Convulsive status epilepticus (CSE), the most common pediatric neurologic emergency (DeLorenzo et al., 1995), is associated with significant mortality and morbidity (Raspall-Chaure et al., 2006). The incidence of CSE is highest within the first 3 years of life (Chin et al., 2006), a period during which critical developmental events occur (Committee on Integrating the Science of Child Development, 2000). Early neurologic insults are associated with worse longer term outcomes in retrospective studies (Riney et al., 2006; Cormack et al., 2007; Scott, 2010), and animal studies have shown that enriching an animal's environment can modulate the degree of functional impairments following CSE in the longer term (Rutten et al., 2002). Therefore, it is imperative to assess the effects of CSE in children soon after CSE to determine their developmental status and examine whether intervention is warranted.
Most studies investigating the consequences of CSE to date: (1) have focused on simple febrile seizures and have included a subsample of children with prolonged febrile seizures (PFS), a type of CSE, within their study sample (Schiottz-Christensen & Bruhn, 1973; Nelson & Ellenberg, 1978; Hesdorffer et al., 2011), (2) have been conducted several years following CSE (Nelson & Ellenberg, 1978; Verity et al., 1985, 1993; Kölfen et al., 1998), and (3) have been performed without the use of standardized neuropsychological instruments (Aicardi & Chevrie, 1970; van Esch et al., 1996). The aims of the current study were the following: (1) to investigate cognitive, language, and motor functions in children within 6 weeks of CSE and a year later to determine their developmental trajectories; and (2) to identify risk factors for poor outcomes at baseline (within 6 weeks) and follow-up (1 year later). PFS, which occur in children with normal development, were investigated separately from those with nonfebrile CSE, who often have previous neurologic abnormalities.
- Top of page
- Supporting Information
This is the first study to report on the longitudinal neuropsychological outcomes of infants within 6 weeks of CSE and 1 year later. Our results show that following CSE, infants manifest a wide range of neurodevelopmental impairments that are present at both time points. It is important to note that these impairments are not only confined to the nonfebrile CSE cases, who are already associated with neurologic abnormalities at baseline, but are extended to the PFS cases, who perform worse than controls on the assessed measures. No significant differences were revealed between baseline and follow-up performance, thereby demonstrating that within the first year post CSE, developmental outcomes remain unchanged.
Our most unexpected finding was that children with PFS were shown to lag developmentally behind controls. Moreover, although, the PFS group was still found to perform within the clinically normal range, their scores were similar to those obtained by infants born very prematurely (<28 weeks of gestation) and/or infants of an extremely low birth weight (<1,000 g; Anderson et al., 2010). These findings were paralleled by our observations in two sets of twins, where the affected twins had lower developmental scores than their siblings. In a separate study, we recently reported that children following PFS manifest recognition memory impairments within the first year following their seizure (Martinos et al., 2012).
A caveat to the above finding was that we present data only on children with PFS younger than 42 months as we wanted to use the same neuropsychological instrument for all participants. By definition, PFS occur from the age of 6 months to the age of 72 months. Nevertheless, most PFS occur before the age of 42 months (Chin et al., 2006) and, in the present study, the mean age of PFS was found to be 18.4 months, which is skewed to the lower end of that age range. The FEBSTAT study, which describes 199 cases following PFS, stated the mean age at PFS to be 16 months, with an interquartile range of 12–24 months (Hesdorffer et al., 2012) Therefore, the above reports suggest that the current findings represent most of the PFS population and are not excluding a sizeable chunk. Moreover, in our recognition memory paper where the same experimental task could be used for the entire age range, our results were not dependent upon the age of the child (Martinos et al., 2012).
Results in the literature are mixed with respect to the long-term outcome of children following PFS, with some studies reporting normal development (Nelson & Ellenberg, 1978; Verity et al., 1993, 1998; Chang et al., 2000) and other studies reporting impairments (Schiottz-Christensen & Bruhn, 1973; van Esch et al., 1996; Kölfen et al., 1998). However, such discrepancies may be due to differences in methodology and definition of normality across studies. For example, one study of monozygotic twins discrepant only for a history of febrile seizures found that the affected twin had a lower IQ than the unaffected twin (Schiottz-Christensen & Bruhn, 1973). Nevertheless, their IQ was still within the normal range. Moreover, studies have often used different durational cutoffs to each other, with some studies splitting their sample population into children that have seizures lasting less than and more than 15 min (e.g., Verity et al., 1998; Chang et al., 2000) and other studies using the 30-min durational cutoff adopted in the current study (e.g., Verity et al., 1993; van Esch et al., 1996). Given indications that seizures of the prolonged kind (>30 min) are the ones that carry an association with mesial temporal sclerosis (Meldrum & Brierley, 1973; Baram & Shinnar, 2001), the present study was designed specifically to only investigate those type of seizures. It is notable, however, that recent evidence has revealed that expressive language deficits are present in a subset of children following short febrile seizures (<5 min): children with recurrent febrile seizures (Visser et al., 2012).
There are at least three possible explanations for the reduced performance in the PFS group. The first is that PFS led to a brain injury that causes a cognitive lag. There is extensive evidence from animal models that CSE can cause injury, predominantly to the hippocampus, but also in other brain regions (Sankar et al., 1998; Ravizza et al., 2005; Choy et al., 2010). Moreover, long-term cognitive impairments has been identified in an animal model of PFS, where animals with previously normal brains were made to seize under high temperature conditions (Dubé et al., 2006, 2009). The second is that the factors that predispose an individual to develop PFS may also be responsible for the reduced performance we observed in the present study. Hippocampal abnormalities in unaffected members of families with a history of febrile seizures and temporal lobe epilepsy provide support for the hypothesis that preexisting abnormalities may predate the seizure (Fernandez et al., 1998). The third option would be a combination of the above two alternatives, whereby there is a cumulative effect of having a brain-at-risk along with an effect of the seizure itself. Recent animal studies support this view by showing that experiencing seizures during early development while having a brain with malformations of cortical development may worsen cognitive outcomes in the short but not the longer term (Lucas et al., 2011).
Ninety-six percent of PFS cases and 59% of nonfebrile CSE cases were recruited into this study following their first ever CSE, that is, prior to the potential onset of epilepsy. This enabled us to isolate the effects of CSE from the effects of ongoing seizures and/or medication, especially in the case of the PFS group. A different approach with a similar aim was adopted by Adachi et al. (2005), who carried out FSIQ assessments of adult patients with a diagnosis of epilepsy at two time points and compared those who had experienced a CSE in between assessments to those who had not. No differences were observed between the two groups in FSIQ, suggesting that CSE in itself was not the critical factor influencing performance in the context of ongoing epilepsy.
In the current study, we have shown that performance remains unchanged in the first year post CSE. Namely, although the majority of children in our study acquired new skills from baseline to follow-up, their standardized scores were similar at both time points. Moreover, we have demonstrated that seizure-related variables such as duration were not predictive of developmental outcomes. The latter results are in agreement with those of a recent study that found no statistically significant differences in cognitive and motor development between children with febrile seizures lasting a mean of 3.82 min and those with febrile seizures lasting a mean of 39.82 min (Hesdorffer et al., 2011). The mean cognitive scores reported within this study were similar to those obtained in our study, even though the mean seizure length of our patients was almost twice as long. Taken together, these findings exclude the theoretical possibility that PFS has a transient effect on performance a few weeks onward. Namely, if seizure activity in itself affects outcome it does so in a more permanent fashion.
It was perhaps not surprising to find that children with previous neurologic deficits, that is, structural abnormalities and prior developmental delay, had the worst developmental outcomes. Past reports investigating outcomes following CSE may have failed to consider the impact of such confounding factors, resulting in an overestimation of the cognitive morbidity attributed to CSE (e.g., Aicardi & Chevrie, 1970). Therefore, in the future, it may be important to use standardized questionnaires to query developmental functions antedating the seizure to better represent premorbid intellectual abilities.
Age at testing was also identified as an important predictor of performance. However, when we looked at each assessed area in turn, we found that this age dependency stemmed from a relationship between age and language performance in the PFS and the control groups only. Obtaining the same relationship within our control group points away from an insult-related explanation of this phenomenon. Nevertheless, this is an unexpected finding when using a standardized test, where age has been accounted for in the process of standardization. The lack of a relationship between age and language scores in the higher functioning nonfebrile CSE group argues against an administration and/or test issue. Therefore, it remains plausible that the older children assessed in this study had better language abilities than their younger counterparts. This possibility does not compromise our conclusions, since this observation was made for both the PFS and the control groups.
A possible limitation of this study is that the investigated CSE cohort may not be representative of the population as a whole. Specifically, our cohort contains a lower proportion of children with AS (5.6% vs. 22.6%) compared to the nonparticipating cohort. Although this is an important limitation, we believe that it does not compromise the current results. The inclusion of these children possibly would have widened the performance gap between the nonfebrile CSE and the other two groups, as the acute symptomatic group were among the lowest performers. A second potential limitation is that only 35% of the identified sample agreed to take part in our study. However, participants and nonparticipants did not differ on seizure duration or any demographic variables, suggesting that the participating sample is a good representation of the population as a whole. Moreover, the recruited number of participants makes this study one of the largest in the literature, taking into account that we employed standardized neuropsychological and imaging measures and were able to reassess 70.4% of our baseline cohort a year onward. Finally, within the PFS group, there was a bigger representation of female patients than would be expected from an epidemiologic perspective (Chin et al., 2006). Nevertheless, there were no gender effects on performance in our group, suggesting that PFS were not differentially affecting girls and boys at this developmental age and, therefore, that the female skew of our sample is not biasing our results.