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Keywords:

  • status epilepticus;
  • refractory status epilepticus;
  • children;
  • epilepsy

Summary

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

Purpose: The aims of this retrospective study were: (1) to compare the demographics, clinical characteristics, etiology, and EEG findings of status epilepticus aborted with medication (ASE) and refractory status epilepticus (RSE), (2) to describe the treatment response of status epilepticus (SE), and (3) to determine predictors of long-term outcome in children with SE.

Methods: Medical records and EEG lab logs with ICD-9 diagnostic codes related to SE were reviewed. Patients younger than 18 years of age, hospitalized in 1994–2004 at the Mayo Clinic, Rochester, were included.

Results: One hundred fifty-four children had SE; 94 (61%) had ASE, and 60 (39.0%) had RSE. Family history of seizures, higher seizure frequency score, higher number of maintenance antiepileptic drugs (AEDs), nonconvulsive SE, and focal or electrographic seizures on initial EEG were associated with RSE by univariate analysis. In-hospital mortality was significantly higher in RSE (13.3%) than in ASE (2.1%). In the long term, survivors with RSE developed more new neurological deficits (p < 0.001) and more epilepsy (p < 0.004) than children with ASE. Children treated in a more aggressive fashion appeared to have better treatment responses (p < 0.001) and outcomes (p = 0.03). Predictors of poor outcome were long seizure duration (p < 0.001), acute symptomatic etiology (p = 0.04), nonconvulsive SE (NCSE) (p = 0.01), and age at admission <5 years (p = 0.05).

Discussion: Several patient and clinical characteristics are associated with development of RSE and poor outcome. Prospective, randomized trials that assess different treatment protocols in children with SE are needed to determine the optimal sequence and timing of medications.

Status epilepticus (SE) is the most common neurological emergency in childhood (Chin et al., 2006). The incidence ranges from 18 to 41 per 100,000 children per year. Ten to 25% of children with epilepsy will develop SE in their life time (Shorvon, 2001). However, SE occurs mostly in patients without a previously existing seizure disorder (Hesdorffer et al., 1998a, 1998b; Koul et al., 2002; Garzon et al., 2003). SE is either aborted with antiepileptic drugs (AEDs), i.e., aborted status epilepticus (ASE) or refractory to drugs, i.e., refractory status epilepticus (RSE). Although treatment advances have been made, SE remains associated with substantial mortality and morbidity (Chin et al., 2006).

The data regarding SE and RSE in children are derived predominantly from studies that combine adult and pediatric patients (DeLorenzo et al., 1996; Logroscino et al., 1997; Hesdorffer et al., 1998a; Lowenstein & Alldredge, 1998; Treiman et al., 1998; Logroscino et al., 2001; Mayer et al., 2002; Riviello & Holmes, 2004; Logroscino et al., 2005; Lowenstein, 2006; Rossetti et al., 2005). Relatively few studies are limited to children only (Maytal et al., 1989; Gilbert et al., 1999; Kim et al., 2001; Sahin et al., 2001; Koul et al., 2002; Kwong et al., 2004; Maegaki et al., 2005; Ozdemir et al., 2005; Chin et al., 2006). A wide range in mortality (3.6%–50%) is described in those pediatric studies. This could reflect the use of different study designs and definitions (Raspall-Chaure et al., 2006). Only two studies exclusively in children (Sahin et al., 2001; Koul et al., 2002) report the frequency of RSE in a cohort of children with SE; at 26% and 59%, respectively. These two studies did not further compare the children that were refractory to initial treatment to those who were not. Therefore, it is uncertain which demographic and clinical factors predispose to the development of RSE in children. Furthermore, it is uncertain how the outcome of children with ASE differs from that of children with RSE.

We reviewed a large cohort of children and sought to: (1) compare the demographics, clinical characteristics, etiologies, and EEG findings of ASE and RSE, (2) describe the treatment response of SE to commonly used AEDs, and (3) determine predictors of long-term outcome in a strictly pediatric cohort of children with SE.

Methods

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

Study population

The patients included in this retrospective study met the following inclusion criteria: hospitalized at Mayo Clinic Rochester between the years of 1994 and 2004, and less than 18 years of age. Ascertainment of the patients was done by searching the Mayo Clinic medical records linkage system for ICD-9 diagnostic codes of SE (345.3 and 345.2), epilepsy partialis continua (345.7), petit mal status (345.2), or grand mal status (345.3). The ICD-9 diagnostic codes were assigned by professional coders based upon review of the medical record. In addition, EEG laboratory logs were reviewed for diagnoses of SE during this period in the indicated age group. The study was approved by the Mayo Clinic Institutional Review Board.

Definitions

Status epilepticus

Although SE has been defined in the literature as more than 30 min of continuous seizure activity without complete recovery of consciousness, recently there has been a move to use a shorter duration to define SE (Lowenstein et al., 1999; Mayer et al., 2002). In this study, the diagnosis of SE was established when either of the following criteria was met: “(1) continuous tonic–clonic or electrographic seizure activity for at least 10 min or (2) intermittent tonic–clonic or electrographic seizure activity without recovery of consciousness for at least 30 min.” We equated these criteria because continuous SE has a worse prognosis than intermittent SE and because intermittent SE of more than 30 min carries a worse prognosis than seizure episodes lasting 10–29 min. The definition was adopted from a recent study (Mayer et al., 2002) in order to facilitate comparison of results. When the precise onset of SE was unknown it was judged to have occurred when it was diagnosed.

Treatment

A survey of neurologists indicated that there is no consensus about the optimal treatment of SE and RSE and what medications should be considered first-, second-, third-, or fourth-line therapy (Claassen et al., 2003). In this study benzodiazepines were considered first-line AEDs whereas phenytoin, Phenobarbital, and valproic acid were considered second-line AEDs. Third-line AEDs included midazolam, pentobarbital, thiopental, and propofol. If an additional AED was required, it was considered a fourth-line therapy.

Refractory status epilepticus

Again, there is no single definition of RSE. As recently described, the definitions used in the literature vary in the number of AEDs that need to be failed and the duration of time that the seizures need to persist (Lowenstein, 2006). This study used the following definition for RSE: clinical or electrographic seizures lasting longer than 60 min despite treatment with at least one first-line AED (i.e., benzodiazepine) and one second-line AED (i.e., phenytoin, phenobarbital, or valproic acid) (Sahin et al., 2001; Mayer et al., 2002).

Aborted status epilepticus

The designation aborted status epilepticus (ASE) was used to indicate those patients who had SE that was aborted/terminated with medication (first-, second-, third-, or fourth-line) within less than 60 min after administration of the first drug (regardless of the time that had elapsed between the onset of seizures and administration of the AED).

Etiology

The etiology was classified according to previous studies on SE conducted at our institution as following; (a) acute symptomatic, (b) remote symptomatic (c) progressive symptomatic, (d) idiopathic, and (e) febrile (Logroscino et al., 1997, 2001, 2002). It is recognized that other classifications for etiologies underlying SE have been proposed, e.g., JAMA consensus report (JAMA, 1993).

Status type

The initial seizure type of SE was categorized as generalized convulsive status epilepticus (GCSE), nonconvulsive status epilepticus (NCSE) or simple partial SE (Mayer et al., 2002). The GCSE category includes, primarily and secondarily generalized tonic–clonic seizures and myoclonic seizures whereas the NCSE category includes complex partial and absence seizures. The classification of seizure type was based on the clinical description in the medical record and EEG recordings. Seizures were categorized as GCSE if any of the following was described: generalized tonic–clonic seizures, grand mal seizures, convulsions, bilateral rhythmic jerking, or similar descriptions. Seizures were categorized as NCSE if the patient was stuporous or comatose, symptoms suggestive of partial seizures were present and none of the descriptions for GCSE was used. Ictal discharges that correlated with the clinical symptomatology were required. Subtle motor seizures (i.e., facial twitching, tonic eye deviation, and nystagmus) could be present in NCSE.

Outcome

The outcome was evaluated at discharge and at follow up using the following criteria: death, development of a new neurological deficit, and/or development of epilepsy or returned to base line (i.e., same neurological condition as prior to ASE or RSE). A “poor outcome” was defined as death, the occurrence of a new neurological deficit or the development of epilepsy.

Seizure frequency

Evaluation of seizure frequency was done using the latest description in the medical history before admission. Frequency was scored according to the seizure frequency scoring system of Engel (Engel et al., 1993), which has been previously used and validated (So et al., 1997). The scores range between 0 and 12. A score between 0 and 4 indicates a seizure-free state without the use of AEDs to nondisabling nocturnal seizures only. A score of 5 refers to 1–3 seizures per year and a score of 6 includes up to 11 seizures per year. Scores of 7, 8 or 9 refer to multiple seizures despite adequate treatment per month, week, or day, respectively. The highest score of 12 indicates SE without barbiturate coma.

Statistical analysis

Univariate analysis was used to determine factors associated with the development of RSE in children with SE. Means were used for variables with a normal distribution whereas medians were used for those with a skew distribution. To compare short-term outcome between children with ASE and children with RSE chi-square tests of difference of proportions were used. In analyses investigating factors associated with poor long-term outcome (i.e., development of new neurologic deficits, epilepsy or death) we used Cox proportional-hazards models.

All Cox models were adjusted for RSE status at baseline to determine the incremental independent usefulness of predictors beyond association with RSE status. Long and short seizure durations were defined separately within ASE and RSE children, as ASE and RSE are defined in part, by using seizure duration. Thus, the estimate for this analysis investigates whether; given RSE status, a respective long or short duration is incrementally useful. The median seizure duration was used as the cut-point, separately within the two seizure types. For all statistics a p < 0.05 was considered to be significant.

Results

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

One hundred seventy-eight patients with possible ASE or RSE were identified. Twenty-four children were excluded because they did not meet inclusion criteria; six were not hospitalized at the Mayo Clinic, Rochester, during their episode and 18 had incomplete data which made it impossible to determine if the patient met the definitions of SE and of ASE or RSE (data were missing regarding treatment and/or duration of seizures). After the exclusion of those 24 children, 154 patients with SE remained. Seventy patients (48.3%) were residents of Olmsted County. Of the 154 patients, there were 94 children (61%) with ASE (i.e., SE was aborted with AEDs within 60 min after the administration of the initial first-line drug). The other 60 children (39.0%) had RSE (i.e., seizures continued for 60 min or more after the administration of at least one first- and one second-line AED).

Demographic and clinical characteristics of ASE compared to RSE

The demographic and clinical characteristics of the study population are shown in Table 1. Gender and age at the admission did not differ significantly between ASE and RSE groups. There was no significant difference in occurrence of ASE and RSE between residents of Olmsted County, and other patients. The median seizure duration was 30 min for ASE and 210 min for RSE. The precise onset of seizures was unknown in 17 children, without a significant difference in children with ASE and children with RSE. Significantly more black than Caucasian children did not have their SE controlled with initial therapy and progressed to RSE. In total, 76 children (49.4%) with SE had a previous diagnosis of epilepsy; whereas 50.6% of episodes were new onset seizures. The children with a previous diagnosis of epilepsy in the RSE group had a significantly higher seizure frequency score and used a higher number of AEDs prior to their episodes of SE when compared to children in the ASE group. In addition, a positive family history of seizures was associated with RSE. Finally, there were significantly more children with RSE and initial NCSE (45%) than children with ASE and initial NCSE (16%).

Table 1.  Demographic and clinical characteristics of aborted status epilepticus compared to refractory status epilepticus
 Total N (% or range)ASE N (% or range)RSE N (% or range)p
  1. ASE, aborted status epilepticus; RSE, refractory status epilepticus; AEDs, antiepileptic drugs; GCSE, generalized convulsive status epilepticus; NCSE, nonconvulsive status epilepticus.

Gender 
 Female83 (53.9)55 (58.5)28 (46.7)0.150
 Male71 (46.1)39 (41.5)32 (53.3)0.150
Age at admission years (mean)   6.65 (birth-17.8)6.63 (birth-17.7)6.66 (birth-17.9)0.976
Olmsted County resident70 (48.3)42 (44.6)28 (46.6)0.174
Race
 Caucasian140 (90.9) 90 (95.7)50 (83.3)0.009
 Black10 (6.5) 2 (2.1) 8 (13.3)0.006
 Other4 (2.6)2 (2.1)2 (3.3)0.646
History of epilepsy76 (49.4)45 (47.8)31 (51.7)0.893
Age epilepsy onset (mean)  2.21 (birth-16)  2.11 (birth-11)  2.38 (birth-16)0.682
Duration (years) of epilepsy at 5.64 (0–17.9)6.05 (0–17.7)4.87 (0–17.9)0.288
 RSE episode (mean) 
Seizure frequency score (mean)7.20 (0–11) 6.34 (0–10) 8.53 (4–11) <0.001  
Number previously used AEDs (mean)3.91 (2–8)  3.13 (2–6) 5.05 (3–8)  0.001
Family history of seizures16 (10.4)3 (3.2)13 (21.7)<0.001  
History of febrile seizures19 (12.3)14 (14.9)5 (8.3)0.227
Status classification at onset 
 GCSE106 (68.8) 74 (78.7)32 (53.3)0.001
 NCSE42 (27.3)15 (16.0)27 (45.0)<0.001  
 Simple Partial6 (3.9)5 (5.3)1 (1.7)0.253
Seizure duration min (median)   126 (10–6480)  30 (10–55)210 (60–6480)0.001
Unknown onset17 (11.0)10 (10.6)7 (11.7)0.642

Etiology

The etiologies of ASE and RSE are shown in Table 2. An acute symptomatic etiology was significantly more prevalent in children with RSE. The highest frequency of SE episodes was in children younger than one year of age (16.8%). The group of children younger than one year of age included five neonates (3.2%), four children (2.6%) between 1 and 3 months of age and 17 children (11.0%) between 3 months and 1 year of age. A febrile etiology predominated in children younger than 2 years of age in both the ASE and RSE groups (p = 0.002). In children older than 2 years of age there was a significantly higher frequency of unprovoked (remote symptomatic, progressive symptomatic, or idiopathic) etiologies (p = 0.01). For the total sample, the most common specific etiologies within the acute symptomatic etiology group were acute metabolic derangements in 13 children (32.5%) and encephalitis in 10 children (25%). Other relatively common causes in the acute symptomatic group included brain trauma (12.5%), stroke (12.5%), and hypoxic ischemic encephalopathy (10%). Drug noncompliance accounted for 9% of acute symptomatic etiologies. The remote symptomatic etiology group included 21 children (44.2%) with static encephalopathy and/or cerebral palsy and/or severe developmental delay. Nine children (12.8%) had a congenital malformation, six (10.9%) had a history of intracranial hemorrhage or stroke, and three (5.5%) had a history of brain trauma. The remaining 16 children in the remote symptomatic group had histories of several different of neurological pathologies, e.g., cranial synostosis, hydrocephalus, Crouzon's syndrome, hemimegacephaly, and Cockayne syndrome. The progressive symptomatic etiology group included four children (30.7%) with a brain tumor and three children (23.1%) with neuronal ceroid-lipofuscinoses. Other progressive symptomatic causes included Vanishing White Matter disease, Sturge Weber syndrome, Rett's syndrome, and Sandhoff disease. The idiopathic group included 11 children (36.7%) with new onset seizures, i.e., they presented with SE as a first manifestation of idiopathic epilepsy. The other 19 children in the idiopathic group had a diagnosis of idiopathic epilepsy. Their SE developed in the course of this and no other precipitant was found (children with epilepsy and an acute symptomatic precipitant such as drug noncompliance or underlying neurological pathology were placed in the acute symptomatic or remote symptomatic group, respectively).

Table 2.  Etiology of children with aborted status epilepticus compared to children with refractory status epilepticus
 Total N (%)ASE N (%)RSE N (%)p-value
  1. ASE, aborted status epilepticus; RSE, refractory status epilepticus.

Acute symptomatic40 (26.0) 18 (19.1%) 22 (36.6%)0.023
Remote Symptomatic55 (35.7)32 (34.0) 23 (38.3%)0.654
Progressive symptomatic13 (8.4) 8 (5.2)5 (8.3) 0.843
Idiopathic30 (19.5)19 (20.2)11 (18.3) 0.172
Febrile16 (10.4)12 (12.8)6 (10.0)0.357

EEG findings

An EEG was performed in 85.1% of children with ASE and in all children with RSE. Of the children with ASE 58 (61.7%) had continuous EEG monitoring, the remainder of children with ASE were recorded with serial EEGs. All of the patients with RSE had continuous EEG monitoring. Complete cessation of clinical and electrographic seizures was used as an end point in all children. Findings on initial EEG (first routine or first 30 min of continuous EEG) are shown in Table 3. Focal discharges were significantly more common in children with RSE. Furthermore, electrographic seizures without clinical manifestations were significantly more common in children with RSE. Nineteen of the 42 children with NCSE had new onset seizures, i.e., they did not have a history of epilepsy. As Table 3 displays only the initial EEG findings, it does not show the evolution of GCSE into NCSE, i.e., presence of electrographic seizures after treatment of GCSE. This occurred in 11 children (18.3%) with RSE and in four children with ASE (4.2%) (p = 0.003).

Table 3.  Initial EEG findings in children with status epilepticus
VariableTotal SE N (%)ASE N (%)RSE N (%)p
  1. aElecectrographical seizures without clinical correlate.

  2. EEG, Electro-encephalogram; SE, status epilepticus; ASE, aborted status epilepticus; RSE, refractory status epilepticus.

EEG performed140 (90.9) 80 (58.1)60 (100) 
Focal discharges39 (25.3)16 (17.0)23 (38.3)0.003
Generalized discharges81 (52.5)52 (55.3)29 (48.3)0.478
Focal Slowing7 (4.5)5 (5.3)2 (3.3)0.706
Diffuse slowing83 (53.8)56 (59.5)27 (45)  0.077
Interictal spikes and sharp waves35 (22.7)17 (18.1)18 (30)  0.085
Electrographic seizuresa32 (20.7)13 (13.8)19 (31.7)0.027

Treatment response of SE

Of the total 154 SE episodes, 46 (29.9%) responded to treatment with a first-line AED (diazepam; 0.3–0.4 mg/kg or lorazepam; 0.05–0.1 mg/kg) (Fig. 1). In 37 of 109 children (24%) that continued having seizures after initial medication, a second-line AED (phenytoin; 18–20 mg/kg, phenobarbital; 10–20 mg/kg, or valproate acid; 15–20 mg/kg) was successfully used.

image

Figure 1. Treatment response of status epilepticus. SE, status epilepticus; AED, antitepileptic drug; RSE, refractory status epilepticus.

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Seventy-one children (46.1%) continued having seizures despite the first- and second-line AED treatments. In 11 (7.1%) of those 71 children, an additional second-line AED was administered “early” (prior to 60 min after seizures did not stop with first- and initial second-line AED treatments). The mean interval between the initial- and additional second-line AED was 18 min. These children were considered in the ASE group as seizures were terminated at less than 60 min after giving the first AED. In the other 60 children that continued having seizures despite the first- and second-line AED treatments (39%), additional medication was given later than 60 min after the administration of the initial first-line AED. The mean interval between the initial- and additional second-line AED was 36 min. These children were considered the RSE group.

Treatment response of RSE

Only thirteen children (21.6%) who did not receive an additional second-line AED prior to 60 min of the first AED, stopped having seizures after treatment with an additional second-line AED (compared to 100% response to additional second-line AEDs in the group that was treated earlier in the clinical course). Third-line medication was able to stop seizures in 43 children (91.5%) who continued to have seizures (Fig. 2).

image

Figure 2. Treatment response of refractory status epilepticus. RSE, refractory status epilepticus; AEDs, antiepileptic drugs.

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Twenty-eight (82.3%) of the children treated with third-line therapy received midazolam alone. All of these patients received a bolus of midazolam (0.15 mg/kg iv.) followed by continuous infusion of midazolam at 1 mcg/kg/min increased by 1 mcg/kg/min increments. Seizures were controlled with midazolam with a mean infusion rate of 4.6 mcg/kg/min (range 1–30 mcg/kg/min). The mean time of infusion of midazolam until complete cessation of electrographic seizures was 1.39 h (range: 15 min to 5 h). Pentobarbital (2–5 mg/kg iv. load, 1–2 mg/kg/h continuously) was given as a third-line agent to three children (8.8%), propofol (1–2 mg/kg iv. load, 1–2 mg/kg/h continuously) to two children (5.8%), and thiopental (7 mg/kg iv.) to one child (2.9%).

Four children were treated with a fourth-line AED. They received midazolam in combination with pentobarbital or thiopental as a fourth-line agent (two children—midazolam + pentobarbital and two children—midazolam + thiopental). All 10 children (100%) treated with pentobarbital, thiopental, or propofol required intubation and ventilation. In contrast, most of the children treated with midazolam alone did not have significant complications such as respiratory depression or hypotension and only eight children (28.6%) required intubation.

Outcome at discharge

Outcome at discharge was worse in the RSE group compared to the ASE group. Significantly less children in the RSE than in the ASE group returned to their baseline neurological status (66.6% vs. 82.9%; p = 0.05) Furthermore, a total of 10 children (6.5%) died during hospitalization; eight (13.3%) in the RSE group compared to two (2.1%) in the ASE group (p = 0.006). Death was associated with an acute symptomatic etiology in three children (one encephalitis, one toxic shock; one neonate; hypoxic ischemic encephalopathy), with a remote symptomatic etiology (previous birth trauma) in two children, and with a progressive underlying disease in three children (one medulloblastoma, one Cockayne syndrome, and one Vanishing White Matter). The remaining two deaths were due to complications of the SE episode (aspiration of gastric contents and bradycardia).

Long-term outcome

Of the 144 initial survivors of ASE and RSE there were 17 children for whom there was no follow-up information after discharge. The long-term outcome, i.e., outcome at last follow-up compared to status at discharge, of the remaining 127 children was evaluated with a mean duration of follow-up of 3.89 years (range: 0.8–12.2 years). Children with RSE had an increased risk to develop new neurological deficits and/or epilepsy compared to children with ASE (Table 4).

Table 4.  Long-term outcome of aborted status epilepticus compared to refractory status epilepticus
Short-term outcome EventASE N = 94RSE N = 60Hazard of event for RSE vs. ASE
N(%)N(%)HR(95% CI)p
  1. ASE, aborted status epilepticus; RSE, refractory status epilepticus.

Development of a new deficit1516 1220 1.48(0.79–3.97)0.77
Death 2 2.1 813.32.51(1.35–4.49) 0.006
Returned baseline7781.94066.61.73(1.55–2.97)0.01
 
Long-term outcome EventN = 78N = 49RSE vs. ASE
N(%)N(%)HR(95% CI)p
 
Development of a new deficit4355.13571.42.49(1.57–3.97)  0.0001
Development of epilepsy1620.51530.62.91(1.40–6.07) 0.004
Death 5 6.4 3 6.11.51(0.35–6.48)0.58
Stayed at baseline3038.51122.41.13(0.55–2.30)0.74

Death during follow-up was related to complications of subsequent SE episodes in five of eight children (asphyxia due to aspiration of gastric contents in two children, aspiration pneumonia in two children, and bradycardia in one child) and to encephalitis in one child. In two children the cause of death was an underlying disease (astrocytoma in one child and Batten disease in the other).

Few children that returned to their baseline neurological status at discharge remained free of new deficits during follow-up, i.e., stayed at their baseline during follow-up; 38.5% in the ASE group and 22.4% in the RSE group.

Predictors of poor outcome

Table 5 shows several demographic and clinical characteristics of children with SE and the hazard ratios of a having a poor outcome (death + new neurological deficit and/or development of epilepsy) associated with those characteristics. As children with RSE had a poorer outcome than children with ASE (described above in “long-term outcome”), we adjusted for RSE status in this model. First, older age at admission (> 5 years) was associated with a better outcome compared to a younger age at admission. Second, “long” seizure duration (seizure duration above the median of 33.5 min for ASE and above the median of 120 min for RSE) predicted a poor outcome. Furthermore, children with an acute symptomatic etiology had a significantly increased risk of having a poor outcome. Finally children with NCSE had significantly poorer outcomes compared to children with GCSE.

Table 5.  Potential predictors of poor long-term outcome
CovariateTotal NPoor outcome
N Event(%)HR (95% CI)ap
  1. aAll hazard ratios (HR) are adjusted for RSE status.

  2. bDefined differently in ASE and RSE groups. “Long” seizure duration for ASE is seizure duration above the median seizure duration of ASE, i.e., 30 min. “Long” seizure duration of RSE is seizure duration above the median seizure duration of RSE, i.e., 210 min.

  3. cFebrile seizures excluded because of too small N for analysis.

  4. dIncludes remote symptomatic, progressive symptomatic, and idiopathic seizures.

  5. eSimple partial seizures excluded because of too small N for analysis.

  6. GCSE, generalized convulsive status epilepticus; NCSE, nonconvulsive status epilepticus.

Sex
 Women654163.11.00 (ref)
 Men624572.61.15 (1.48–3.63)0.53
Age at admission
 <5 years625182.31.00 (ref)
 ≥5 years654670.80.65 (0.42–0.89)0.05
Duration of Seizureb
 Short603050.01.00 (ref)
 Long675683.62.68 (1.64–4.38)<0.001 
Etiology groupc
 Unprovokedd925863.01.00 (ref)
 Acute symptomatic252288.01.38 (1.12–1.97)0.04
Seizure typee
 GCSE644265.61.00 (ref)
 NCSE584170.71.83 (1.15–2.94)0.01

Because the retrospective nature of this study did not enable us to reliably determine the “pretreatment” duration of SE, we were not able to analyze the relationship between this time interval and treatment outcome. However, accurate data regarding the time intervals between the administration of the first-, second- additional second-, third-, and fourth-line AEDs were available from the medical records. This allowed comparison of children in whom an additional AED was administered after the first- and second-line medications within 60 min of the initial treatment with those that did not receive additional treatment within 60 min. All of the 11 children in the first group who received additional medication sooner (Fig. 1, thick lined compartment) responded to second-line medication, compared to 21.6% of patients in whom the additional medication was given after 60 min (Fig. 2, thick-lined compartment). Nine of the 11 children that were treated aggressively with additional second-line AEDs had returned to their baseline at discharge and eight of them stayed at their baseline during follow-up. On the contrary, all of the 13 children in the delayed additional treatment group had developed new neurologic deficits at discharge and continued to deteriorate during follow-up or developed epilepsy (p = 0.003). There was no significant difference in other variables that, as described above, predict outcome, i.e., age at admission, etiology, and initial NCSE.

Discussion

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

This study describes the experience of 154 pediatric patients with SE at a single institution with ascertainment optimized by use of relevant ICD-9 codes and EEG lab logs of cases during the specified time period. The frequency of SE that was not aborted with first- and second-line medication within 60 min after administration of the first drug (i.e., RSE) was 39%. This is within the range reported in the literature (11.7–55.9%) in both pediatric and adult populations (Maytal et al., 1989; Koul et al., 2002; Mayer et al., 2002; Garzon et al., 2003; Rossetti et al., 2005; Holtkamp et al., 2005).

Although multiple studies on SE exist, the present study has several important advantages. First, this study addresses children exclusively, which eliminates the possibility that results from mixed pediatric and adult patients may miss risk factors specific to the pediatric population. Second, these findings supplement a recent prospective study on SE in children (Chin et al., 2006) in that we analyzed short- and long-term outcome. In addition, the outcome of ASE was analyzed separately from RSE, which is important for future studies because the results demonstrate that RSE is associated with a significantly poorer outcome. Thus investigating outcome of SE in general will result in overestimating mortality and morbidity for ASE. Finally, investigating ASE separately from RSE made it possible to compare the clinical and demographic characteristics that distinguish ASE and RSE. This enabled identification of potential risk factors that are associated with the development of RSE. A recent review concludes that the best hope for dealing with RSE is to prevent development (Lowenstein, 2006). Therefore the identification of those factors is an important step in helping clinicians to anticipate on RSE. Anticipation makes early administration of additional drugs possible and might contribute to better outcomes.

Limitations of this study include its retrospective nature and the use of data obtained from an administrative database. The latter depends on the ability of professional coders to determine the diagnosis based upon chart review that is dependent upon physician documentation. Furthermore, the current study used seizure activity for at least 10 min as one of the two possible criteria for inclusion. As the concept of SE with shorter duration than 30 min has not been utilized until relatively recently, it is highly likely that some cases were not coded as SE and not included. Finally, the reality that not 100% of children had an EEG contributes to the possibilities of missed cases. Therefore, this report is a conservative estimate of the frequency of SE in the pediatric population.

Risk factors for RSE

First, a positive family history of seizures predisposed to RSE. This is in line with previous evidence that genetic factors contribute to the development of SE. A twin study revealed that three of 13 monozygotic twins were concordant for the development of SE compared to none of the 26 dizygotic twins (Corey et al., 1998). Another study found that recurrence of seizures among relatives of epileptic probands without NCSE was significantly higher than among the general population (Brinciotti et al., 1991). Furthermore, the same study found an increased incidence of convulsions among the relatives of probands with NCSE compared to the general population.

The second set of risk factors for development of RSE that provided measures of epilepsy severity was a high seizure frequency score and the number of maintenance AEDs in children with a previous diagnosis of epilepsy. It is not surprising that RSE is more likely to develop in this population with already intractable seizures. There is evidence that changes in GABAA receptor after prolonged seizures and down regulation of GABAA receptor subunits play a role in development of intractable seizures (Wu et al., 2006)

Third, there was a higher frequency of black than Caucasian patients that developed RSE. This is in line with a previous study (Logroscino et al., 2005) and could reflect socioeconomic differences or genetic predisposing factors. However, if the five neonates in this study, who were all black and had RSE, were excluded, there was no significant difference in race between the remaining children with ASE and RSE.

Fourth, RSE was associated with a significantly higher proportion of children with initial NCSE, which is similar to the observation in adults (Mayer et al., 2002; Holtkamp et al., 2005). A possible explanation is that in contrast to seizures that rapidly generalize and spontaneously abate, seizures that do not readily generalize and involve motor cortex may be associated with more severe underlying brain pathology and hence may be more refractory to therapy (Mayer et al., 2002). The frequency of children with RSE and initial NCSE in this study (45%) was consistent with a previous study in the pediatric population of RSE (43.5%) (Kim et al., 2001). However, it is much higher than the 27% reported in a previous study in adults (Mayer et al., 2002). As further analysis demonstrated that NCSE was associated with a remote symptomatic etiology, the discrepancy in frequency of NCSE is likely a result of the etiology difference in adults and children. Although these associations are statistically significant, univariate analysis was utilized, thereby raising the possibility of decreased strength of association by other statistical methods.

Etiology

For the total sample we found a remote symptomatic etiology to be the most frequent, whereas studies in adults have reported an acute symptomatic etiology, e.g., AED noncompliance to be most common (Lowenstein & Alldredge, 1993). Stratifying etiology by age revealed that remote symptomatic SE is significantly more common in children older than 2 years while febrile SE is most common in children younger than 2 years. This can be explained by the fact that young children more often develop high fever and by the heightened susceptibility for febrile seizures due to developmental changes that skew the balance between excitatory and inhibitory neurotransmitter systems in the brain in favor of a state of excitation (Shinnar et al., 2001; Brooks-Kayal, 2005). As in adults, the prevalence of an acute symptomatic etiology was significantly higher in children with RSE (Mayer et al., 2002; Rossetti et al., 2005).

EEG findings

In 32 of 42 children that were comatose and turned out to have NCSE, only electrographic seizures were present. Subtle clinical signs of seizures such as twitching movements of the face, fingers, hands, or eyes, were seen only in 10 children. A recent practice parameter on the diagnostic assessment of the child with SE, noted the lack of sufficient data on the prevalence of NCSE in children who presented with SE, and no previous history of epilepsy (Riviello et al., 2006). It was therefore unable to support or refute whether an EEG should be obtained to establish the diagnosis of NCSE. The current study provides additional data on NCSE in children; i.e., 19 of the 42 children with NCSE had new onset SE. As only 10 children had clinical signs of NCSE other than being comatose, and these symptoms were very subtle, we agree with recommendations of others that EEG monitoring is important in the diagnosis of NCSE (Treiman et al., 1990; Murthy & Naryanan, 2004).

The practice parameter pointed out topics for future research, one of which was the question regarding the frequency of NCSE after control of GCSE. We found that 4.2% of children with ASE and 18.3% of children with RSE evolved from GCSE into NCSE. A recent study reports in line with our data: 5 of 11 patients developed NCSE after GCSE (Tay et al., 2006). The current data provide additional evidence of the importance of continuous EEG monitoring of children with SE, namely to detect possible evolution into NCSE, which should be treated accordingly (Treiman et al., 1990; Murthy & Naryanan, 2004).

Treatment

Guidelines based upon expert opinion for the treatment of pediatric epilepsy have recommended lorazepam or diazepam as initial therapy for all types of pediatric SE (Wheless et al., 2005). For generalized tonic–clonic SE, rectal diazepam and fosphenytoin were also first line; for complex partial SE, fosphenytoin was also first line; and for absence SE, intravenous valproate was also first line. We agree with recommendations for treatment with a benzodiazepine early in the clinical course, followed soon thereafter by a second-line AED. The finding in this study that the response to additional second-line AEDs was 100% in patients that were treated within 60 min and only 21.6% in patients that were treated later raises the question about the timing of additional AEDs when the initial mediations fail to control SE. However, the retrospective nature of this study and lack of a randomized treatment regimen preclude any conclusions regarding this issue. Rather the need for prospective trial is indicated. When therapy with first- and second-line agents fails, our experience indicates that midazolam would be a reasonable choice for the treatment of SE in children as response is good and the need for intubation is low. This is in line with conclusions of others that found good response to treatment with midazolam and few complications (Rivera et al., 1993; Hamano et al., 2005; Nobutoki et al., 2005).

Outcome

In this study, in-hospital mortality for the total group of children with SE was 6.5%. This is in line with the 3.2%–6.8% mortality reported by others that studied the pediatric population (Maytal et al., 1989; Kwong et al., 2004; Maegaki et al., 2005; Chin et al., 2006). For adults with SE the literature reports a higher mortality, ranging from 19% to 43% (Logroscino et al., 1997, 2002; Garzon et al., 2003). The discrepancy likely reflects the higher frequency of febrile seizures in children, which tend to be associated with less-severe underlying brain pathology (DeLorenzo et al., 1996). Some authors (Lowenstein & Alldredge, 1998; Mayer et al., 2002) have reported a mortality of 19%–50% in children, which is more similar to the mortality reported in adults. A recent review (Raspall-Chaure et al., 2006) describes that the relatively large differences in reported mortality can, at least in part, be explained by the use of different definitions of SE (e.g., failure to respond to two or three AEDs and minimum duration of seizures 1 h or 2 h), different inclusion criteria (e.g., SE in general, ASE or RSE, and in- or exclusion of febrile seizures), differences in study population (e.g., mean age), differences in the time at which outcome was evaluated (e.g., at discharge or at follow-up), and differences in treatment utilized. In addition, an explanation for the higher mortality reported by some authors that studied children with SE (Kim et al., 2001; Sahin et al., 2001; Ozdemir et al., 2005) is that more children with acute symptomatic etiologies were included, which are associated with a poorer outcome.

There was a significant difference between the in-hospital mortality of children with ASE (2.1%) and children with RSE (13.3%). In addition, RSE was associated with a significant higher risk (2.45-fold increased) for developing new neurological deficits on the long term as compared to ASE. Because of the significant difference in mortality and morbidity, it is important to distinguish ASE from RSE when outcome is investigated in future studies.

Predictors of outcome

This study underlines the importance of demographic and clinical determinants of outcome, i.e., age at admission, seizure duration, etiology, and seizure type. Because it was found that age at admission varies with etiology, and etiology is associated with seizure duration, which is associated with seizure type (i.e., NCSE), it remains difficult to determine which is the primary determinant of outcome. Indeed, a great amount of contradictory data exist about which risk factors play the most prominent role in outcome (Logroscino et al., 1997; Sahin et al., 2001; Koul et al., 2002; Logroscino et al., 2002; Mayer et al., 2002; Kwong et al., 2004; Logroscino et al., 2005; Maegaki et al., 2005; Rossetti Maegaki et al., 2005; Holtkamp et al., 2005). A recent study concluded that severity of status and duration are more reflective of underlying insult and not necessarily due to delay in treatment (Chin et al., 2004). Our findings support the concept that etiology is an important determinant of outcome. In addition, there is the suggestion that a more aggressive treatment regimen may influence outcome. A randomized treatment trial in children, which analyzes the time before administration of the first AED and different treatment timing paradigms, is required to clarify this issue.

Conclusions

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

In summary, this study confirms that SE frequently becomes refractory in children. Several characteristics, i.e., family history of seizures, higher seizure frequency, number of maintenance AEDs, NCSE, and focal or electrographic seizures on initial EEG are associated with the occurrence of RSE. If these risk factors are confirmed by prospective studies, it is possible to identify those children in whom additional treatment beyond an initial benzodiazepine and second-line therapy may be needed to stop seizures. The goal is to decrease the short-term and long-term morbidity and mortality associated with SE in children. Outcome is predicted by several characteristics including etiology. In addition the early administration of medication, in particular in those children at risk for RSE, might contribute to better outcomes. Prospective, randomized trials that assess different treatment protocols in children with SE are needed to determine the optimal sequence and timing of medications.

Acknowledgments

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References

The authors would like to thank and acknowledge the expert statistical analysis provided by Brandon Grossardt.

Disclosure statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with these guidelines. The authors state to have no conflict of interest.

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  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. Conclusions
  6. Acknowledgments
  7. References
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