Indian J Pediatr (2011) 78:219226 DOI 10.

1007/s12098-010-0291-y

SYMPOSIUM ON PICU PROTOCOLS OF AIIMS

Status Epilepticus
Dinesh Raj & Sheffali Gulati & Rakesh Lodha

Received: 11 October 2010 / Accepted: 28 October 2010 / Published online: 11 December 2010 # Dr. K C Chaudhuri Foundation 2010

Abstract Status epilepticus is a common neurological emergency in childhood and associated with significant morbidity and mortality. Status epilepticus (SE) has been defined as continuous seizure activity lasting more than 30 min or 2 or more seizures in this duration without gaining consciousness between them. However, the operational definition has brought the time down to 5 min. Management can be broadly divided into initial stabilization, seizure termination, and evaluation and treatment of the underlying cause. Diagnostic evaluation and seizure control should be achieved simultaneously to improve outcome. Seizure termination is achieved by pharmacotherapy. Benzodiazepines are the first line drugs for SE. Commonly used drugs include lorazepam, diazepam, and midazolam. In children without an IV access, buccal or nasal midazolam or rectal diazepam can be used. Phenytoin as a second line agent is usually indicated when seizure is not controlled after one or more doses of benzodiazepines. If the seizures continue to persist, valproate, phenobarbitone or levetiracetam is indicated. Midazolam infusion is useful in refractory status epilepticus. Thiopentone, propofol or high dose phenobarbitone are considered for treatment of refractory status epilepticus. Prolonged SE is associated with higher morbidity and mortality. Long term neurological sequelae include epilepsy, behavioural problems, cognitive decline, and focal neurologic deficits. Keywords Benzodiazepine . Children . Phenobarbitone . Phenytoin . Status epilepticus . Valproate Status epilepticus is a common neurological emergency in childhood and associated with significant morbidity and
D. Raj : S. Gulati : R. Lodha (*) Department of Pediatrics, AIIMS, Ansari Nagar, New Delhi 110029, India e-mail: rakesh_lodha@hotmail.com

mortality. Protocols need to be developed for its management so that emergency care and pediatric intensive care staff is familiar with its management and therapy is standardised. We discuss a protocol being followed at AIIMS for the management of status epilepticus based on review of available evidence.

Definition Status epilepticus has been defined as continuous seizure activity lasting more than 30 min or 2 or more seizures in this duration without gaining consciousness between them [1]. This definition was based on earlier animal data that neuronal damage started beyond 30 min of seizure activity [2, 3] and the evidence that this prolonged duration was associated with increased morbidity and mortality [4]. However, with recent data suggesting that neuronal damage started much early and prolonged seizures are refractory to the first-line therapy, there was need to redefine status epilepticus. It has also been observed that most seizures will terminate on their own within 2 min [5], and if seizure persists beyond 5 min it is unlikely to stop on its own and hence, require therapy for termination. Therefore, the 30 min definition is used for research and epidemiological purposes only and the operational definition has brought the time down to 5 min. So, any patient who presents to the health care facility in a convulsing state should be assumed to be in status epilepticus and managed accordingly.

Epidemiology A prospective population based study from North London suggested the incidence of convulsive status epilepticus (CSE) to be between 17 to 23 per 100,000 per year [6]. The

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incidence was highest in children younger than 1 year (51 per 100,000 per year) with maximum children in the acute symptomatic group. The most common cause of CSE in this study cohort was prolonged febrile seizure. In our emergency services, 1520 patients present with status epilepticus every month, of which approximately half are first episode status epilepticus (unpublished data).

institutions. It has also been observed that often protocols are not followed leading to longer duration of status and higher admission rates to intensive care [15]. Management can be broadly divided into (1) initial stabilization, (2) seizure termination, and (3) evaluation and treatment of the underlying cause. Diagnostic evaluation and seizure control should be achieved simultaneously to improve outcome. (1) Initial stabilization Initial stabilization, as in any other critically ill child, includes adequate airway, breathing, and circulation. Airway patency can be maintained by oral airway, or other devices. 100% oxygen should be provided to prevent hypoxia. In case of respiratory failure, or Glasgow coma scale score <8, rapid sequence intubation should be considered. Vital parameters including heart rate, respiratory rate, ECG, and oxygen saturation, should be monitored. In case IV access is not easily accessible, intraosseous route can be considered. Benzodiazepines, phenytoin, and barbiturates are effective when given by intraosseous route. (2) Seizure termination Seizure termination is achieved by pharmacotherapy. Various drugs in use and their current status are given in Table 2. Pharmacotherapy Benzodiazepines Benzodiazepines are the first line drugs for SE. Commonly used drugs include lorazepam, diazepam, and midazolam (Table 2). Benzodiazepines act at the GABAA receptor and inhibit neuronal transmission. However, as seizures progress, these receptors are internalized resulting in the lesser efficacy of these drugs in prolonged seizures [16]. The potency of benzodiazepines may decrease 20-fold in 30 min of SE [17].

Etiology Etiologically status epilepticus has been classified as cryptogenic, remote symptomatic, acute symptomatic, febrile, or progressive encephalopathic (Table 1) [7].

Pathophysiology The emergence of SE requires a pool of neurons capable of initiating and sustaining abnormal firing [8]. This abnormal discharge is facilitated by loss of inhibitory synaptic transmission mediated by -amino butyric acid (GABA) and sustained by excitatory transmission mediated by glutamate [9]. The N-methyl-d-aspartate (NMDA) linked channels appear to be important in the pathogenesis of neuronal injury in SE [10]. Studies have shown that during SE, reduction in the GABA-mediated inhibition correlated with a reduction in the surface expression of the benzodiazepine-sensitive GABAA receptors but not the benzodiazepine-insensitive GABAA receptors [1114]. This activity-dependent decrease in benzodiazepine-sensitive receptors is a potential mechanism to explain the failure of benzodiazepines to treat SE in its late stages.

Management There is limited consensus on the management protocol for SE and wide variability is noticed between different

Table 1 Classification of Status Epilepticus (SE) based on the etiology Etiology Cryptogenic(Idiopathic) Remote symptomatic Febrile Acute symptomatic Progressive encephalopathy Definition SE in the absence of an acute precipitating CNS insult or metabolic dysfunction in a patient without a pre-existing neurologic abnormality SE in a patient with a known history of a neurologic insult associated with an increased risk of seizures (e.g., traumatic brain injury, stroke, static encephalopathy) SE provoked solely by fever in a patient without a history of afebrile seizures SE during an acute illness involving a known neurologic insult (e.g., meningitis, traumatic brain injury, hypoxia) or metabolic dysfunction (e.g., hypoglycemia, hyponatremia, hypocalcemia) SE in a patient with a progressive neurologic disease (e.g., neurodegeneration, malignancies, neurocutaneous syndromes)

Indian J Pediatr (2011) 78:219226 Table 2 Drugs used for termination of seizures Drug Lorazepam Diazepam Midazolam Route Intravenous Intravenous Rectal Intravenous Intramuscular Buccal Intranasal Intravenous Intravenous Intramuscular Intravenous Intravenous Intravenous Intravenous Intravenous Intravenous Intravenous Oral Dose 0.1 mg/kg 0.20.3 mg/kg 0.5 mg/kg 0.150.2 mg/kg 0.2 mg/kg 0.3 mg/kg 0.3 mg/kg 20 mg/kg loading (another loading of 10 mg/kg may be required) 20 mg/kg Phenytoin Equivalent 2030 mg/kg 20 mg/kg 2030 mg/kg 5 mg/kg bolus followed by infusion @ 35 mg/kg/hr 1015 mg/kg bolus followed by infusion @ 13 mg/kg/hr 12 mg/kg bolus followed by infusion @ 12 mg/kg/h (max of 5 mg/kg/h) 1.5 mg/kg loading followed by infusion @ 0.010.05 mg/kg/hr 25 mg/kg loading; increase by 510 mg/kg/d to maximum of 25 mg/kg/d Comments (side effects/precautions) Sedation, respiratory depression Sedation, respiratory depression Sedation, respiratory depression

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Phenytoin Fosphenytoin Valproate Phenobarbitone Levetiracetam Thiopental Pentobarbital Propofol Ketamine Topiramate

Cardiac arrhythmia, hypotension, thrombophlebitis Cardiac arrhythmia, hypotension, thrombophlebitis (less common) Encephalopathy, hyperammonemia, hepatotoxicity (contraindicated in liver dysfunction) Sedation, respiratory depression Sedation at high doses Hypotension, decreased myocardial contractility, immunosuppression Hypotension, decreased myocardial contractility, immunosuppression Avoid in children <16 years due to risk of propofol infusion syndrome Tachycardia, raised intracranial pressure Lethargy, ataxia, metabolic acidosis, IV preparation not available

Of the various routes of administration, intravenous route is the preferred route. In the prehospital setting or when IV access is difficult, either diazepam can be used via per rectal route, or midazolam can be given by intramuscular, buccal or nasal route. The dose of benzodiazepine may be repeated after 35 min, if required. A recent Cochrane collaboration review suggested that intravenous lorazepam is at least as effective as intravenous diazepam (70% vs. 65%) and is associated with fewer adverse events in treatment of acute tonic-clonic convulsions [18]. Buccal midazolam was more effective than rectal diazepam in terminating seizures [19]. Various studies have demonstrated the efficacy of intranasal midazolam [20, 21]. Buccal midazolam is administered by turning the child onto one side and drug is put between teeth and cheek with the help of a syringe. In case child is resisting administration, or having excessive oral secretions, nasal administration is preferred. For nasal administration, concentrated formulation should be used, as large volume of dilute solution would run down the throat. Preferably half the drug should be put in each nostril, thereby increasing the surface area available for absorption. Bioavailability would be increased if nasal sprays are used. Since specific oral or nasal/buccal formulations are not available in India, concentrated intravenous solutions can be used instead.

Phenytoin Phenytoin as a second line agent is usually indicated when seizure is not controlled after one or more doses of benzodiazepines. Phenytoin acts by slowing the rate of recovery of voltage-activated sodium channels. It is also given sometimes to prevent recurrence of seizures especially if the child needs to be maintained on long term anti-epileptic therapy. A randomized controlled study of 178 children with SE comparing lorazepam to diazepam-phenytoin combination reported 100% efficacy in both groups [22]. Phenytoin is infused at a loading dose of 20 mg/kg. It is not compatible with dextrose containing solutions as it gets precipitated. Therefore, infusion should be made up only in normal saline, at a maximum concentration of 10 mg/mL, and infused at no more than 1 mg/kg/min in children (up to 50 mg/min in adolescents). In the absence of clinical effect, an additional 10 mg/kg may be given because many patients may require higher plasma levels (2530 mg/L) to achieve seizure control [23]. Adverse effects of phenytoin include thrombophlebitis, hypotension, and cardiac arrhythmias. Heart rate, blood pressure, and ECG should be monitored during infusion. Fosphenytoin is a water-soluble phosphate ester of phenytoin. It is a prodrug of phenytoin and has no

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anticonvulsant action of its own. It is rapidly converted to phenytoin by non-specific serum phosphatases. It can be administered three times faster than phenytoin, because of its water solubility and absence of propylene glycol solvent. Phenobarbitone Phenobarbitone is a potent antiepileptic drug that acts by enhancing GABAA activity. It is commonly used as a firstline agent in neonatal seizures. Its efficacy in status epilepticus is around 6070%. Phenobarbitone is used at a dose of 20 mg/kg, infused at no more than 30 mg/min. It has unacceptably high incidence of sedation and respiratory depression, especially when used in addition to benzodiazepines because of which it has gone out of favour and is usually indicated after phenytoin and/or valproate [24]. It may be difficult to perform neurological assessment in these children for up to 24 to 36 h. Valproate Valproate acts through several mechanisms of action including modulation of sodium and calcium currents, and increasing inhibitory GABA transmission. It has especially low risk of hemodynamic adverse effects even at very high infusion rates. Variable doses ranging from 20 to 40 mg/kg have been used with success. Various studies have demonstrated the efficacy of valproate in control of status epilepticus [25, 26]. Safety of intravenous valproate has been shown over a wide range of doses (2040 mg/kg) and various infusion rates of upto 11 mg/kg/min [27]. Rare side effects of valproate include hepatotoxicity, hyperammonemia, and encephalopathy, however the incidence of these side effects is quite low. The broad spectrum efficacy, low incidence of adverse effects, ability to administer rapidly and ease of conversion to oral therapy make valproate a good choice as second line AED after benzodiazepines. Levetiracetam Levetiracetam is a new broad spectrum anticonvulsant and has recently been used with success in acute seizures and SE. Bioavailability is same as far as oral and intravenous routes are concerned. It is minimally protein bound and excreted via renal route, hence requiring dosage modification in renal dysfunction. It is free of any significant drug interactions. It has multiple sites of action including calcium channels, glutamate receptors and GABA modulation [28]. Neuroprotective effects have been shown in animal models [29].

Preliminary studies suggest that intravenous levetiracetam could have a potential place in the initial management of SE given its broad spectrum efficacy, limited side effects, and absence of drug interactions. Although randomized controlled trials are lacking, use of levetiracetam is increasing in acute seizures and SE after parental consent [3032]. Loading dose used is 2030 mg/kg at 5 mg/kg/min [33]. Midazolam Infusion Midazolam is effective not only as a bolus dose in the initial management of SE but also later in SE or refractory SE when second line drugs have failed. Midazolam is a water soluble benzodiazepine that is rapidly acting, and has a short half life. It is metabolized in the liver and excreted by the kidneys. Encouraging results have been seen with midazolam infusion in refractory status epilepticus in children [3437]. Midazolam has been used upto 32 mcg/kg/min with no serious side-effects [37]. While rapid escalation of infusion rate after a bolus dose may be associated with rapid seizure control [37], there would be a concern about early need for intubation and mechanical ventilation. Refractory Status Epilepticus Various studies have used different definitions of refractory status epilepticus (RSE). Some suggest seizure duration, more than 1 or 2 h, while others suggest the lack of response to different number (two or three) of anticonvulsants [3840]. The more widely acceptable definition is seizure (clinical or electrographic) persisting despite failure of two or more anticonvulsants. Epidemiological studies in children have suggested that SE lasted >1 h in 2645%, >2 h in 1725%, and >4 h in 10% [4143]. These children usually require aggressive management in pediatric intensive care unit and evaluation by a pediatric neurologist. They often have the systemic complications of status epilepticus, require hemodynamic and respiratory support, need continuous EEG monitoring, and have poor outcome. No randomized clinical trials are available comparing anticonvulsants in RSE, and most of the data comes from retrospective reviews, case series, and audits of treatment protocol. Drugs used in RSE are levetiracetam, valproate, midazolam infusion, anaesthetic agents (pentobarbital, thiopentone, propofol, and inhaled anaesthetics), high dose phenobarbitone, ketamine, and topiramate. Barbiturate Coma (Thiopental and Pentobarbital) Thiopental and pentobarbital are barbiturate anaesthetics, and have good efficacy in RSE but associated with serious adverse effects. Pentobarbital is not available in India.

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Pentobarbital is the initial metabolite of thiopental. It has a short elimination half-life and penetrates central nervous system quickly. It gets deposited into fat and is very slowly eliminated after prolonged administration. Thiopental has been used in a loading dose of 35 mg/kg followed by further boluses of 12 mg/kg within 35 min till seizure cessation (maximum dose of 10 mg/kg) followed by a continuous infusion of 35 mg/kg/h [44, 45]. Pentobarbital is administered as 1015 mg/kg initial bolus followed by further 25 mg/kg boluses every 5 min till seizure control followed by a continuous infusion of 13 mg/kg/h [46]. Barbiturate coma is associated with serious side effects including hypotension, respiratory depression, and decreased cardiac contractility. These drugs may also cause suppression of lymphocyte activation which is a cause of concern in critically ill patients [47]. As there may be risk of breakthrough seizures once barbiturate coma is tapered off, it would be advisable to add on other drugs like topiramate (discussed later) or hike the maintenance doses of other AED. Propofol Propofol is an intravenous general anaesthetic, and acts through GABAA receptors via a mechanism probably different from benzodiazepines and barbiturates. It has a short elimination half life and does not get accumulated in fat, allowing rapid awakening after discontinuation of infusion. Propofol can cause propofol infusion syndrome in children, characterized by cardiac failure, rhabdomyolysis, metabolic acidosis, renal failure, and sometimes death. Because of this reason, propofol is not approved for use as a sedating agent in children less than 16 years of age. A retrospective study of 33 children with RSE reported that propofol was more effective than thiopental in terminating seizures (64% vs 55%) [48]. Propofol is used as an initial bolus of 12 mg/kg, followed by a continuous infusion of 12 mg/kg/h and titrated to a maximum of 5 mg/kg/h [48]. Inhaled Anaesthetics Inhaled anaesthetics have a role in RSE when all other drugs fail. Desflurane and isoflurane are the inhaled anaesthetics which are preferred for RSE because of their better safety profile with long-term administration [49]. Side-effects include hypotension requiring fluids and vasopressors. High-Dose Phenobarbitone Phenobarbitone has significantly longer half-life as compared to pentobarbital and thiopental; it has been used in doses upto 80 mg/kg, with a resulting serum levels >1,000 mcg/mL [50, 51].

Ketamine Ketamine may be effective in late stages of SE as it acts independent of GABA pathway. It is a non-competitive NMDA receptor antagonist, and may also have an additional neuroprotective effects. It is administered intravenously; initial bolus of 1.5 mg/kg is followed by an infusion at a rate of 0.010.05 mg/kg/h. However, ketamine may increase intracranial pressure and hence, should be used only after neuroimaging has ruled out space occupying lesion. Topiramate Topiramate is an oral novel anticonvulsant that has multiple sites of action. It potentiates GABA receptor activity, reduces glutamate release, and blockade of voltagesensitive sodium and calcium channels. It has been found to be effective in controlling seizures while weaning of coma inducing drugs is being done [5254]. Side effects include lethargy, ataxia, and metabolic acidosis. No evidence based schedule is available for loading of topiramate. Small case series have used topiramate both rapid loading and slow loading [5254]. Table 3 shows the step wise management algorithm for status epilepticus based on the review of available evidence.

Evaluation and Treatment of the Underlying Cause A good history and general physical examination gives important clues to diagnosis and in most cases, will suggest the diagnostic workup required. Evaluation and treatment of the underlying cause of status is as important as rapid seizure control and both should be done simultaneously to improve outcome. Blood sugar and serum electrolytes (calcium, sodium, magnesium) should be a part of initial workup as they are easily correctable, although they are less common causes of SE. Hyponatremia is a cause of SE in 1% of new-onset childhood SE [55]. Other investigations include BUN, AED levels, urine and blood toxic screen. In case the patient is febrile, complete blood count should be done. Lumbar puncture should be considered whenever there is any clinical suspicion for meningitis or encephalitis, especially in young children (<2 years of age) [56]. CNS infection rate was found to be 12.8% in a review of 1,859 children presenting with SE [57]. Neuroimaging (CT/MRI) may be considered if there are clinical indications or if etiology is unknown. It should only be done once seizures are controlled and child is hemodynamically stable. Neuroimaging is especially important in the evaluation of new-onset SE. At least 8% of patients with CSE have an imaging abnormality [57], more commonly in patients presenting with coma [58]. An EEG

224 Table 3 Algorithm for management of status epilepticus

Time 0 min Drug treatment IV Access available: Inj Lorazepam- 0.1 mg/kg/IV (max 4 mg) OR Inj Midazolam-0.150.2 mg/kg/IV (Max 5 mg) IV accessnotavailable:Buccal Midazolam 0.3 mg/kg (Max 5 mg) OR PR Diazepam 0.5 mg/kg (Max 10 mg) Inj Lorazepam- 0.1 mg/kg/IV (max 4 mg) OR Inj Midazolam-0.15-0.2 mg/kg/IV (Max 5mg)

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5 min

General measures Airway Breathing Circulation Establish IV access Temperature Oxygen inhalation Cardio respiratory monitoring: ECG, BP, SpO2

Investigations Glucose, Sodium, Potassium, Calcium, Magnesium

Glucose May consider: CRP, complete blood counts, AED level, Toxic screen, BUN

10 min

Refractory SE-even after 10 min of phenytoin/ fosphenytoin administration

Check whether the child is on AED* (please see next page Repeat inj. Phenytoin 10 mg/kg / Inj Fosphenytoin 10 mg PE/ kg, if no response to initial dose for the dose adjustment) IV Valproate 20- 30 mg/kg-IV @ max 6 mg/kg/minute. Consider: Continue OR CT head monitoring as above IV Phenobarbitone 20 mg/kg in NS @ 1.5 mg/kg/min; Repeat 10 mg/kg if no response to LP- for CNS Use vasopressors, if initial dose infections needed OR EEG Identify and treat IV Levetiracetam (If Liver disease/Metabolic disease/coagulopathy/ on chemotherapy) medical conditions 20-30 mg/kg @ 5 mg/kg/min infusion and electrolyte disturbances Consider IV Pyridoxine 100 mg infusion in children <2 years of age without clear etiology for seizures, and in those with Isoniazid overdose Coma induction - seizure continues 10 min after completion of phenobarbitone infusion
Shift to PICU PICU Management Drug treatment Inj Midazolam-0.2 mg /kg bolus then infusion @ 1 g/kg/min, increasing 1 g/kg/min, every 5- 10 min, till seizures stop, upto a maximum of 30 g/kg/min, start tapering 24 h after seizure stops @ 1 g/kg/min, every 3 h If PICU admission delayed or ventilation facility not available then use 1. Inj Levetiracetam or inj Valproate if not used earlier 2. Paraldehyde (If available)-0.4 mL/kg per rectal with equal volume of olive oil.

IV Phenytoin* 20 mg/kg (Max: 1000mg) in NS @ 1 mg/kg/min (Max 50 mg per min), OR Inj Fosphenytoin 20 mg PE/ kg, Rate: 3 mg PE/kg/min

If seizures persist on midazolam infusion

Inj Thiopentone: Loading Dose: 5 mg/kg bolus followed by 3-5 mg /kg /hr infusion rate to achieve Burst suppression. Start tape ring after 24 h seizure free period Short-term Propofol: Initial bolus of 1-2 mg/kg, followed by a continuous infusion of 1-2 mg/kg/hour and titrated to a maximum of 5 mg/kg/hour. Limit use to < 48 hrs. High dose Phenobarbitone: Boluses of 5-10 mg/kg every 30 min upto 80 mg/kg in a 24 hour period, target seizure control and burst suppression and blood levels upto- 1000 g/mL, maintenance upto 40 mg/kg/d

General measures Intensive care: Consider intubation and mechanical ventilation. Monitoring of cardiorespiratory status Identify and treat raised ICP Optimize AEDs Consider in those relapsing on tapering Topiramate2- 5 mg/kg loading; increase by 5- 10 mg/kg/d to maximum of 25 mg/kg/d Ketamine- IV Load 1.5 mg/kg followed by 0.01- 0.05 mg/kg/hr.

Investigations CEEG AED levels Rest of evaluation individualized

AED Anti epileptic drugs, PE Phenytoin equivalent, CEEG continuous EEG monitoring *If the child is already on anti epileptic drugs (AED): For Phenytoin 6 mg/kg/day, Phenobarbitone 5 mg/kg/day, Valproate 30 mg/kg/day, Levetiracetam 30 mg/kg/day OR If the child has missed few doses of AED or child has vomiting/diarrhea: Give half the loading dose of the respective AED If the child is receiving AEDs at doses higher than mentioned in the sentence above, avoid loading with that AED and move to next step

may be considered in a child presenting with new onset SE as it may determine whether there are focal or generalized abnormalities that may influence diagnostic and treatment decisions [57]. It also helps in diagnosing nonconvulsive SE, which is particularly useful in patients who continue to be in altered sensorium after motor seizure control. Rarely, testing for metabolic and genetic causes might be required if clinically indicated.

Complications of Status Epilepticus Numerous systemic complications are observed during SE some of which can be life threatening. In the initial phase,

tachycardia, hypertension and increased cardiac output are present due to increased sympathetic discharge. Blood flow to the central nervous system is increased to meet the increased metabolic demands. With ongoing seizure, hypotension develops, leading to a fall in cerebral blood flow, although it is still higher than normal. Hypoxia is commonly observed in SE due to impaired ventilation, increased oxygen consumption, and aspiration of secretions. Metabolic acidosis is commonly observed as a result of increased lactic acid production. Respiratory acidosis develops as a result of impaired ventilation, excessive secretions, and increased metabolic production of carbon dioxide. Hyperpyrexia is seen due to excessive muscular contractions. Hyperglycemia is

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225 4. Hauser WA. Status epilepticus: epidemiologic considerations. Neurology. 1990;40:913. 5. Theodore WH, Porter RJ, Albert P, et al. The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology. 1994;44:14037. 6. Chin RFM, Neville BGR, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population based study. Lancet. 2006; 368:2229. 7. Shinnar S, Pellock JM, Mosh SL, et al. In whom does status epilepticus occur: age-related differences in children. Epilepsia. 1997;38:90714. 8. Noe KH, Manno EM. Mechanisms underlying status epilepticus. Drugs Today (Barc). 2005;41:25766. 9. Nandhagopal R. Generalised convulsive status epilepticus: an overview. Postgrad Med J. 2006;82:72332. 10. Lothman E. The biochemical basis and pathophysiology of status epilepticus. Neurology. 1990;40:1323. 11. Naylor DE, Liu H, Wasterlain CG. Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci. 2005;25:772433. 12. Terunuma M, Xu J, Vithlani M, et al. Deficits in phosphorylation of GABAA receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci. 2008;28:37684. 13. Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J. Subunitspecific trafficking of GABAA receptors during status epilepticus. J Neurosci. 2008;28:252738. 14. Rajasekaran K, Zanelli SA, Goodkin HP. Lessons from the laboratory: the pathophysiology, and consequences of status epilepticus. Semin Pediatr Neurol. 2010;17:13643. 15. Chin RF, Verhulst L, Neville BG, Peters MJ, Scott RC. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. J Neurol Neurosurg Psychiatry. 2004;75:15848. 16. Chen JW, Naylor DE, Wasterlain CG. Advances in the pathophysiology of status epilepticus. Acta Neurol Scand Suppl. 2007; 186:715. 17. Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Timedependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814:17985. 18. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008;3: CD001905. 19. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet. 2005;366:20510. 20. Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006;34:3559. 21. Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr. 2006;73:9758. 22. Sreenath TG, Gupta P, Sharma KK, Krishnamurthy S. Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: a randomized controlled trial. Eur J Paediatr Neurol. 2010;14:1628. 23. Bialer M. Clinical pharmacology of parenteral use of antiepileptic drugs. Epilepsia. 2007;48:468. 24. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339:7928.

seen in the initial phase of SE as result of catecholamine surge. However, with prolonged seizures, hypoglycemia develops. Other less common complications of SE include neurogenic pulmonary edema, renal failure due to rhabdomyolysis, aspiration pneumonia, and shock.

Outcome Case fatality rate in the recent North London Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) was 3% [6]. Another systematic review showed short-term mortality of 2.75.2% if studies with high quality scores are considered [59]. However, prolonged SE is associated with higher morbidity and mortality. A study reported mortality of 28% for SE up to 2 h, 50% for SE more than 24 h [60]. Long term neurological sequelae include epilepsy, behavioural problems, cognitive decline, and focal neurologic deficits.

Conclusions Aggressive therapy is required for management of SE as prolonged seizures are less responsive to therapy. As not many good randomized controlled trials are available in childhood SE, and regional availability of anticonvulsant drugs could be problematic so institution based protocols are important for standardization of therapy in SE at different places to prevent delay in therapy. However, audit of institutional protocols should be done.
Acknowledgements The authors thank Dr Naveen Sankhyan for his inputs for developing the management algorithm. Conflict of Interest None.

Role of Funding Source None.

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