Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children

Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood seizures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94 (SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent seizures.     

Buccal midazolam for treatment of prolonged seizures in children

Midazolam is a relatively new anticonvulsive agent in the benzodiazepine group. It has a short onset of duration and is practical for use, providing several alternatives such as intravenous, intramuscular, and intranasal routes. The buccal route could be an alternative choice for seizure control in an emergency setting. However, no sufficient reports are available on buccal midazolam administration. The present study was designated to examine the efficacy of buccal midazolam in children at different ages with seizures of more than 5 min duration. Nineteen previously unreported children, aged from 1 month to 15 years, were treated with a 0.3 mg/kg dose of buccal midazolam; 13 had prolonged seizures, and six had status epilepticus, with a duration of 5-45 min (mean 22 min). Sixteen of 19 seizures (84.2%) stopped within 10 min of buccal midazolam being given. The drug efficacy in patients with status epilepticus was 50%. However, all patients with convulsions shorter than 30 min showed a perfect response (100%). Convulsion episodes stopped within 3.89+/-2.22 min (median time 3 min). Seizure duration was correlated with cessation of seizure (r=0.76, P<0.001). No clinically important side effects were seen in any patient. On the basis of this experience, we concluded that a 0.3 mg/kg dose of buccal administration of midazolam might offer an effective treatment in all ages of children.     

A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures

The objective of this study is to compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of acute childhood seizures. A randomized controlled study was conducted in a pediatric emergency department in a tertiary general hospital. Fifty children aged from 1 month to 12 years presenting with acute seizures of at least 10 min duration were enrolled during a 12 month period. Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg) were administered. The main outcome measures were interval between arrival at hospital and starting treatment and interval between arrival at hospital and cessation of seizures. Intranasal midazolam and intravenous diazepam were equally effective. Overall 18 of 27 seizures were controlled with midazolam and 15 of 23 with diazepam. The mean interval between arrival at hospital and starting treatment was significantly shorter in the midazolam group [3.37 min (SD 2.46)] as compared to the diazepam group [14.13 min (SD 3.39)]. The mean interval between cessation of seizures and arrival at hospital was significantly shorter in the midazolam group [6.67 min (SD 3.12)] as compared to the diazepam group [17.18 min (SD 5.09)]. The mean interval between control of seizures and administration of the drug was shorter in the diazepam group [2.67 min (SD 2.31)] as compared to the midazolam group [3.01 min (SD 2.79)]. No significant side effects were observed in either group. Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Midazolam was as safe and effective as diazepam. The overall interval between arrival at hospital and cessation of seizures was shorter with intranasal midazolam than with intravenous diazepam. The intranasal route can be possibly used not only in medical centres, but with appropriate instruction by the parents of children with acute seizures at home.     

Midazolam in treatment of epileptic seizures.

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.     

Intranasal midazolam for prolonged convulsive seizures

In order to determine the efficiency of intranasal midazolam in prolonged convulsive episodes, we conducted a prospective study in children with various types of seizures. Nine patients (six boys, three girls; age range 6 months to 9 years) with prolonged convulsions lasting more than 10 min were treated with intranasal midazolam, 0.3 mg/kg. The success rate was 100% with only one case requiring a second dose. Estimated duration of seizures was 12-30 min (mean 18.6) while mean time elapsed until cessation of seizures was 139.6 s (range 60-480). No significant adverse effects were noted except for one patient who had seizures secondary to serious CNS infection and respiratory depression after intranasal midazolam.     

Midazolam treatment for status epilepticus of children

We investigated the efficacy and safety of midazolam given intravenously for the treatment of status epilepticus in children. Patients received one to three bolus injections of midazolam (0.15 to 0.40 mg/kg) until seizures disappeared completely. In other patients, continuous infusion of midazolam (0.06 to 0.48 mg/kg/hr) followed a bolus of midazolam or other anti-epileptic agents. The dose was increased every 15 minutes until the seizures were brought under control. The etiology of 62 episodes of status epilepticus was epilepsy in 43, acute encephalopathy/encephalitis in 11, febrile seizures in 7 and hypoxic encephalopathy in 1. The age of the patients ranged from 0.2 to 18.4 years (average: 3.7 years). Bolus injections were administered in 53 episodes. The average loading dose was 0.35 +/- 0.22 mg/kg (range 0.15 to 0.90 mg/kg). Of the 42 episodes in which seizures disappeared, 13 required no further continuous infusions. Of the remaining 29 in which continuous infusion was done at the rate of 0.06 to 0.60 mg/kg/hr (mean 0.30 mg/kg/hr), 21 ended in cessation of the seizures. The duration of continuous infusions ranged from 4 to 288 hours (average 49.0 hours). In 6 episodes there were adverse effects:transient hypoxemia (5) and agitation during withdrawal (1). No intervention was needed except oxygenation by mask for less than 72 hours. Midazolam is effective and safe, and can be used as the first line drug in the treatment of status epilepticus in children.     

Epilepsy control following intracranial monitoring without resection in young children

Purpose: Intracranial monitoring (IM) is a key diagnostic procedure for select patients with treatment‐resistant epilepsy (TRE). Seizure focus resection may improve seizure control in both lesional and nonlesional TRE. IM itself is not considered to have therapeutic potential. We describe a cohort of patients with improved seizure control following IM without resective surgery. Methods: Over 12.5 years, 161 children underwent 496 surgeries including intracranial monitoring. We retrospectively reviewed the patients’ charts, operative reports, and radiologic scans, under an institutional review board–approved protocol. Key Findings: Seventeen patients underwent only IM, without additional resective surgery, and seven had a dramatic improvement in their epilepsy; six of the seven patients are seizure‐free (Engel class I), and one rarely has seizures (Engel class II). All seven patients had frequent seizures that led to IM: either daily (five patients) or 1–2 per week (two patients). The mean age (± standard deviation, SD) at seizure onset was 1.6 ± 1.3 years (range 0.5–4 years). Etiologies were tuberous sclerosis (3 patients), trauma (1 patient), and unknown (3 patients). Mean age at surgery (± SD) was 4.1 ± 2 years (range 1–7 years), and duration of epilepsy 2.5 ± 1.1 years (range 0.5–4 years). Duration of IM was 11.7 ± 5.6 days (5–19 days). Six patients had bilateral and one unilateral invasive electrodes. At last follow‐up, four patients required fewer antiepileptic drugs (AEDs), one had the same medication but a higher dose, and two patients were taking additional AEDs. Follow‐up was 30.6 ± 9.5 months (range 19–41 months). Significance: Although uncommon, patients with TRE may improve after IM alone. The explanation for this observation remains unclear; however, perioperative medications including steroids, direct cortical manipulation, or other factors may influence the epileptogenic network.     

Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study

In this study, the effects and side effects of rectal diazepam and intranasal midazolam were compared in the treatment of acute convulsions in children to develop a practical and safe treatment protocol. In the diazepam group, the seizures of 13 (60%) patients terminated in 10 minutes; however, 9 (40%) patients did not respond. In the midazolam group, 20 (87%) patients responded in 10 minutes, but 3 (13%) patients did not respond. Regarding the anticonvulsant effect, midazolam was found to be more effective than diazepam, and the difference was statistically significant (P < .05). The necessity of a second drug for the seizures that did not stop with the first drug was higher in the diazepam group than the midazolam group, and the difference was statistically significant (P < .05). We conclude that as an antiepileptic agent, intranasal midazolam is more effective than rectal diazepam. After administration, we did not observe any serious complications. Further investigations are necessary; however, intranasal administration is easy, so if the nasal drop and spray forms used in some European countries and the United States are available worldwide, it will be very useful for physicians in the emergency room.     

Midazolam as a first-line agent for status epilepticus in children

Midazolam is a water-soluble benzodiazepine, and has recently emerged as a safe and effective treatment option after ordinary antiepileptic therapy in the management of status epilepticus. However, midazolam as a first-line agent for status epilepticus in children has not been fully investigated. Intravenous midazolam was used for status epilepticus in 27 children (38 convulsive episodes) from January 1997 to December 1999 in our hospital. Among them, 10 patients (16 convulsive episodes) were treated with intravenous midazolam as a first-line agent. The causes of the seizures varied. Midazolam was administered as an intravenous bolus dose (0.1-0.3 mg/kg), followed by continuous intravenous infusion (1-8 microg/kg per min). In all epileptic episodes but one, the seizures stopped within 1 min without any adverse effects. These results were compatible with the previously reported ones. It is important to terminate status epilepticus which can cause brain damage. Midazolam seems to be effective and safe as a first-line therapy for status epilepticus in children.     

Intramuscular and rectal therapies of acute seizures

The intramuscular (IM) and rectal routes are alternative routes of delivery for antiepileptic drugs (AEDs) when the intravenous route is not practical or possible. For treatment of acute seizures, the AED used should have a short time to maximum concentration (T_max). Some AEDs have preparations that may be given intramuscularly. These include the benzodiazepines (diazepam, lorazepam, and midazolam) and others (fosphenytoin, levetiracetam). Although phenytoin and valproate have parenteral preparations, these should not be given intramuscularly. A recent study of prehospital treatment of status epilepticus evaluated a midazolam (MDZ) autoinjector delivering IM drug compared to IV lorazepam (LZP). Seizures were absent on arrival to the emergency department in 73.4% of the IM MDZ compared to a 63.4% response in LZP-treated subjects (p < 0.001 for superiority). Almost all AEDs have been evaluated for rectal administration as solutions, gels, and suppositories. In a placebo-controlled study, diazepam (DZP) was administered at home by caregivers in doses that ranged from 0.2 to 0.5 mg/kg. Diazepam was superior to placebo in reduced seizure frequency in children (p < 0.001) and in adults (p = 0.02) and time to recurrent seizures after an initial treatment (p < 0.001). Thus, at this time, only MZD given intramuscularly and DZP given rectally appear to have the properties required for rapid enough absorption to be useful when intravenous routes are not possible.Some drugs cannot be administered rectally owing to factors such as poor absorption or poor solubility in aqueous solutions. The relative rectal bioavailability of gabapentin, oxcarbazepine, and phenytoin is so low that the current formulations are not considered to be suitable for administration by this route. When administered as a solution, diazepam is rapidly absorbed rectally, reaching the T_max within 5–20 min in children. By contrast, rectal administration of lorazepam is relatively slow, with a T_max of 1–2 h.The dependence of gabapentin on an active transport system, and the much-reduced surface area of the rectum compared with the small intestine, may be responsible for its lack of absorption from the rectum.This article is part of a Special Issue entitled “Status Epilepticus”.     

Anticonvulsant actions and interaction of GABA agonists and a benzodiazepine in pars reticulata of substantia nigra

In a previous study, infusion of flurazepam and midazolam, but not GABA or muscimol into the pars reticulata of substantia nigra (SNpr), blocked the tonus induced by a high dose of pentylenetetrazol (PTZ). It was hypothesized that the divergence of GABAA agonist and benzodiazepine (BZ) actions might be due to a complex action of the GABAA agonists in SNpr that is not shared by the BZs, and which is specific for certain experimental seizures. This was tested in the present study in which GABA, muscimol, midazolam, and combinations of midazolam with GABA and with muscimol were tested against seizures induced by PTZ (40 or 100 mg/kg, i.p.), bicuculline (0.5 mg/kg, i.v.) and maximal electroshock (MES). Intranigral midazolam was effective against PTZ, bicuculline and MES seizures. Intranigral GABA or muscimol, infused together with midazolam, prevented midazolam from blocking tonus induced by the high dose of PTZ. For bicuculline seizures, midazolam alone had a better overall anticonvulsant effect than did the combination of midazolam plus muscimol. Intranigral muscimol, midazolam and a combination of two were equally effective against the low dose PTZ (40 mg/kg, i.p.) and MES seizures. Since the effect of intranigral drugs was model-specific, it was suggested that different populations of nigral output neurons were involved in regulating the generalization of these seizures.     

A reversible generalized movement disorder in critically III children with cancer

Introduction: Some children treated for cancer become critically ill because of immune suppression and sepsis requiring prolonged intensive care support and assisted ventilation. Methods: Over a 3-year-period, we have identified six children (four with brain tumors) who developed a generalized movement disorder during a protracted intensive care unit stay. Median age was 2 years (range 1–6 years). Movement disorder developed while receiving multiple medications. Results: Sedation was achieved with midazolam and opioid infusions. Dystonic posturing of limbs, jaw movements, tongue thrusting, and intermittent eye deviations were present in all. Movements increased if the child was stimulated and an electroencephalogram performed in five children excluded seizures. Conclusions: This movement disorder should be differentiated from seizures to prevent inappropriate treatment. Exacerbation with stimulation is a clinical clue to the correct diagnosis and an electroencephalogram can help differentiate this movement disorder from seizures.     

Severe refractory status epilepticus owing to presumed encephalitis

The severe refractory type of status epilepticus is very rare in the pediatric population. Eight children with the severe refractory type of status epilepticus owing to presumed encephalitis are described. The age at the onset of status epilepticus of the eight study children ranged between 2.5 and 15 years. Seven of the eight children presented with fever several days prior to the onset of seizures. A comprehensive clinical and laboratory investigation failed to delineate a cause for their seizures. Burst suppression coma was induced by pentothal, midazolam, propofol, or ketamine in all of the children. The mean duration of anesthesia was 28 days (range 4-62 days), but the seizures persisted in spite of repeated burst suppression cycles in all of them. Two children died. Four of the surviving children continued to suffer from seizures, and cognitive sequelae were present throughout follow-up in four children. In summary, the severe refractory type of status epilepticus of the acute symptomatic type owing to relatively mild encephalitis carries a high mortality rate and poor morbidity in terms of seizures and cognition at follow-up.     

A case of sudden unexpected death in epilepsy 3 years after the onset of acute encephalitis with refractory, repetitive partial seizures

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a peculiar form of encephalitis mainly affecting children. Although not usually lethal, we report a case of sudden unexpected death in epilepsy (SUDEP) 3 years after the onset of AERRPS. A 6-year-old boy was admitted to our hospital because of fever and extremely refractory partial and secondary generalized seizures with delirium and psychiatric change. The seizures were highly resistant to anticonvulsants and suppressed only by large dose intravenous administration of midazolam. Seven months after the onset, the seizures were ameliorated by treatment with potassium bromide and clorazepate. After the acute phase, the patient developed complex partial seizures that tended to present with cyanosis. At the age of 10, he was found lying prone in respiratory arrest with facial pallor. Although he regained cardiac function after being taken to our emergency room, the patient died 12 days later. Six SUDEP cases after the onset of AERRPS, including this one, have been reported to date. Since epilepsy following AERRPS is one of the risk factors of SUDEP, clinicians should consider SUDEP to be a rare but high risk syndrome in AERRPS-afflicted children.     

Eight-year study on the treatment with intravenous midazolam for status epilepticus and clusters of seizures in children

Eighty-two episodes of status epilepticus or clusters of seizures in 45 children were treated with intravenous midazolam. Twenty-two children had epilepsy and 23 had acute symptomatic seizures. Midazolam was administered as an intravenous bolus dose at 0.06-0.4 mg/kg (mean 0.173 mg/kg), followed by continuous intravenous infusion at 0.05-0.4 mg/kg/hr (mean 0.191 mg/kg/hr). The mean duration of the treatment was 132.7 hours. Complete arrest of seizures was achieved in 62 episodes, and decrease by more than 50% in seizure frequency in 8 clusters of seizures. In these 70 successfully treated cases (85.4%), the effect appeared within 45 minutes after the initiation of therapy. No severe adverse effects were noted except stridor and mild respiratory suppression in 2 cases. Midazolam is an effective and safe drug to be used in a first-line or second-line therapy for status epilepticus and clusters of seizures in children.     

Choice and administration sequence of antiepileptic agents for status epilepticus and frequent seizures in children

We investigated the sequence of the administration, the efficacy and the safety of antiepileptic drugs (AED) given intravenously for the treatment of status epilepticus and frequent seizures in children. Our institute has a recommended sequence of AED administration for treatment of status epilepticus: the first-line agent is diazepam (0.3 - 0.5 mg/kg administered intravenously, once or twice). The second-line drugs include midazolam (0.15 - 0.4 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 0.06 - 0.18 mg/kg/hour), lidocaine (1 - 2 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 2 - 4 mg/kg/hour) and phenytoin (10 - 20 mg/kg, infused slowly). For those patients who previously experienced a seizure which was refractory to diazepam but responsive to the second-line agent, it was recommended to use the second-line agent as a first-line agent. When seizures were refractory to the first and second-line agents, thiopental was administered (3 - 10 mg/kg intravenously, and if necessary, followed by continuous infusion at 2 -5 mg/kg/hour). The etiologies of 177 occasions of status epilepticus and frequent seizures were categorized into two groups:epilepsy (n = 95) and situation-related seizures (n = 82). Situation-related seizures included febrile seizures (n = 44), acute encephalopathy/encephalitis (n = 31) and benign infantile convulsions (n = 7). The ages of the patients ranged from 0.1 to 18.4 years (average +/- SD:3.69 +/- 3.15 years). Diazepam was administered as the first-line drug on 157 of 177 occasions (88.7%). On 116 occasions the second-line agents were administered. Midazolam and lidocaine were injected as the second-line agent on 54 (46.6%), and on 33 (28.4%) occasions, respectively, although both midazolam and lidocaine injections were off-label use for seizure control in Japan. Thiopental was used as the third to fifth-line agent. Effective ratios (effective occasions/total occasions) of each drug were the following: thiopental 19/21 (90.4%), midazolam 57/99 (57.6%), lidocaine 25/60 (41.7%), phenytoin 16/41 (39.0%), diazepam 59/164 (36.0%). Thiopental was statistically more effective than midazolam, lidocaine, diazepam or phenytoin (p < 0.01), and midazolam was statistically more effective than diazepam (p < 0.01) or phenytoin (p < 0.05). Administration of thiopental caused complications more frequently than the other agents (p < 0.01): The complications by thiopental were severe in some cases requiring intratracheal intubations and artificial ventilation. From the viewpoint of both efficacy and safety, midazolam should be recommended as one of the first-line agents for status epilepticus.     

Efficacy of continuous midazolam infusion and mortality in childhood refractory generalized convulsive status epilepticus.

PURPOSE: Continuous midazolam infusion is commonly used for the management of status epilepticus (SE). The purpose of this study was to assess the efficacy of midazolam and mortality in childhood refractory generalized convulsive SE. METHODS: We included 27 children with refractory generalized convulsive SE. Midazolam was given 0.2 mg/kg as bolus, followed by 1-5 microg/kg/min as continuous infusion. Clinical data and response to treatment were recorded for each patient. RESULTS: Acute symptomatic SE accounted for 52%, and central nervous system (CNS) infections were the most frequently associated etiologic condition (44%). Complete control of seizures was achieved with midazolam infusion in the 26 (96%) children within 65 min; at a mean midazolam infusion rate of 3.1 microg/kg/min. Adverse effects such as hypotension, bradycardia or respiratory depression did not occur during midazolam infusion. In one (4%) patient with acute meningoencephalitis, SE could not be controlled. Five (19%) patients died; four had acute symptomatic aetiology and one had progressive encephalopathy. CONCLUSION: Midazolam is effective and safe in the control of refractory generalized convulsive SE. The response to treatment and mortality were related to the underlying aetiology.     

Nasal midazolam effects on childhood acute seizures

Sixteen children, aged from 2 months to 14 years, with a diagnosis of acute seizures and seen at Dr. Sami Ulus Child Health and Disease Center, were included in this study. Midazolam (5 mg/mL) 0.2 mg/kg was administered intranasally in 30 seconds by an injector. The heart rate, respiratory rate, blood pressure, and oxygen saturation were recorded at 0, 5, and 10 minutes after administration. The seizures of three (18.7%) patients terminated within 1 minute, of seven (43.7%) patients in 1 to 2 minutes, and of three (18.7%) patients in 2 to 5 minutes. However, three (18.7%) patients did not respond to treatment. As a result, it was concluded that intranasal midazolam administration is easy and effective. The half-life of midazolam is shorter than diazepam, and midazolam has fewer complications when compared with diazepam. It is easier to use in nasal drop and spray forms.     

Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus

The objective of this study was to compare the efficacy of continuous midazolam and diazepam infusion for the control of refractory status epilepticus. An open-label, randomized control study was undertaken at the Pediatric Emergency and Intensive Care Service of a multidisciplinary teaching and referral hospital. Subjects included 40 children, 2 to 12 years of age, with refractory status epilepticus (motor seizures uncontrolled after two doses of diazepam, 0.3 mg/kg per dose, and phenytoin infusion, 20 mg/kg). Either continuous midazolam (n = 21) or diazepam infusion (n = 19) in incremental doses was administered. The primary outcome measure was the proportion of children in each group with successful control of refractory status epilepticus. The secondary outcome measure was the time to control seizure activity, recurrence of seizure after initial control, if any, the frequency of hypotension, and the need for ventilation. The two groups were similar in age (mean +/- SD = 4.9 +/- 43.6 months) and etiology. Twenty-three (57.5%) patients had acute central nervous system infection. Refractory status epilepticus was controlled in 18 (86%) and 17 (89%) patients in the midazolam and diazepam groups, respectively (P = not significant). The median time to seizure control was 16 minutes in both groups, but in the midazolam group, seizures recurred in more children (57% versus 16% in diazepam group; P < .05). The maximum dose (mean +/- SD) of midazolam and diazepam required was 5.3 +/- 2.6 microg/kg/min and 0.04 +/- 0.02 mg/kg/min, respectively. About half of the patients needed mechanical ventilation and 40% had hypotension in both groups, but the mortality was higher in the midazolam group (38%) as compared to the diazepam group (10.5%, P < .1 > .05). Continuous midazolam and diazepam infusions were equally effective for control of refractory status epilepticus. However, midazolam was associated with more seizure recurrence and higher mortality in refractory status epilepticus predominantly caused by central nervous system infections.     

Broad-spectrum efficacy of zonisamide at 12 months in children with intractable epilepsy

In a retrospective study of 35 children (ages 8 months to 22 years; mean age 9 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of zonisamide therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications, and the number of previous anticonvulsant drugs. Good to excellent seizure control (50-100% reduction) was attained in seven (54%) patients with generalized seizures, two (40%) patients with focal seizures, five (35%) patients with mixed seizures, and one (33%) patient with infantile spasms. In this group of children, the efficacy of zonisamide was comparable for focal, generalized, and mixed seizures. The efficacy of zonisamide was independent of cognitive status.Adverse effects were not associated with a higher mean dose. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of zonisamide and levetiracetam had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of mechanisms of action of zonisamide and levetiracetam and/or their pharmacodynamic interactions.