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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.
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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|
| Female||83 (53.9)||55 (58.5)||28 (46.7)||0.150|
| Male||71 (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 resident||70 (48.3)||42 (44.6)||28 (46.6)||0.174|
| Caucasian||140 (90.9) ||90 (95.7)||50 (83.3)||0.009|
| Black||10 (6.5) ||2 (2.1)|| 8 (13.3)||0.006|
| Other||4 (2.6)||2 (2.1)||2 (3.3)||0.646|
|History of epilepsy||76 (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 seizures||16 (10.4)||3 (3.2)||13 (21.7)||<0.001 |
|History of febrile seizures||19 (12.3)||14 (14.9)||5 (8.3)||0.227|
|Status classification at onset|| |
| GCSE||106 (68.8) ||74 (78.7)||32 (53.3)||0.001|
| NCSE||42 (27.3)||15 (16.0)||27 (45.0)||<0.001 |
| Simple Partial||6 (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 onset||17 (11.0)|| 10 (10.6)||7 (11.7)||0.642|
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|
|Acute symptomatic||40 (26.0)|| 18 (19.1%)|| 22 (36.6%)||0.023|
|Remote Symptomatic||55 (35.7)||32 (34.0)|| 23 (38.3%)||0.654|
|Progressive symptomatic||13 (8.4) ||8 (5.2)||5 (8.3) ||0.843|
|Idiopathic||30 (19.5)||19 (20.2)||11 (18.3) ||0.172|
|Febrile||16 (10.4)||12 (12.8)||6 (10.0)||0.357|
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
|Variable||Total SE N (%)||ASE N (%)||RSE N (%)||p|
|EEG performed||140 (90.9) ||80 (58.1)||60 (100)|| |
|Focal discharges||39 (25.3)||16 (17.0)||23 (38.3)||0.003|
|Generalized discharges||81 (52.5)||52 (55.3)||29 (48.3)||0.478|
|Focal Slowing||7 (4.5)||5 (5.3)||2 (3.3)||0.706|
|Diffuse slowing||83 (53.8)||56 (59.5)||27 (45) ||0.077|
|Interictal spikes and sharp waves||35 (22.7)||17 (18.1)||18 (30) ||0.085|
|Electrographic seizuresa||32 (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.
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).
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).
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 Event||ASE N = 94||RSE N = 60||Hazard of event for RSE vs. ASE|
|Development of a new deficit||15||16 ||12||20 ||1.48||(0.79–3.97)||0.77|
|Death|| 2|| 2.1|| 8||13.3||2.51||(1.35–4.49)|| 0.006|
|Long-term outcome Event||N = 78||N = 49||RSE vs. ASE|
|Development of a new deficit||43||55.1||35||71.4||2.49||(1.57–3.97)|| 0.0001|
|Development of epilepsy||16||20.5||15||30.6||2.91||(1.40–6.07)|| 0.004|
|Death|| 5|| 6.4|| 3|| 6.1||1.51||(0.35–6.48)||0.58|
|Stayed at baseline||30||38.5||11||22.4||1.13||(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
|Covariate||Total N||Poor outcome|
|N Event||(%)||HR (95% CI)a||p|
| Women||65||41||63.1||1.00 (ref)||—|
| Men||62||45||72.6||1.15 (1.48–3.63)||0.53|
|Age at admission|
| <5 years||62||51||82.3||1.00 (ref)||—|
| ≥5 years||65||46||70.8||0.65 (0.42–0.89)||0.05|
|Duration of Seizureb|
| Short||60||30||50.0||1.00 (ref)||—|
| Long||67||56||83.6||2.68 (1.64–4.38)||<0.001 |
| Unprovokedd||92||58||63.0||1.00 (ref)||—|
| Acute symptomatic||25||22||88.0||1.38 (1.12–1.97)||0.04|
| GCSE||64||42||65.6||1.00 (ref)||—|
| NCSE||58||41||70.7||1.83 (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.
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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.
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).
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).
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).
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.
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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.