carbamazepine monotherapy. However, of 101 cases (30%) were due to encephalitis, when intravenous antiepileptic drugs are used, another 25% were from other CNS infection. one should be aware of the potential deleterious The etiologies of the encephalitis were JE in effect of respiratory suppression, and lowering of 9, HSE in 1, dengue in 1, and in 17 patients no blood pressure on the brain with high intracranial etiology agent could be established. Generalized pressure. convulsive status epilepticus was the commonest (21), followed by partial status epilepticus with Management of status epilepticus secondary generalization (5) and nonconvulsive status epilepticus in 4 patients. The seizures As mentioned above, encephalitis is an important were difficult to control. Nine of our patients had cause of status epilepticus, and is associated with refractory status epilepticus, and 10 died. MRI high mortality. Diagnosis of convulsive seizures changes and Glasgow Coma Scale were related is easy, but subtle seizures and nonconvulsive to outcome. We concluded that status epilepticus seizures require EEG. The subtle seizures manifest in encephalitis requires aggressive therapy. (Misra with eye deviation, nystagmus, hyperventilation UK, Kalita J, unpublished observations) and subtle tremulous movement of fingers, chin, and eyelids. Management of status epilepticus in MANAGEMENT OF SEIZURES IN VIRAL encephalitis is similar to status epilepticus from ENCEPHALITIS other causes.

Seizures can occur at any stage of encephalitis, Prophylactic antiepileptic drug treatment from being the presenting feature to late sequelae. Their severity, frequency and response to In encephalitis from HSV and JE, where there is

10 high incidence of seizures, which may contribute 10. Damasio AR, Van Hoesen GW. The to the high mortality and morbidity, one may argue and the localisation of herpes simplex encephalitis. for the routine use of prophylactic antiepileptic J Neurol Neurosurg Psychiatry 1985; 48: 297-301. 11. Fodor PA, Levin MJ, Weinberg A, Sandberg E, drugs during acute encephalitis, without clinical Sylman J, Tyler KL. Atypical herpes simplex virus seizures. However, the benefit of such a practice encephalitis diagnosed by PCR amplification of viral awaits confirmation from further studies. DNA from CSF. Neurology 1998; 51:554-9. 12. McGrath N, Anderson NE, Croxson MC, Powell KF. Duration of use of antiepileptic drug treatment Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg In encephalitis with seizures that is easily Psychiatry 1997; 63:321-6 controlled by antiepileptic drugs, there is no study 13. Hsieh WB, Chiu NC, Hu KC, Ho CS, Huang FY. to address the issue of the duration to continue Outcome of herpes simplex encephalitis in children. the antiepileptic drugs. Based on the consideration J Microbiol Immunol Infect 2007; 40:34-8. 14. Chen SF, Huang CC, Wu HM, Chen SH, Liang that the seizures is related to acute pathology, the YC, Hsu KS. Seizure, neuron loss, and mossy fiber antiepileptic drugs should thus cover the duration sprouting in herpes simplex virus type 1-infected of active pathology, which in most cases, is less organotypic hippocampal cultures. Epilepsia 2004; than 3 months. 45: 322-32. 15. Chen YJ, Fang PC, Chow JC. Clinical characteristics ACKNOWLEDGEMENT and prognostic factors of postencephalitic epilepsy in children. J Child Neurol 2006; 21: 1047-51. We acknowledge Rakesh Kumar Nigam for 16. Yamada S, Kameyama T, Nagaya S, Hashizume Y, secretarial help. Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J REFERENCES Neurol Neurosurg Psychiatry 2003; 74: 262-4. 17. Hokkanen L, Launes J. Cognitive recovery instead . Johnson RT. Acute encephalitis. Clin Infect Dis 1996; of decline after acute encephalitis: a prospective 23: 219-24. follow up study. J Neurol Neurosurg Psychiatry 1997; 2. Koskiniemi M, Rantalaiho T, Piiparinen H, et al. 63:222–7. Infections of the of suspected 18. Jay V, Hwang P, Hoffman HJ, Becker LE, Zielenska viral origin: a collaborative study from Finland. J M. Intractable seizure disorder associated with Neurovirol 2001; 7: 400-8. chronic herpes infection. HSV1 detection in tissue 3. Downs AGARBO viruses. In: Evans AS, ed: Viral by the polymerase chain reaction. Childs Nerv Syst infections of humans: epidemiology and control. 1998; 14:15-20. NewYork, Planum, 1989: 105-32. 19. Asenbauer B, McEntagart M, King MD, Gallagher 4. Annegers JF, Hauser WA, Beghi E, Nicolosi A, P, Burke M, Farrell MA. Chronic active destructive Kurland LT. The risk of unprovoked seizures after herpes simplex encephalitis with recovery of viral encephalitis and meningitis. Neurology 1988; 38: DNA 12 years after disease onset. Neuropediatrics 1407-10. 1998; 29:120-3. 5. Whitley RJ. Herpes simplex virus. In: Schield WM, 20. Cornford ME, McCormick GF. Adult-onset temporal Whitley RJ, Durack DT, eds: Infections of the central lobe epilepsy associated with smoldering herpes nervous system, 2nd ed. Philadelphia: Lippincott- simplex 2 infection. Neurology 1997; 48: 425-30. Raven, 1997: 73–89. 21. Millner M. Complicated febrile convulsion vs herpes- 6. Koskiniemi M, Piiparinen H, Mannonen L, Rantalaiho encephalitis. Pediatr Padol 1993; 28:A7-9. T, Vaheri A. Herpes encephalitis is a disease of middle 22. Wu HM, Huang CC, Chen SH, Liang YC, Tsai JJ, aged and elderly people: polymerase chain reaction Hsieh CL, Hsu KS. Herpes simplex virus type 1 for detection of herpes simplex virus in the CSF of inoculation enhances hippocampal excitability and 516 patients with encephalitis. The Study Group. J seizure susceptibility in mice. Eur J Neurosci 2003; Neurol Neurosurg Psychiatry 1996; 60: 174-8. 18:3294-304. 7. Aurelius E, Johansson B, Skoldenberg B, Forsgren 23. Solomon T. Flavivirus encephalitis. N Engl J Med M. Encephalitis in immunocompetent patients due 2004; 351: 370-8. to herpes simplex virus type 1 or 2 as determined by 24. Mostashari F, Kulldorff M, Hartman JJ, Miller JR, type-specific polymerase chain reaction and antibody Kulasekera V. Dead bird clusters as an early warning assays of cerebrospinal fluid. J Med Virol 1993; 39: system for West Nile virus activity. Emerg Infect Dis 179-86. 2003; 9:641-6. 8. Baringer JR, Pisani P. Herpes simplex virus genomes 25. O’Leary DR, Marfin AA, Montgomery SP,et al. The in human nervous system tissue analyzed by epidemic of West Nile virus in the United States, polymerase chain reaction. Ann Neurol 1994; 36: 2002. Vector Borne Zoonotic Dis 2004; 4: 61-70. 823-9. 26. Monath TP. Epidemiology. In: Monath TP, ed: St 9. Johnson RT. Viral infections of the nervous system, Louis encephalitis. Washington, D.C.: American 2nd ed. Philadelphia, Lippincott Raven, 1998: 133- Public Health. 1980:239-312. 68. 27. Nash D, Mostashari F, Fine A, et al. The outbreak

11 Neurology Asia June 2008

of West Nile virus infection in the New York City comparison of clinical and radiological findings in area in 1999. N Engl J Med 2001; 344: 1807-14. adults and children with Japanese encephalitis. Arch 28. Brinker KR, Monath TP. The acute disease. In: Neurol 2003; 60:1760-4. Monath TP, ed: St. Louis encephalitis Washington, 47. Soloman T, Dung MN, Kneen R , Thao LTT, D.C.: American Public Health. 1980:503-34. Gainsborough M, Nisalak A, Day NPT Kirkham FJ, 29. Desai A, Shankar SK, Jayakumar PN, Chandramuki A, Voughn DW, Smith S, White NJ. Seizure and raised Gourie-Devi M, Ravikumar BV, Ravi V. Co-existence in Vietnamese patients with of cerebral cysticercosis with Japanese encephalitis: Japanese encephalitis. Brain 2002;125:1084-93. a prognostic modulator. Epidemiol Infect 1997; 118: 48. Misra UK, Hashmi AA, Kalita J. Alpha coma in 165-71. Japanese encephalitis. Neurol India 1995; 43: 113-4. 30. Libraty DH, Nisalak A, Endy TP, Suntayakorn S, 49. Lum LC, Lam SK, Choy YS, George R, Harun F. Vaughn DW, Innis BL. Clinical and immunological Dengue encephalitis: a true entity? Am J Trop Med risk factors for severe disease in Japanese encephalitis. Hyg 1996; 54: 256–59. Trans R Soc Trop Med Hyg 2002; 96:173-8. 50. Solomon T, Dung NM, Vaughn DW, et al. 31. Kalita J, Misra UK. Comparison of CT scan and MRI Neurological manifestations of dengue infection. findings in the diagnosis of Japanese encephalitis. J Lancet 2000; 355: 1053–9. Neurol Sci 2000; 174: 3-8. 51. Misra UK, Kalita J, Syam UK, Dhole TN. 32. Zimmerman HM. Pathology of Japanese encephalitis. Neurological manifestations of dengue virus Am J Pathol 1946; 22: 965-91. infection. J Neurol Sci 2006; 244:117-22. 33. Shankar SK, Rao TV, Mruthyunjayanna BP, Gourie 52. Kalita J, Misra UK. EEG in dengue virus infection Devi M, Deshpande DH. Autopsy study of brains with neurological manifestations: A clinical and CT/ during an epidemic of Japanese encephalitis in MRI correlation. Clin Neurophysiol 2006; 117:2252- Karnataka. Indian J Med Res 1983; 78:431-40. 56. 34. Misra UK, Kalita J. Movement disorders in Japanese 53. Powell RE, Blakey DL. St Louis encephalitis. JAMA encephalitis. J Neurol 1997; 244: 299-303. 1977; 237:2294-98. 35. Solomon T, Kneen R, Dung NM, et al. Poliomyelitis- 54. Hinson VK, Tyor WR. Update on viral encephalitis. like illness due to Japanese encephalitis virus. Lancet Curr Opin Neurol 2001; 14:369-74. 1998; 351:1094-7. 55. Ahmed S, Libman R, Wesson K, Ahmed F, Einberg 36. Kalita J, Misra UK. Markedly severe dystonia in K. Guillain Barre syndrome: An unusual presentation Japanese encephalitis. Mov Disord 2000; 15: 1168- of West Nile virus infection. Neurology 2000; 55: 72. 144-6. 37. Misra UK, Kalita J. Prognosis of Japanese encephalitis 56. Petersen LR, Roehrig JT, Sejvar JJ. West Nile virus patients with dystonia compared to those with in the Americas. In: Fong W, Alibek K, eds: New parkinsonian features only. Postgrad Med J 2002; and evolving infections of the 21st century. Springer, 78: 238-41. 2007: 3-56. 38. Hsu YK. Cerebral cysticercosis and acute 57. Deresiewicz RL, Thaler SJ, Hsu L, Zamani AA. poliomyeloencephalitis. Chinese Med J 1940;57: Clinical and neuroradiographic manifestations of 318-9. Eastern equine encephalitis. New Engl J Med 1997; 39. Lin YF, Teng CL, Liu-Kai. Chinese Med J 1977, 336:1867-74. 75:101. Quoted by Gourie Devi M, Ravi V, Shankar 58. Chua KB, Goh KJ, Wong KT, Kamarulzaman A, et SK. Japanese encephalitis an overview. Clifford al. Fatal encephalitis due to Nipah virus among pig- Rose F ed: Recent advances in Tropical Neurology. farmers in Malaysia. Lancet 1999; 354:1257-59. Elsevier. 1995:211-35. 59. Chua KB, Koh CL, Hooi PS, et al. Isolation of Nipah 40. Shankar SK, Rao TV, Mruthyunjayanna BP, Gourie virus from Malaysian flying-foxes. Microbs Infect Devi M, Deshpande DH. Autopsy study of brains 2002; 4:145-51. during an epidemic of Japanese encephalitis in 60. Chong HT, Tan CT. Relapsed and late-onset Nipah Karnataka. Indian J Med Res 1983;78:431-40. encephalitis, a report of three cases. Neurol J 41. Gourie Devi M, Ravi V, Shankar SK. Japanese Southeast Asia 2003; 8:109-112. encephalitis an overview. Clifford Rose F, ed: Recent 61. Wong KT, Shieh WJ, Kumar S, et al. Pathology and advances in Tropical Neurology. Elsevier. 1995: pathogenesis of an emerging paramyxoviral zoonesis. 211-35. Am J Pathol 2002; 161: 2153-67. 42. Misra UK, Nag D, Shukla R, Kar AM. Parkinsonism 62. Tan CT, Goh KJ, Wong KT, et al. Relapsed and and diencephalic epilepsy as sequelae of Japanese late-onset Nipah encephalitis. Ann Neurol 2002; encephalitis. Neurol Ind 1980; 28: 252. 51:703-8. 43. Misra UK, Kalita J. A comparative study of Japanese 63. Ahmad Sarji S, Abdullah BJJ, Goh KJ, Tan CT, Wong and Herpes simplex encephalitis. Electromyog Clin KJ. MR imaging features of Nipah encephalitis. AJR Neurophysiol 1998; 38: 41-6. 2000; 175:437-42. 44. Misra UK, Kalita J. Seizures in Japanese encephalitis. 64. Chew NK, Goh KJ, Tan CT, Ahmad Sarji S, Wong KT. J Neurol Sci 2001; 190: 57-60. in acute Nipah encephalitis. 45. Kalita J, Misra UK. EEG in Japanese encephalitis: A Neurol J Southeast Asia 1999; 4: 45-51. clinicoradiological correlation. Electroencephalogr 65. Chong HT, Kamarulzaman A, Tan CT, et al. Treatment Clin Neurophysiol 1998; 106: 238-43. of acute Nipah encephalitis with ribavarin. Ann Neurol 46. Kalita J, Misra UK, Pandey S, Dhole TN. A 2001; 49:810-13.

12 66. Gilden DH, Lipton HL, Wolf JS, Akenbrandt W, Smith JE, Mahalingam R, Forghani B. Two patients with unusual forms of varicella-zoster virus vasculopathy. N Engl J Med 2002; 347:1500-3. 67. Gilden DH, LaGuardia JJ. Varicella-Zoster virus infection. Nath A, Berger JR, eds: Clinical Neuroviology. Marcel Dekker 2003; 129-53. 68. Bang Ho, Bang J. Involvement of central nervous system in mumps. Acta Med Scand 1943; 113:487-90 69. Russell RR, Donald JC. The neurological complications of mumps. Br Med J 1958; 2:27-30. 70. Levitt LP, Rich TA, Kinde SW, Lewis AL, Gates EH, Bond JO. Central nervous system mumps. A review of 64 cases. Neurology 1970; 20:829-34. 71. Yoshiokawa H, Yamazuki S, Watanabe T, Abe T. Study of influenza virus associated encephalitis /encephalopathy in children during 1997 to 2000 influenza seasons. J Child Neurol 2001; 16:885- 890. 72. Johnson RT. Meningitis, encephalitis and poliomyelitis In: Viral infections of the nervous system 2nd ed Newyork, Lippincort Raven 1998; 87-132 73. Nakajima H, Hosoya M, Takahashi Y, et al. A chronic progressive case of enteroviral associated with autoantibody to glutamate receptor. Eur Neurol 2007; 57:238–40. 74. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999; 341:936-42. 75. Chang LY, Shih SR, Huang LM, Lin TY. Enterovirus 71 encephalitis. In: Fong W, Alibek K, eds: New and evolving infections of the 21st century. Springer, 2007: 295-325. 76. Gibbs FA, Gibbs EL, Carpenter PR, Spies HW. Electroencephalographic abnormality in “uncomplicated” childhood diseases. JAMA 1959; 171:1050-55. 77. Chong HT, Ramli N, Wong KT, et al. Subacute measles encephalitis: A case of long term survival with follow-up MR brain scans. Neurol Asia 2007;12:121-5. 78. Struve O, Zambir SS. Pathogenesis, diagnosis and treatment of acute disseminated encephalomyelitis. Curr Opin Neurol 1999; 12:395-401. 79. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ. Clinical and neuroradiologic features of acute disseminated enepahalomyelitis in children. Neurology 2001;56:1308-12. 80. Tenembaum S, Chamoles N, Fejerman N. Acute disseminatalomyelitis aerm folowup study of 84 pediatric patients. Neurology 2002; 59:1224-31.

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