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 3% 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 are estimates that HSE is the most important Encephalitis refers to acute inflammatory process cause of treatable viral encephalitis with an affecting the brain. Viral infections are the most incidence of case/million population/year. important cause of encephalitis. There are over Certain viruses are prevalent in certain regions. 00 viruses that can result in encephalitis. The Japanese encephalitis (JE) in South East Asia, patients present with fever 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, malaria, bacterial meningitis and non from USA and Nipah virus encephalitis from infectious causes of encephalopathy 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 3.5-7.4/00,000 population/year; however specific features of anatomical involvement in children the incidence is much higher. such as behavioral changes, aphasia or partial Encephalitis may occur in sporadic or epidemic complex seizure 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 cerebrospinal fluid (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 myelitis. In this study, Vericella retrograde transport of virus resulting in herpes zoster was the most common infection (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 arbovirus 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 meningoencephalitis 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 3% for HSV. The virus may travel by cell to cell contact bacterial meningitis with early seizures.4 In the across the meninges into adjacent cortices. The present review, the seizures in HSE, Flavivirus 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 HSV.0 This affinity is attributed to distinctive virus encephalitis will be discussed. anatomical, neurochemical and immunological properties of these cortices. HERPES SIMPLEX ENCEPHALITIS Clinical spectrum Herpes simplex virus 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 56 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 ). However there are no characteristic more than 90% of HSE occurs due to infection series of findings pathognomonic of HSE. with HSV- 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 HSV 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- 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- has remarkable capability for producing was behavioral abnormality in 45% followed by latency, persistent infection and for reactivation.8 seizures in 24.7%.2 Seizures were the presenting Primary HSV 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 2 with HSE where 47 patients were evaluated, 26 (65%) had good outcome and 4 (35%) had poor outcome. Seizures occurred at the time of presentation in 63% and 7% of them had poor outcome. Abnormal neuroimaging (79%) and EEG (92%) were more prevalent in patients with poor outcome group.3 Temporal and frontal cortices are highly epileptogenic compared to parietal and occipital cortex. Change in excitability of hippocampal A3 neuronal network and HSV