Treatment of Pediatric Status Epilepticus Tobias Loddenkemper, MD 1,* Howard P. Goodkin, MD, PhD 2

Transcription

1 Current Treatment Options in Neurology (2011) 13: DOI /s Pediatric Neurology (Harvey S. Singer, Section Editor) Treatment of Pediatric Status Epilepticus Tobias Loddenkemper, MD 1,* Howard P. Goodkin, MD, PhD 2 Address *,1 Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Fegan 9, Children s Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA tobias.loddenkemper@childrens.harvard.edu 2 Departments of Neurology and Pediatrics, University of Virginia Health Systems, PO Box , Charlottesville, VA 22908, USA hpg9v@virginia.edu Published online: 29 September 2011 * Springer Science+Business Media, LLC 2011 Opinion statement Status epilepticus is characterized by a prolonged, self-sustaining seizure or repeated seizures without return to baseline. The clinical manifestations of status epilepticus in children and adults range from overt generalized convulsions to more subtle behavioral manifestations, including unresponsiveness in the setting of the intensive care unit. Status epilepticus is the most common neurologic emergency of childhood. A large proportion of these episodes are the result of a prolonged febrile seizure or an acute symptomatic etiology. Fortunately, status epilepticus occurs without consequence for many children, but for others, it is correlated with long-term neurologic dysfunction or death. Treatment of status epilepticus should commence promptly upon its recognition, using predefined treatment protocols. The goal of treatment is the rapid termination of the seizure, to minimize the acute and chronic effects of this emergency and to allow for the prompt assessment and management of the underlying precipitant. Currently, the drug class of first choice in the in-hospital and out-of-hospital treatment of status epilepticus is the benzodiazepines, which may need to be quickly followed by a next-line agent, as the efficacy of the benzodiazepines is negatively correlated with seizure duration. Traditionally, these next-line agents have included phenobarbital and phenytoin, but emerging evidence supports the use of intravenous formulations of other antiepileptic drugs. If the first two agents fail, high-dose intravenous midazolam or anesthetic therapy should be rapidly initiated. This paper reviews the current treatment options and strategies for pediatric patients with status epilepticus. Introduction Status epilepticus (SE) presents as a prolonged, selfsustaining seizure or as recurrent seizures without return to baseline. The behavioral characteristics of SE range from overt primary or secondarily generalized convulsions to the nonconvulsive forms characterized by periods of altered mental status that varies from prolonged confusion (absence SE, complex partial SE) to unresponsiveness.

2 Pediatric Status Epilepticus Loddenkemper and Goodkin 561 Independent of its behavioral characteristics, SE represents a dynamic, evolving syndrome. The initial or impending stage is characterized by repeated isolated seizures. These seizures begin to lengthen and then merge, resulting in established SE [1]. If the seizure persists, the established phase evolves to a later stage during which the clinical manifestations may be subtle, electromechanical dissociation ensues, and the EEG is characterized by periodic epileptiform discharges. Early in SE, homeostatic mechanisms are capable of compensating for metabolic demands, but as the seizure persists, these mechanisms fail, producing a situation in which the CNS is susceptible to injury. SE represents the most common neurologic emergency of childhood. In a prospective, population-based study performed in Richmond, Virginia, the incidence of SE was estimated at approximately 50 episodes of SE per year per 100,000 population [2, Class III]. In that study, the highest incidence of SE occurred in children, primarily before 1 year of age, and in adults older than 60 years of age. In the recent prospective, communitybased North London Status Epilepticus in Childhood Surveillance Study (NLSTEPSS), the incidence of SE during childhood was 17 to 23 episodes of SE per year per 100,000 population; again, the highest incidence was in children less than 1 year of age [3, ClassIII].Many of these children had no prior history of seizures or neurologic disorder [4, Class IV]. SE in children may have both acute and remote causes. In the NLSTEPSS study, prolonged febrile seizures and acute etiologies (e.g., trauma, CNS infection, stroke, metabolic abnormalities) accounted for 50% of the episodes of SE. Death and neurologic morbidity are severe consequences of SE. Recent case fatality rates for children have ranged from 3% [3] to 9.3% [5, Class IV], with the higher value reported in a study restricted to children with SE treated within the setting of an intensive care unit (ICU). Outcome is most highly predicted by etiology and age. Factors that have also intermittently been linked to outcome include duration [6, Class IV] and response to treatment. Treatment Diagnosis of convulsive SE typically is not difficult, but pseudostatus epilepticus should be considered, although it is rare in children. Nonconvulsive forms of SE (NCSE), especially in the ICU setting, require EEG for diagnosis and management. In a recent study of 100 critically ill children with an acute encephalopathy in an ICU setting, electrographic seizures were recorded in 46 patients and SE was diagnosed in 19 [7, Class IV]. In the child who has undergone apparently successful treatment for convulsive SE but continues to have encephalopathy, continuous EEG may be required to ensure the absence of NCSE. The first step in SE treatment, as in other emergency situations, is to secure the airway, provide breathing support, and ensure circulation. In parallel, a glucose check should be performed. The additional diagnostic evaluation of a child with SE is reviewed in the American Academy of Neurology s practice parameter [8, Class IV]. Current treatment protocols for convulsive SE in children and adults are based on a stepwise progression of medications that begins with the rapid application of a benzodiazepine, followed by a loading dose of an intravenous agent such as phenytoin (Fig. 1). It should be noted that these protocols are based on limited controlled trials performed predominantly in adults. The most beneficial treatment algorithm for both children and adults is not known.

3 562 Pediatric Neurology (Harvey S. Singer, Section Editor) Figure 1. A potential approach to convulsive status epilepticus in children. The first step should always be to take care of airway, breathing, and circulation (ABCs). The first-line antiepileptic drug (AED) is usually a benzodiazepine (lorazepam), followed by a loading dose of phenytoin, and then another intravenous (IV) epilepsy medication, most frequently phenobarbital, levetiracetam, or valproic acid. Additional (and overlapping) systemic management should consider potential correction of hypoxia, hemodynamics, hyperthermia, hypoglycemia, and hyponatremia. Diagnostic laboratory tests, EKG, and imaging may be obtained simultaneously. If status epilepticus becomes refractory (at the latest, after failure of the second medication), continuous EEG monitoring should be initiated. If treatment with two or three AEDs fails, burst suppression with midazolam or pentobarbital may be initiated. In children less than 2 years of age, a pyridoxine trial should be considered. PE phenytoin equivalents; PR per rectum. The first-line and second-line treatment of complex partial and absence SE is similar to the treatment of convulsive SE. It is unusual for these forms of SE to require coma induction and the therapies for refractory SE that are described below. These forms of SE can typically be approached with small, repeated doses of intravenous lorazepam or midazolam and the start of a long-term antiepileptic agent. The need for rapid treatment of NCSE encountered in the ICU setting is debated, as the long-term effects of these nonconvulsive seizures are largely unknown and may depend on the underlying cause. Although studies suggest that NCSE is associated with mortality and neurologic morbidity [9, Class IV], it is not known whether treating it alters outcome. In the absence of a rigid national standard for the treatment of SE [10, Class IV], SE treatment is guided by clinical guidelines and practice parameters [8]. As these parameters represent suggestions and recommendations, it is suspected that treatment protocols vary between medical centers. Nevertheless, an overriding principle that should guide all protocols is that rapid treatment of SE is mandatory both in and out of the hospital, as seizure duration is negatively correlated with the probability of a seizure self-terminating [11, Class IV] and with treatment efficacy [12, Class I; 13, 14, Class III]. Recognition of the essential need for rapid treatment of SE is reflected in current operational definitions of SE, which have defined SE as seizure durations as short as 5 min [15, Class IV]. Furthermore, rapid effective treatment not only minimizes the potential untoward effects

4 Pediatric Status Epilepticus Loddenkemper and Goodkin 563 Pharmacologic treatment of the seizure but also allows for the prompt assessment and management of the underlying precipitant. SE is increasingly being treated in the out-of-hospital setting. Current options for out-of-hospital treatment include buccal midazolam [16, ClassI],intranasalmidazolam[17, Class III], intramuscular midazolam, and rectal diazepam [17, ClassIV].A study that compared the pre-hospital treatment of SE in adults using diazepam (5 mg) or lorazepam (2 mg) versus placebo demonstrated that these out-of-hospital treatments were safe in that patient population [18, Class I]. In a case of the child who is known to be predisposed to SE, the family or long-term care facility should be provided with a set of guidelines for acute, out-of-hospital seizure management as well as back-up plans for activating emergency medical services. For all children with convulsive SE, every minute of delay between SE onset and emergency room arrival is associated with a 5% cumulative increase in the risk that the episode will last longer than 60 min [13], illustrating the importance of having a treatment plan that includes out-of-hospital treatment. For all medications listed below, a known hypersensitivity to that medication is a contraindication. First-Line treatment: The 1,4-benzodiazepines The 1,4-benzodiazepines are positive allosteric modulators of the GABA A receptors. These receptors are heteropentameric, ligand-gated chloride channels that mediate both synaptic and tonic inhibition. The receptor s benzodiazepine sensitivity is dependent on the presence of an α subunit in the receptor assembly. The binding of the benzodiazepine to the receptor appears to increase the apparent association of GABA to the receptor, with the net result of an increase in GABA-mediated inhibition. Factors making the 1,4-benzodiazepines the drug class of first choice in the treatment of SE include their effectiveness against a number of seizure types, their rapid onset of action upon entering the brain, and their relative safety [19, Class IV]. Basedonbothadultdata[18, 20, Class III] and pediatric data [21, Class IV], adequate first-line treatment with a benzodiazepine is crucial for seizure termination. In children, underdosing of benzodiazepines in the emergency room was correlated with ICU admission [21]. The success of benzodiazepine therapy is inversely related to seizure duration. This decrease in efficacy in established and late SE is potentially the result of a rapid modification in the postsynaptic GABA A

5 564 Pediatric Neurology (Harvey S. Singer, Section Editor) Lorazepam Diazepam Midazolam receptor population that is due, in part, to activity-dependent, subunitspecific trafficking of the receptors [22, ClassIV]. Meta-analyses comparing the efficacy of benzodiazepines in the acute management of convulsive SE in children have concluded that intravenous lorazepam was at least as effective as intravenous diazepam and was associated with fewer adverse effects [23, Class IV]. Midazolam, by any route, was superior in efficacy to diazepam given by any route [24, Class IV]. Ease of administration and degree of patient satisfaction favor nonrectal routes (buccal or intranasal application). With buccal or intranasal application, there are some concerns, however, regarding possible aspiration or lack of effectiveness in patients with nasal congestion. As a class, the major adverse effects of the 1,4-benzodiazepines include sedation, respiratory depression, cardiac dysrhythmia, and ataxia. Paradoxic excitation can be observed. Treatment with more than two doses of benzodiazepines was associated with respiratory depression, defined as a fall in oxygen saturation below 92% [13]. The absence of respiratory monitoring is a relative contraindication to the repetitive use of benzodiazepines. The use of the benzodiazepines in combination with other CNS depressants can synergistically increase the risk of CNS depression. Benzodiazepine dosing in neonates may differ from provided dose ranges. Benzodiazepines have been associated with myoclonic jerks in neonates and very-low-birth-weight infants [25, Class IV]. Therefore, the drug of first choice for neonates diagnosed with seizures traditionally has been phenobarbital. Lorazepam may be given at a dose of 0.05 to 0.1 mg/kg (maximum, 4 mg/ dose) intravenously over 2 to 5 min. The dose may be repeated if needed, with monitoring for respiratory depression. A buccal formulation is available in Canada and Europe (up to 2 mg per dose). Diazepam may be given at a dose of 0.2 to 0.5 mg/kg intravenously over 2 to 5 min. The rectal dose is based on age and weight. Typical doses range from 0.5 to 0.75 mg/kg. Doses may be repeated if needed, with monitoring for respiratory depression. Intravenous midazolam is typically reserved for the treatment of prolonged, refractory SE (see below). Buccal [16] orintranasalmidazolam doses range from 0.2 to 0.5 mg/kg, up to 10 mg per dose. Currently, no buccal midazolam has been approved by the US Food and Drug Administration (FDA). Buccal or intranasal application of the intravenous midazolam solution may be an option. One randomized trial found no difference in efficacy between intranasal midazolam and rectal diazepam

6 Pediatric Status Epilepticus Loddenkemper and Goodkin 565 as a rescue medication for terminating seizures at home in children with epilepsy [17 ]. Second-Line treatment Phenytoin and fosphenytoin The second-line medications are all available in intravenous formulations. Phenytoin and its prodrug, fosphenytoin, are traditionally the drugs of first choice among this group, but no comparative treatment trials have compared these agents. Special points Cost Phenobarbital Phenytoin limits the repetitive firing of action potential through stabilization of the inactive form of neuronal voltage-dependent sodium channels. Fosphenytoin is the water-soluble disodium phosphate ester of phenytoin. It is rapidly and entirely converted to free phenytoin by serum and tissue alkaline phosphatases. It is increasingly used instead of intravenous phenytoin in treating SE, as it does not result in tissue injury upon extravasation and has a lower risk of cardiac arrhythmia. Fosphenytoin is dosed in phenytoin equivalents (PE). In a study comparing 90 children treated with lorazepam and 88 treated with a diazepam-phenytoin combination, no difference in SE termination was found [26, Class III]. Phenytoin may be given at a dose of 20 mg/kg at a rate of 1 mg/kg per minute (maximum 50 mg/minute). Fosphenytoin may be given at a dose of 20 mg PE/kg intravenously at a rate of 3 mg PE/kg per minute (maximum 150 mg PE/minute). Cardiovascular monitoring is recommended during intravenous application. Because fosphenytoin must be converted to phenytoin, the time to optimal CNS phenytoin concentration is roughly similar despite the faster infusion rate of fosphenytoin. The main adverse effects associated with these medications are bradyarrhythmia, hypotension, and local tissue necrosis (with phenytoin). There are rare reports of purple glove syndrome in children [27, Class IV]. Phenytoin is highly protein-bound and a strong P450 enzyme inducing agent. When intravenous access is not available, fosphenytoin may be given intramuscularly. In infants, it can be difficult to maintain therapeutic levels of phenytoin and fosphenytoin. Fosphenytoin is relatively more expensive than phenytoin. Phenobarbital is a long-acting barbiturate that not only enhances GABAmediated inhibition but also may antagonize AMPA receptors and inhibit neurotransmitter release. Phenobarbital may be given at a dose of 20 mg/kg as single or divided application (2 mg/kg per minute in children G40 kg up to 100 mg/minute in children 940 kg). This dose will achieve a plasma level of about 20 mg/l (86.2 μmol/l). A dose of 5 to 20 mg/kg may be repeated every 15 to 20 min as needed, with cardiorespiratory monitoring. Repetitive intravenous phe-

7 566 Pediatric Neurology (Harvey S. Singer, Section Editor) nobarbital doses have been used for coma induction and treatment of persistent refractory SE. Oral loading doses of up 80 mg/kg (reaching plasma level concentrations of 283 μmol/l) have also been described [28, Class IV]. Valproic acid Intravenous loading of phenobarbital is associated with CNS and respiratory depression as well as hypotension. Respiratory and cardiac monitoring is recommended. High levels of phenobarbital can suppress brainstem reflexes. Phenobarbital can exacerbate porphyria. Phenobarbital is a potent enzyme inducer. Special points Levetiracetam Several mechanisms of action have been reported, including increasing GABA synthesis, inhibiting GABA transaminase, stabilizing voltage-gated sodium channels, and inhibiting T-type calcium channels. The ideal loading dose of this medication has not been established. Previous pediatric studies have used doses of 20 to 40 mg/kg. Although the manufacturer recommends slow rates of infusion (G20 mg/min), an open-label, randomized controlled study comparing valproic acid and diazepam demonstrated the efficacy and safety of an initial valproic acid loading dose of 30 mg/kg infused over 1 to 5 min [29, Class III]. Intravenous valproic acid stopped clinical SE and NCSE in 32 (78%) of 41 children in one series [30, Class IV]. SE remained refractory in 9 patients (22%). Treatment success differed based on the type of SE, varying from 0% (0/2) in epilepsia partialis continua to 90% (9/10) in generalized tonic-clonic SE. The black box warnings for valproic acid include serious or fatal hepatic failure and pancreatitis. The risk factors for hepatoxicity include underlying metabolic disorders in children less than 2 years of age, mitochondrial disorders, and polytherapy. In addition to these idiosyncratic reactions, a doserelated increase in serum transaminases, Stevens-Johnson syndrome, and thrombocytopenia may occur. Valproic acid is contraindicated in those with active hepatitis, pancreatitis, or known or suspected mitochondrial disease. Valproic acid is an enzyme inhibitor and will compete with other proteinbound drugs. Children may develop an encephalopathy following the administration of valproic acid. Although an elevated ammonia level may be present, its absence does not exclude valproic acid as the cause. Carnitine supplementation has been recommended, specifically for critically ill and developmentally delayed children treated with valproic acid. It is proposed that levetiracetam inhibits neurotransmitter release via its binding of the vesicular protein Synaptic Vesicle Protein 2A (SV2A). The absence of drug-drug interactions, renal clearance, low risk of sedation, and the absence of cardiac side effects makes it an ideal drug to consider for the treatment of SE. The ideal loading dose has not been established, but 20 to 40 mg/kg intravenously has been safely administered in the past. Doses of 30 mg/kg were well tolerated in children and appeared most effective in single seizure events [31, Class IV]. The dose may need to be adjusted for children with renal dysfunction.

8 Pediatric Status Epilepticus Loddenkemper and Goodkin 567 Lacosamide With the exception of agitation, this medication is well tolerated. Overdosing has occasionally resulted in respiratory depression and coma [32]. None. Lacosamide was recently approved by the FDA for the adjunct treatment of partial seizures in patients older than 17 years of age. Its proposed mechanism of action is the enhancement of the slow inactivation of voltage-dependent sodium channels. The ideal loading dose has not been established. The successful treatment of refractory SE in an 8-year-old boy using 25 mg twice daily has been described [33, Class IV]. We have used lacosamide in children (age 8 years or older) with refractory epilepsy, using median starting doses of 1.3 mg/kg per day and maintenance doses of 4.7 mg/kg per day [34, Class IV]. Lacosamide can prolong the PR interval. Therefore, it should be used with caution in patients with known cardiac conduction problems. None known. Intravenous treatment of refractory SE and special episodes of SE SE is considered refractory when seizures persist despite adequate treatment with two different medications, independent of its duration. A recent review of 542 children found that convulsive SE was terminated after first-line treatment in 42% and after second-line treatment in 35%. [4 ]. These results are similar to those in the NLSTEPSS study, in which 18% of children required anesthesia for seizure termination [13]. Special circumstances involving SE include SE in postoperative patients or patients with head trauma, metabolic disorders prone to increase intracranial pressure, CNS infection, or organ dysfunction [35, Class IV]. In these circumstances, early seizure control is required, and failure of a benzodiazepine may need to be followed immediately by anesthetic control of the seizure. Treatment of these children requires a team approach within an ICU setting. Continuous bedside EEG monitoring is essential to assist in medication titration. The aim of treating persistent refractory SE is to usually achieve a burst suppression EEG pattern for at least 24 to 48 h to stop seizures and to prevent seizure recurrence during weaning from coma-inducing medication. However, no completed randomized controlled trials are available to support the current practice of duration and depth of coma or to define the superiority of one medication over another [36, Class IV]. The diagnosis of pyridoxine-dependent seizures should be considered in a patient with refractory SE for which no other cause has been determined. Following the administration of pyridoxine under EEG,

9 568 Pediatric Neurology (Harvey S. Singer, Section Editor) Midazolam Pentobarbital Propofol clinical seizures may stop within minutes to hours and improvement of the EEG may be noted. The standard recommended dose is 100 mg given intravenously. If the child fails to respond, a second dose up to 500 mg can be considered. Given the possible untoward effects of apnea, bradycardia, and hypotension, respiratory monitoring is required when this vitamin is administered. Intravenous overdose (usually 10 g or higher) or long-term use is associated with an irreversible sensory neuropathy. In a follow-up study 2 years after refractory SE, all patients continued to have intractable epilepsy and severe learning disabilities [37,ClassIV]. Midazolam can be given as a loading dose of mg/kg followed by a continuous infusion starting at 1 μg/kg per minute. The infusion can be titrated upwards every 5 min as needed to terminate the seizure or achieve burst suppression. The reported range has been 1 to 18 μg/kg per minute with a mean of 2.3 μg/kg per minute Among 358 children who received intravenous midazolam therapy for SE [38, Class IV], seizure suppression was obtained in 231 (64.5%). The effectiveness of midazolam was lower when midazolam was initiated more than 3 h after seizure onset. None of the 10 deaths that occurred during the treatment period were associated with midazolam therapy. Pentobarbital can be given as a loading dose of 3 to 15 mg/kg followed by a typical maintenance dose of 1 to 5 mg/kg per hour. Among 23 pediatric patients treated with pentobarbital [39, Class IV], 12 were controlled, 6 were unresponsive, and 5 relapsed after discontinuation or during tapering. The mortality rate among the relapsing and nonresponding groups combined was 90.9%. No deaths occurred among the responders. Intravenous loading is associated with CNS and respiratory depression as well as hypotension. Respiratory and cardiac monitoring is recommended. High levels of pentobarbital can suppress brainstem reflexes. Pentobarbital can exacerbate porphyria. Pentobarbital is a potent enzyme inducer. In addition, concurrent use with valproic acid may lead to hyperammonemia. Propofol is a short-acting, intravenous sedative hypnotic that enhances GABA-mediated inhibition through direct activation of GABA A receptors. It is also reported to inhibit NMDA receptors and reduce the concentration of extracellular glutamate. Intravenous loading doses of up to 2 mg/kg have been described. In older adolescents, this dose may be followed by maintenance doses of 2 to 5 mg/kg per hour. The short half life of 1 to 2 h permits rapid titration and withdrawal. Doses of 5 mg/kg per hour over prolonged periods should be avoided because of propofol infusion syndrome (PrIS). Propofol leads to sedation and potentially respiratory depression. PrIS may lead to cardiovascular compromise due to lactate acidosis, hyper-

10 Pediatric Status Epilepticus Loddenkemper and Goodkin 569 Ketamine Lidocaine triglyceridemia, and rhabdomyolysis [40, Class IV]. In a retrospective review, PrIS was found in 10% of patients treated with high-dose propofol and in none of the 10 patients treated for refractory SE without propofol [40]. Frequent lactate checks may facilitate earlier recognition of PrIS. Partial exchange transfusion may prevent death in children with PrIS [41, ClassIV]. Because of the possible induction of PrIS, prolonged used is relatively contraindicated in infants and young children and in those with mitochondrial disorders, metabolic acidosis, or hypertriglyceridemia. None. Ketamine is an NMDA receptor antagonist. A loading dose of 0.5 to 2 mg/kg followed by continuous intravenous infusion of 5 to 20 μg/kg per minute has been used in adults [42, Class IV]. The oral application of the parenteral ketamine solution (50 mg/ml) in pediatric patients with NCSE at a dosage of 1.5 mg/kg per day in two divided doses has been reported to terminate NCSE within 24 to 48 h [43, ClassIV]. Ketamine can lead to hypertension, tachycardia, and respiratory depression. Ketamine is relatively contraindicated in patients who may be harmed by an elevation in blood pressure (such as those with increased intracranial pressure). Ketamine is both an enzyme inhibitor and inducer (CYP2C9). Lidocaine is another intravenous agent that has been used in treating refractory SE. Additional treatment options for refractory SE Inhalational anesthetics If intravenous agents are ineffective or cause unacceptable adverse effects, or if intravenous access cannot be maintained, the inhalational anesthetic isoflurane can be considered. Oral antiepileptic medications Topiramate Multiple mechanisms of action have been proposed, including enhanced GABA-mediated inhibition, inhibition of sodium currents, enhanced potassium channel conduction, inhibition of L-type calcium channels, decrease of glutamatergic transmission, and inhibition of carbonic anhydrase. The ideal dose of this medication has not been established. Loading doses of 5 to 10 mg/kg per day via a nasogastric route were reported in 14 selected children with refractory SE the median time to seizure ces-

11 570 Pediatric Neurology (Harvey S. Singer, Section Editor) Special points Other oral antiepileptic medications sation in 12 of the 14 patients was 5.5 h (range 2 48), and 2 patients did not respond [44, ClassIV]. Topiramate is associated with metabolic acidosis, sedation, oligohidrosis, acute myopia, and secondary angle closure glaucoma. Topiramate may enhance the risk of encephalopathy induced by valproic acid and may increase phenytoin levels when phenytoin metabolism is near saturation. An intravenous solution is in preparation. Oxcarbazepine, carbamazepine, rufinamide, felbamate, pregabalin [45, Class IV], and others may also be added by nasogastric tube. Surgical procedures Resective epilepsy surgery Standard procedure Special points Vagus nerve stimulation Standard procedure Complications Immunomodulatory approaches Surgery aims to remove the epileptogenic zone, resulting in seizure freedom or a reduction that allows tapering of antiepileptic medications [46, Class IV]. The resection is based on location of the epileptogenic zone, as determined by EEG seizure onset and possibly structural lesions, avoiding suspected eloquent areas. Following the surgery, the patient should be monitored for neurologic deficits resulting from the resection of eloquent cortex and for postsurgical complications such as hemorrhage or infection. The seizure onset zone may be difficult to recognize on EEG after several days or weeks of SE. Left vagus nerve stimulation at settings ranging from 1 to 1.75 ma (pulse width 500 μs, signal frequency 30 Hz, on time 30 s, off time 5 min) was reported to slowly abort SE [47, Class IV]. Rare complications of vagus nerve stimulation include asystole and bradycardia. Ketogenic diet Standard procedure Complications Special points Standard procedure Immunomodulation may be attempted in several forms: corticosteroids, adrenocorticotropic hormone (ACTH) therapy, intravenous immunoglobulin (IVIG), and plasmapheresis. Infection. Renal complications and aseptic meningitis may be seen with IVIG, and aseptic meningitis and hypertension with ACTH. These therapies are relatively contraindicated in children with congenital immune defects or those at risk from immunosuppression. The therapeutic effect may in part be related to the etiology of SE, such as NMDA receptor encephalitis or Hashimoto encephalitis. The ketogenic diet can be administered via gastrostomy tube or modified parenteral nutrition.

12 Pediatric Status Epilepticus Loddenkemper and Goodkin 571 Hypothermia Complications Hypoglycemia, electrolyte imbalance, dehydration, hepatitis, pancreatitis, metabolic acidosis. Selected metabolic disorders. Although the ketogenic diet may be beneficial for patients with pyruvate dehydrogenase deficiency and glucose transporter 1 deficiency syndrome, it is contraindicated in pyruvate carboxylase deficiency, disorders of fatty acid oxidation and metabolism, or porphyria, as well as in some other metabolic disorders. Standard procedure Complications Electroconvulsive therapy Standard procedure Complications Moderate hypothermia (31 35 C) achieved via an endovascular cooling system has been described, in conjunction with barbiturate or benzodiazepine coma [48, Class IV]. Older data indicate effectiveness of deeper hypothermia in SE. Hypothermia may influence medication clearance by decreasing P450 enzyme activity. No absolute contraindications. Electroconvulsive therapy (ECT) has been reported to successfully terminate SE in children and adults [49, 50, Class IV]. Postictal agitation and cardiovascular compromise. ECT may initially exacerbate the SE. Preexisting cardiovascular conditions are a relative contraindication to ECT. Emerging treatments Future treatment options may include adjunct application of magnesium, deep brain stimulation or closed loop stimulation, transcranial magnetic stimulation, and Doppler ultrasound, as well as targeted drug delivery systems or chronotherapy. Disclosure Dr. Loddenkemper serves on the Laboratory Accreditation Board for Long-Term (Epilepsy and ICU) Monitoring (ABRET); performs video-eeg long-term monitoring, EEGs, and other electrophysiological studies at Children s Hospital Boston and bills for these procedures; is funded by an Early Career Physician-Scientist Award by the Milken Family Foundation and American Epilepsy Society, by the Epilepsy Foundation of America, by the Center for Integration of Medicine and Innovative Technology, by the NIH, by the Translational Research Program at Children s Hospital Boston, by the Program for Patient Safety and Quality at Children s Hospital Boston, and by a Career Development Fellowship Award from Harvard Medical School and Children s Hospital Boston; and received investigator-initiated research support from Eisai Inc within the past year. Dr. Goodkin has served as a consultant to Avanir Pharmaceuticals within the past year. He receives research support from the National Institutes of Health.

13 572 Pediatric Neurology (Harvey S. Singer, Section Editor) References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Chen JWY, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol. 2006;5: DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46: Chin RF, Neville BG, Peckham, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective populationbased study. Lancet. 2006;368: Lewena S, Pennington V, Acworth J, et al: Emergency management of pediatric convulsive status epilepticus: a multicenter study of 542 patients. Pediatr Emerg Care 2009;25:83 7. This multicenter study provides data on termination of pediatric convulsive SE after first-line, second-line, and additional treatment interventions. It also demonstrates marked variation between sites for some therapeutic interventions. 5. Kravljanac R, Jovic N, Djuric M, et al.: Outcome of status epilepticus in children treated in the intensive care unit: a study of 302 cases, Epilepsia 2011;52: This prospective observational study included 302 children with 489 episodes of SE. It found neurologic consequences in 39 patients (12.9%) and a case-fatality ratio of 9.3%. Etiology of SE and prior neurologic abnormalities predicted mortality, and younger age, etiology, and very long duration of SE predicted morbidity. 6. Neligan A, Shorvon SD. Prognostic factors, morbidity and mortality in tonic-clonic status epilepticus: a review. Epilepsy Res. 2011;93: Abend, NS, Gutierrez-Colina AM, Topjian AA, et al.: Nonconvulsive seizures are common in critically ill children. Neurology 2011;76: In 100 critically ill children, electrographic seizures occurred in 46 and electrographic SE occurred in 19. Seizures were exclusively nonconvulsive in 32. Seizures were detected in the first hour of monitoring in 52% and within 24 hours in 87%. 8. Riviello Jr JJ, Ashwal S, Hirtz D, et al. Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2006;67: Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology. 2003;61: Loddenkemper T, Nichol SM, Allred EN, et al. Fears and promises of comparative effectiveness research. Acta Paediatr. 2010;99: Shinnar S. Who is at risk for prolonged seizures? J Child Neurol. 2007;22(5 Suppl):14S 20S. 12. 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: Chin RF, Neville BG, Peckham C, et al. Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol. 2008;7: Lambrechtsen FA, Buchhalter JR. Aborted and refractory status epilepticus in children: a comparative analysis. Epilepsia. 2008;49: Lowenstein DH, Bleck T, Macdonald RL. It s time to revise the definition of status epilepticus. Epilepsia. 1999;40: Mpimbaza A, Ndeezi G, Staedke S, et al. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics. 2008;121:e Holsti M, Dudley N, Schunk J, et al.: Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Ped Adolesc Med 2010;164: This prospective randomized trial found no difference in efficacy between intranasal midazolam and rectal diazepam. 18. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med. 2001;345: Kapur J. Prehospital treatment of status epilepticus with benzodiazepines is effective and safe. Epilepsy Curr. 2002;2: Aranda A, Foucart G, Ducasse JL, et al. Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia. 2010;51: Chin RF, Verhulst L, Neville BG, et al. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. J Neurol Neurosurg Psych. 2004;75: Goodkin HP, Kapur J. The impact of diazepam s discovery on the treatment and understanding of status epilepticus. Epilepsia. 2009;50:

14 Pediatric Status Epilepticus Loddenkemper and Goodkin Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008;16:CD McMullan J, Sasson C, Pancioli A, et al. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med. 2010;17: Zaw W, Knoppert DC, da Silva O. Flumazenil s reversal of myoclonic-like movements associated with midazolam in term newborns. Pharmacotherapy. 2001;21: Sreenath TG, Gupta P, Sharma KK, et al.: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: a randomized controlled trial. Eur J Paediatr Neurol 2010;14: This randomized controlled trial in 178 children demonstrated that lorazepam is as efficacious and safe as a diazepam-phenytoin combination. 27. Appleton RE, Gill A. Adverse events associated with intravenous phenytoin in children: a prospective study. Seizure. 2003;12: Wilmshurst JM, van der Walt JS, Ackermann SA, et al. Rescue therapy with high-dose oral phenobarbitone loading for refractory status epilepticus. J Paediatr Child Health. 2010;46: Mehta V, Singhi P, Singhi S. Intravenous sodium valproate versus diazepam infusion for the control of refractory status epilepticus in children: a randomized controlled trial. J Child Neurol. 2007;22: Uberall MA, Trollmann R, Wunsiedler U, et al. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology. 2000;13: Reiter PD, Huff AD, Knupp KG, et al. Intravenous levetiracetam in the management of acute seizures in children. Pediatr Neurol. 2010;43: Barrueto Jr F, Williams K, Howland MA, et al. A case of levetiracetam (Keppra) poisoning with clinical and toxicokinetic data. J Toxicol Clin Toxicol. 2002;40: Shiloh-Malawsky Y, Fan Z, Greenwood R, et al. Successful treatment of childhood prolonged refractory status epilepticus with lacosamide. Seizure. 2011;20: Guilhoto LM, Loddenkemper T, Gooty VD, et al. Experience with lacosamide in a series of children with drugresistant focal epilepsy. Pediatr Neurol. 2011;44: Riviello Jr JJ. Seizures in the context of acute illness. Curr Opin Pediatr. 2009;21: Rossetti AO, Milligan TA, Vulliemoz S, et al. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care. 2011;14: Sahin M, Menache CC, Holmes GL, et al. Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children. Neurology. 2003;61: Hayashi K, Osawa M, Aihara M, et al. Efficacy of intravenous midazolam for status epilepticus in childhood. Pediatr Neurol. 2007;36: Kim SJ, Lee DY, Kim JS. Neurologic outcomes of pediatric epileptic patients with pentobarbital coma. Pediatr Neurol. 2001;25: Iyer VN, Hoel R, Rabinstein AA. Propofol infusion syndrome in patients with refractory status epilepticus: an 11-year clinical experience. Crit Care Med. 2009;37: da Silva SS, Wong R, Coquillon P, et al. Partial-exchange blood transfusion: an effective method for preventing mortality in a child with propofol infusion syndrome. Pediatrics. 2010;125:e Hsieh CY, Sung PS, Tsai JJ, et al. Terminating prolonged refractory status epilepticus using ketamine. Clin Neuropharmacol. 2010;33: Mewasingh LD, Sekhara T, Aeby A, et al. Oral ketamine in paediatric non-convulsive status epilepticus. Seizure. 2003;12: Akyildiz BN, Kumandas S. Treatment of pediatric refractory status epilepticus with topiramate. Childs Nerv Syst. 2011;27: Novy J, Rossetti AO. Oral pregabalin as an add-on treatment for status epilepticus. Epilepsia. 2010;51: Vendrame M, Loddenkemper T. Surgical treatment of refractory status epilepticus in children: candidate selection and outcome. Semin Pediatr Neurol. 2010;17: De Herdt V, Waterschoot L, Vonck K, et al. Vagus nerve stimulation for refractory status epilepticus. Eur J Paediatr Neurol. 2009;13: Corry JJ, Dhar R, Murphy T, et al. Hypothermia for refractory status epilepticus. Neurocrit Care. 2008;9: Shin HW, O Donovan CA, Boggs JG, et al. Successful ECT treatment for medically refractory nonconvulsive status epilepticus in pediatric patient. Seizure. 2011;20: Kamel H, Cornes SB, Hegde M, et al. Electroconvulsive therapy for refractory status epilepticus: a case series. Neurocrit Care. 2010;12: