Altered EEG spectral activity and attentional behavioral deficits following prolonged febrile seizures: a pilot study

ARTICLE

Auteur(s) : Sarah Lippé^1,2, Marie-Sylvie Roy^2,3, Claudine Arcand^1,2, Morris H Scantlebury⁵, Lionel Carmant^2,4, Maryse Lassonde^1,2

¹Department of Psychology, University of Montreal, Montreal, Canada
²Research Center, Sainte-Justine University Hospital, Montreal, Canada
³Department of Ophtalmology, Sainte-Justine University Hospital, Montreal, Canada
⁴Department of Pediatrics, University of Montreal, Montreal, Canada
⁵Saul R. Korey Department of Neurology and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY

Article reçu le 12 Septembre 2008, accepté le 11 Février 2009

A febrile seizure (FS) is defined as “an event in neurologically healthy infants and children between 6 months and 5 years of age, associated with fever > 38°C, but without evidence of intracranial infection or a defined cause and with no history of prior afebrile seizure” (Knudsen, 2000). Febrile Seizures (FSs) occur in 2-5% of young children living in North-western countries (Nelson and Ellenberg, 1976, Verity et al., 1985). Even though FSs are the most common type of childhood seizures, their significance and their consequences are still a matter of controversy. Most studies concord that the majority of FSs are benign (Shinnar, 1998); (Verity et al., 1998), however, several retrospective and prospective studies have demonstrated a correlation between prolonged complex FS or febrile status epilepticus and brain damage (VanLandingham et al., 1998), neurological sequelae, seizure recurrence (Bessisso et al., 2001, Maytal et al., 1989, Verity et al., 1993) and cognitive deficits. The risk of developing epilepsy, especially temporal lobe epilepsy (TLE) (Sapir et al., 2000, Trinka et al., 2002, Birca et al., 2005) or Dravet syndrome (Caraballo and Fejerman, 2006) is high in this population. Short generalized FS, on the other hand, have been found to be associated with the development of generalized epilepsy (Trinka et al., 2002). However, according to a British study, the risk of developing epilepsy following simple FS is only 1% compared to 6% after a prolonged FS (Verity and Golding, 1991).

Some studies have suggested that complex FSs may differ from simple FSs with respect to origin and outcome (Al Eissa et al., 1992). A genetic predisposition can often be documented. For instance, studying a cohort of 180 children, Shinnar et al. (2001) found a higher incidence of family history of epilepsy in children with febrile status epilepticus (FSE) than in children with simple FSs (Shinnar et al., 2001). Furthermore, there are evidences that pre-existing brain abnormalities play an important role in the development of prolonged FSs (Shinnar et al., 2001, VanLandingham et al., 1998). For instance, in animal studies conducted by Scantlebury et al. (2004, 2005), a single cortical freeze lesion in neonatal rats was sufficient in creating prolonged hyperthermic seizures and spontaneous recurrent seizures in the majority of animals in adulthood.

Currently, there is a lack of prospective data on children that experienced a prolonged FS and there is no general consensus about the impact of prolonged FSs on the immature brain. Electrophysiology is particularly well suited to study brain functions in babies and young children. This technique not only permits the assessment of the impact of FSs at the time of onset, but can also be used to characterize transient or long-term changes in brain physiology that may occur following a FS.

In this study we tested the effects of FSs in children on the following electrophysiological parameters:

• – pattern visual evoked potentials (pVEP);
• – spectral density measures;
• – coherence analysis.

Pattern visual evoked potentials were tested because they are considered to be a robust measure of the functional capacity of the visual system (Roy et al., 1995) and of the nervous system in general (Lippe et al., 2007). Several characteristics of the pVEP provide clues regarding the developmental physiology of the brain. For example, shifts in latencies have been linked to myelination and conductive capacity (Brusa et al., 2001, Eggermont 1988, Emerson 1998, Tsuneishi and Casaer 1997) whereas changes in amplitude are thought to reflect the number of neurons firing together (Scherg and Picton, 1991). Differences in latency and amplitude measurements have been found in other types of childhood pathology, such as prematurity (Atkinson et al., 2002, Lippe et al., 2007, Roy et al., 1995), indicating that this approach constitutes a sensitive tool to study brain development.

Spectral density measures of the developing brain show a pattern characterized by a predominance of slow activity (Matthis et al., 1980, Gasser et al., 1988, Marshall et al., 2002, Stroganova et al., 1999, Lippe et al., 2007). Seizures may cause transient or long-term changes in intra-cortical activity (Schneiderman 1997, Frantzen et al., 1968) which, in turn, may affect the maturational pattern of the spectral density. Moreover, EEG spectral measures reflect awareness and cognitive processing (Cahn 2006, Reid 2007, Uhlhaas et Singer 2006, Canolty 2006) as well as pathological brain states (Kwak 2006, Knyazev 2005, Claus et al. 1998), thus providing an index of the brain state during sensory processing. In the present study, we investigated spectral density patterns in three brain areas involved in visual processing (occipital, temporal – what pathway – and parietal – where pathway) (Borowsky et al. 2005). Because recordings were carried out when children were visually attentive, these measures should provide a differentiation between the febrile convulsion children and their age-matched peers if the seizure produced any disruption in vigilance or alertness.

Moreover, animal models suggest (Grigonis and Murphy, 1994) that seizures may prevent the normal elimination of exuberant connections, which occurs early in life, thereby interfering with the brain’s ability to generate coherent activity between disparate regions. Given the presumed relationship between FSs and the development of temporal lobe epilepsy (Cendes 2004, Roy et al., 1995, Scantlebury et al., 2005, Shinnar and Glauser, 2002), we expected temporo-occipital coherence to be particularly affected. To study this hypothesis, we explored occipito-temporal (what system) coherence as well as occipito-parietal (where system) and occipital interhemispheric coherence measures in our sample of children.

This constitutes a cross-population study with children tested at three time points, on average one month, 5.75 months and 30.33 months following their first and in most cases the only FS. An additional control group composed of children who had experienced a simple FS was tested 1 month following the episode in order to determine the effect of atypical FS on electrophysiological parameters as compared to simple FS. We also used cognitive and behavioural measures to quantify possible cognitive deficits in the FS group.

Methods

Subjects

Two separate cross population studies were carried out, a prospective and a retrospective one (table 1). The retrospective study allowed the investigation of infants more than two years post-episode. Infants from the prospective study were recruited at the moment of their first seizure from many health services (emergency, neurology, orthopaedics, peadiatrics and ear/throat services) at CHU Ste-Justine in Montreal, whereas infants from the retrospective study were recruited from the hospital medical files. From the 46 participants who originally enrolled in the study, 12 participants (8 FS and 4 controls) were excluded because of substantial amount of artifacts in their electrophysiological recordings. The analyses were conducted on the remaining 34 infants.
Table 1 Experimental subjects description.

Prospective study (n = 22)

Retrospective study (n = 12)

Apparatus and stimuli

Data analysis

Visual evoked potentials analyses

Spectral density and coherence analyses

Developmental data and cognitive testing

Two years post-evaluation, the parents of both experimental groups were invited to complete the Achenbach Child Behaviour questionnaire (CBCL) (Achenbach 1991) to assess their child’s adaptive capacities.
Table 2 Clinical subjects description.

Statistical analysis

Results

PVEPs analyses

Spectral density values

Prospective study

As shown in figure 2B, beta1 frequency band density was significantly reduced 1 month post prolonged FSs (p = 0.018) but not following simple FSs. Figures 2C and D also depict a significant reduction in beta2 and gamma bands density 1 month post prolonged FSs compared to the controls (respectively p = 0.032, p = 0.033). Children with simple FSs did not show significant changes in spectral density in the beta and gamma range.

Retrospective study

Coherence analyses

Cognitive/behavioural measures and follow-up

Two to three years after the electrophysiological evaluation (and up to 7 years post-seizure), an interview was carried out with the parents from the clinical sample. Six out of 14 (43%) children with prolonged FS had presented at least another FS and 6/18 (33%) of children with either simple or prolonged FSs were receiving behavioural or academic intervention by professionals. Thirteen parents agreed to fill out the Child Behavior Checklist, which yielded, on average, normal results on both the internalizing (T score: 51.77 ± 9.68) and externalizing (T score: 52.61 ± 9.39) subscales. However, on average, children with simple or prolonged FSs showed scores close to 1 standard deviation above the mean (T = 59.23, min 50 max 77) on the attentional index. The removal of the child from the simple FS group who had scored in the deficient range during the cognitive assessment did not affect the attentional index results (T = 58.33 min 50 max 77). The averaged scores of the aggressiveness index (T = 57.1, min 50 max 72) was also high, whereas the somatisation (T 55.61 min 50 max 72), anxiety (T = 53.31 min 50 max 70) and withdrawn (T = 51.46 min 50 max 56) indices were, on average, within normal limits.

Discussion

We report here that infants suffering a prolonged FS had an increased delta band density and a reduced density of 13-50 Hz activity. While slow bands are typically associated with lack of awareness, beta and gamma frequency bands are characteristic of the waking state (Bazhenov et al., 2002), which is associated with cognitive processes, such as perception and attention (Bertrand and Tallon-Baudry 2000, Tallon-Baudry et al., 1999, Csibra et al., 2000, Tamas et al., 2004). Yet, the infants with prolonged FSs obtained normal scores on the mental scale of the Bayley or the Stanford-Binet. Furthermore, the removal of the only infant with prolonged FS who obtained a below average score did not affect the spectral results. Thus, while the spectral density results obtained in the present study do not reflect alterations in global cognitive development, they may, however, reflect changes in alertness or attention states. Indeed, two years post-evaluation, reduced attentional capacities, measured by the attention index of the Child Behavior Check List, were reported by the parents of the FS group. In addition, one third of the FS children had required special clinical intervention (e.g. speech therapy, occupational therapy).

Power spectral density measures have been extensively studied in ADHD populations (Clarke et al. 2002, Clarke et al., 2003, Barry et al., 2003). An increase in absolute delta and a reduction in beta power density have been observed over posterior regions (Hobbs et al., 2007). Prolonged FSs at young age have also been found to be a risk factor for developing ADHD in school-aged children with normal global cognitive abilities (Pineda et al., 2007). Although the relationship between the cognitivo-behavioural profile and electrophysiological patterns seen in our FS infants has yet to be confirmed in larger samples, our findings suggest that the EEG of infants who showed an episode of prolonged FS is sufficiently altered to produce a behavioural and electrophysiological profile comparable to that described in older ADHD children.

It is noteworthy that the infants with simple FSs, who were tested one month post-episode, demonstrated an increase in delta band density but failed to show significant changes in spectral density in the high frequency bands (a reduction in beta 1, beta 2 and gamma bands spectral density as seen in the prolonged FS group). This “in between” response pattern seen in children with simple FS may be an indicator of the degree of severity of this FS type. In fact, many studies have reported a deleterious effect of prolonged or complex FS on brain functioning and cognitive behaviour compared to the favourable outcome of simple FS (Al Eissa, 1995, Annegers et al,. 1987, Bessisso et al., 2001, Berg and Shinnar, 1996). The present results suggest that changes in high frequency density may be a better indicator of the severity impact of the seizures or a better marker of FS infants’ functioning. However, its predictive value regarding the long-term prognosis of prolonged FSs still has to be evaluated in a longer prospective study.

The significance of the persistently increased low frequency spectral density seen one month to more than two years post prolonged FSs in regards to brain development and risk of developing epilepsy remains unknown. Recently it has been proposed that seizures in the developing brain may delay or interrupt its maturation leaving certain networks in a persistent immature state (Cohen et al. 2002) and reviewed in Scantlebury et al. (2007). It is noteworthy that in our study the spectral activity pattern seen in the children with prolonged FSs mimicked a pattern found in younger children as described in our larger study of visual electrophysiological development (Lippe et al., 2007); findings consistent with a delay in maturity. It is nonetheless not clear if prolonged FSs themselves will delay the maturation of the brain making it more susceptible to seizures than the adult brain (Moshe et al., 1983) or if this electrophysiological response pattern reflects the consequences of a complex mode of inheritance. Again, a larger multicentre trial using the tests we describe here will be helpful in answering these questions.

Although a widely used method in paediatric research, the pattern visual evoked potentials in the present study failed to reveal significant differences between the groups in terms of amplitude and latency. Since visual evoked potentials are the result of the averaged responses time-locked to the stimulus, differences in electrophysiological activity may not be evident because of hidden information resulting from the averaging process. Furthermore, the failure to reach statistical significance may be attributable to the high variability in amplitude, which is frequently observed in normal and abnormal developmental cohorts.

With respect to coherence analysis, the latter is thought to indicate the degree of correlated changes between the signals of disparate brain regions, thus reflecting the functional connectivity between neuronal networks (Thatcher, 1992, Andrew and Pfurtscheller, 1995). Considering the presumed relationship between FS and the development of temporal lobe epilepsy, we expected temporo-occipital coherence to be particularly affected. On the contrary, no differences in coherence values were found between the groups in any of the paired regions. We have recently shown that coherence values undergo important developmental changes which are most marked at the age interval addressed in the present study (Lippe et al., 2007). These changes could have masked any alteration in connectivity in our FS patients. This explanation is all the more plausible for interhemispheric coherence as it is well established that callosal connections develop gradually and do not reach their functional maturity before puberty (Lassonde et al., 1991). Therefore, any changes in coherence would more likely be demonstrable in adult patients with a history of prolonged FSs.

Conclusion

Acknowledgments

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