Frontal lobe epilepsy (FLE) is considered the second most common type of the localization-related epilepsies of childhood. Still, the etiology of FLE in children, its impact on cognitive functioning and behavior, as well as the response to antiepileptic drug treatment in children has not been sufficiently studied. This review focuses on these aspects of FLE in childhood, and reveals that FLE in childhood is most often cryptogenic, and impacts on a broad range of cognitive functions. The nature and severity of cognitive deficits are highly variable, although impaired attention and executive functions are most frequent. Young age at seizure onset is the only potential risk factor for poor cognitive outcome that has been consistently reported. The behavioral disturbances associated with FLE are also highly variable, although attention deficit/hyperactivity disorder seems most frequent. In 40% of children with FLE satisfactory seizure control could not be achieved. This is a higher percentage than reported for the general population of children with epilepsy. Therefore, pediatric FLE, even if cryptogenic in nature, is frequently complicated by impairment of cognitive function, behavioral disturbances, and therapy-resistance. Given the impact of these complications, there is a need for studies of the etiology of frontal lobe epilepsy-associated cognitive and behavioral disturbances, as well as pharmacotherapy-resistance.
Frontal lobe epilepsy (FLE) is considered the second most common type of the localization-related (partial) epilepsies of childhood, after temporal lobe epilepsy, and accounts for 20–30% of partial epilepsies, although data on its exact incidence are lacking (Manford et al., 1992).
The frontal lobes play pivotal roles in cognitive functioning and behavior, as they mediate essential functions: (1) basic neurologic functions, including motor functions, control of continence, and olfaction; (2) voluntary eye movements; (3) speech and language abilities; (4) executive functions; (5) motivational behaviors; and (6) social competency (Cummings & Miller, 2007). Consequently, both structural lesions and functional lesions, such as an epileptic focus, within the frontal lobes may interfere with a variety of these functions and can lead to impairments of cognitive functioning and behavioral disturbances. In adults with FLE, cognitive deficits and behavioral disturbances range from impaired attention to difficulty with the more complex behaviors involved in planning, selecting goals, anticipating outcomes, and initiating actions (Helmstaedter et al., 1996, 1998; Upton & Thompson, 1996, 1997a,b; Exner et al., 2002). The impact of FLE on cognitive functioning and behavior in children remains largely unknown.
In addition to neuropsychological complications, FLE is frequently complicated by pharmacotherapy resistance. In adult patients referred to epilepsy surgery centers, frontal lobe epilepsy represents 15–30% of pharmacotherapy-resistant seizure disorders (Helmstaedter et al., 1996; Helmstaedter, 2001). For adults, pharmacotherapy-resistant epilepsy is associated with increased morbidity from seizures and medication, social isolation, unemployment, and overall reduced quality of life (Sillanpää et al., 1998). Yet not all patients with FLE will develop pharmacoresistance, and the mechanisms that result in either seizure control or refractoriness have not been explored. This review summarizes the available literature on the etiology of FLE in children, its impact on cognitive functioning and behavior, as well as the response to antiepileptic drug treatment, and it explores areas for future research. Surgical therapy and the effects of surgical therapy on cognitive and behavioral outcomes fall outside the scope of this review.
Search Strategy and Selection Criteria
Data for this review were identified by searches of PubMed (National Center for Biotechnology Information; NCBI; http://www.ncbi.nlm.nih.gov/pubmed/) in January 2010 using the Medical Subject Heading (MeSH) terms “Epilepsy, Frontal Lobe,”“Epilepsies, Partial,” and “Epilepsy, Complex Partial.” For the latter two, the text variable “frontal” was added to narrow the search. Subheadings “classification,”“complications,”“drug therapy,”“epidemiology,”“etiology,”“psychology,”“radiography,” and “therapy” were applied, with limits: “All child 0–18 years” and “English.” References from relevant original and review articles and book chapters were also used.
Cognitive and Behavioral Functioning in Children with FLE
Cognitive functioning in children with FLE
The associations between FLE and cognitive and behavioral functioning have been studied in more detail. The first representative case describing cognitive deficits associated with cryptogenic FLE was reported by Boone et al. (1988). They described a 13-year-old girl with impaired performance on tasks that measure attention and concentration and impairments of verbal fluency, ability to shift cognitive set, motor speed, motor functioning, planning abilities, and response inhibition. Other frontal lobe executive functions such as categorization, sequencing, and conceptual flexibility had remained intact. The deficits were reversible once seizures were sufficiently controlled with antiepileptic drug (AED) treatment. Similarly, Jambaqué and Dulac (1989) observed deterioration of verbal fluency and attention span and marked behavioral and affective changes in an 8-year-old boy of normal intelligence, as well as reduced motor speed and planning ability with deterioration of handwriting, which abated with adequate seizure control. The fact that cognitive deficits improved in these two patients with the initiation of successful AED treatment suggests that they were caused by the seizures or interference by underlying epileptiform activity in affected frontal areas. In addition to these two illustrative case reports, our literature search yielded 10 case series, with a total of 149 children with FLE who had undergone neuropsychological assessment (Lassonde et al., 2000; Culhane-Shelburne et al., 2002; Lendt et al., 2002; Riva et al., 2002; Hernandez et al., 2003; Nolan et al., 2003; Sinclair et al., 2004; Auclair et al., 2005; Riva et al., 2005; Prévost et al., 2006). A summary of the main studies and their findings is recorded in Table 2. Most existing studies are comparative in nature and compare cognitive functioning of children with FLE with children with temporal lobe epilepsy and generalized epilepsy (Lassonde et al., 2000; Culhane-Shelburne et al., 2002; Hernandez et al., 2003; Nolan et al., 2003). In this comparison, children with FLE typically have impairments in executive functions [mainly planning ability, response inhibition, (visuospatial) organization, verbal search, mental flexibility, impulse control, working memory and programming of complex motor sequences], motor coordination, and attention deficits (Lassonde et al., 2000; Culhane-Shelburne et al., 2002; Hernandez et al., 2003; Nolan et al., 2003). The term “executive functions” refers to the mental processes involved in the realization of goal-directed behavior, whether expressed through a mental or a motor act (Lezak, 1995). They are generally thought to control formulation, planning, and effective performance of goal-directed actions (Lezak, 1995). Perhaps as a result, the impairments in executive functions also give rise to impaired reading and mathematical skills (Lagae et al., 2001).
Table 2. A summary of the main studies of children with FLE who had undergone neuropsychological assessment and their findings
Below normative IQ scores, impaired fine-motor coordination, deficits in attention, behavior and executive functions
FLE impacts on a wide scale of cognitive domains other than the executive functions. In one case series of six children with a left frontal epileptogenic focus, a clear dissociation in linguistic performance between comprehension and production was noted (Cohen & Le Normand, 1998). Linguistic comprehension was initially impaired, but gradually improved to reach normal performance levels by age 7, whereas linguistic production, even at later stages, remained poor. This dissociation in the development of linguistic performance in children with left-sided FLE suggests a complex interplay between brain maturation dynamics and FLE-associated dysfunction, modulating the succession of stages in language development. Other researchers have also noted language deficits in children with FLE, including impaired verbal fluency and impaired verbal search (Boone et al., 1988; Jambaqué & Dulac, 1989; Lassonde et al., 2000; Prévost et al., 2006).
Memory deficits have long been attributed mainly to temporal lobe epilepsy; their association with FLE remains controversial. Because memory deficits have been associated specifically with mesial temporal lobe pathology, children with FLE may not be routinely tested for their memory skills. Nevertheless, four studies have noted these deficits in their patients with FLE (Jambaqué et al., 1993; Lendt et al., 2002; Nolan et al., 2004; Prévost et al., 2006). In one study, longer duration of active epilepsy was the most significant risk factor for memory impairment (Nolan et al., 2004). In contrast, other case series have examined this subject and found memory functions intact (Jambaqué & Dulac, 1989).
Interesting similarities between the cognitive impairments of children and adult patients with FLE exist. In adults, neuropsychological deficits are also prevalent. The nature and severity of cognitive deficits in adult FLE patients are highly variable, although here, too, impaired attention and executive functions are most frequent (Helmstaedter et al., 1996; Upton & Thompson, 1997a,b; Helmstaedter et al., 1998; Exner et al., 2002). Unfortunately, studies tend to focus on the typical frontal lobe functions (e.g., executive functions), disregarding functions typical of other lobes, such as memory, which is regarded as a temporal lobe function (Hernandez et al., 2002; Riva et al., 2002, 2005).
How site-specific are cognitive deficits?
One would assume that the pattern of deficits observed in patients with epilepsy reflects the functions controlled in the area that yields the epileptic focus. Indeed, temporal lobe epilepsy is associated with cognitive deficits specific to the temporal lobe functions, mainly learning (especially reading) and memory. Yet, frontal lobe dysfunction has been noted in up to 84% of children and adolescents with temporal lobe epilepsy (Igarashi et al., 2002; Rzezak et al., 2007). These patients had impairments in mental flexibility and set shifting, perseveration, inhibitory control, verbal fluency, and maintenance of attention (Rzezak et al., 2007). It has been hypothesized that a wider anatomic and functional network connects temporal and frontal lobes and allows the temporal epileptogenic focus to affect the frontal and prefrontal functional regions (Igarashi et al., 2002; Rzezak et al., 2007). In accordance with this hypothesis, recent functional neuroimaging studies demonstrated hypometabolism in the prefrontal regions of patients with TLE (Nelissen et al., 2006). This hypometabolism may represent a dynamic process of protection against epileptiform discharge propagation by frontal lobe function inhibition (Nelissen et al., 2006). Nevertheless, it is likely responsible for the cognitive deficits, suggestive of frontal lobe dysfunction, presented by these patients.
There is more evidence that localized epileptic foci impact on connected distal structures and regions. In patients with an epileptogenic focus in the hippocampus, ipsilateral reductions in gray-matter density in the lateral temporal lobe, as well as extratemporal regions, including the thalamus, posterior cingulate cortex, cerebellum, and frontal and parietal opercular cortex have been noted (Cormack et al., 2005). This suggests that structural changes occur in areas connected to, although not part of, the epileptogenic focus (Cormack et al., 2005).
Whether these structural changes in areas connected to the epileptogenic focus are permanent (Rzezak et al., 2007) or reversible (Nelissen et al., 2006) remains a subject of debate. Similarly the post aut propter debate is relevant here; we do not know whether such structural changes precede or follow functional disconnection and thus whether they are causally associated with cognitive impairment.
The same principle applies to hemispheric specificity in the frontal lobes. Although one expects linguistic impairments specifically in FLE with a left hemispheric epileptogenic focus, no such correlations between the affected hemisphere and hemisphere-specific cognitive deficits have been noted (Helmstaedter et al., 1996; Hernandez et al., 2002; Riva et al., 2005). Because epileptic discharges have a tendency for fast propagation, it is possible that the functioning of other connected frontal areas is simultaneously affected (Riva et al., 2005). This may include areas of the contralateral lobe (Helmstaedter et al., 1996). Two separate case series did not detect differences in test performance between subjects with bilateral and unilateral foci (Culhane-Shelburne et al., 2002; Hernandez et al., 2002).
All previously discussed studies provide evidence that, through neural networks, epileptogenic foci affect connected regions and the functions that are organized in such areas. It is, therefore, clear that the relationship between site of the epileptogenic focus and type of cognitive impairment is far from straightforward. Studying the frontal neural networks in patients with FLE, or in fact temporal lobe epilepsy with frontal lobe dysfunction, may yield important clues on the association between the site of the epileptogenic focus and the pattern of cognitive deficits. Recently, prospective memory, that is, the ability to fulfill previously planned intentions, was studied in patients with juvenile myoclonic epilepsy (JME), their unaffected siblings, and healthy controls. Not only patients with JME, but also their siblings, showed deficits on the prospective memory task (Wandschneider et al., 2010). These findings strongly support a genetic predisposition of the distinct neuropsychological impairment patterns, which might be caused by thalamo-frontal-cortical network dysfunction. This hypothesis is supported by a quantitative MRI study on newly diagnosed patients with JME demonstrating impaired executive functioning and structural changes in both the frontal lobes and thalami in early disease (Pulsipher et al., 2009).
Prevalence of cognitive impairment in FLE: the great unknown
The prevalence of cognitive impairment in children with FLE remains unclear. Very few epidemiologic studies have been performed, and this is an area that warrants future research. Upon examination of the existing case series, it seems that cognitive impairment is frequent in children with FLE, although considerable intra- and interindividual variation in cognitive performance exists (Riva et al., 2002). Interestingly, in children with FLE, the learning difficulties may even precede seizure onset (Prévost et al., 2006). This suggests an underlying condition—which could be microstructural or functional in nature—that manifests itself both in cognitive impairment and seizures.
FLE seizures can manifest themselves with various behavioral changes such as mood change, sudden agitation or quietness, subtle changes of awareness or awakening, and subtle decrease in motor activity or social interaction (Fohlen et al., 2004).
In one report of two cases, postictal or interictal psychosis was noted secondary to frequent frontal lobe seizures, which presented as delusional thinking, depression, paranoia, aggression, and bizarre behaviour in conjunction with brief stereotypic events of sudden screaming, agitation, and physical aggression (Sinclair & Snyder, 2008). Psychosis disappeared with adequate seizure control.
The behavioral disturbances associated with FLE are highly diverse, although attention deficit/hyperactivity disorder (ADHD) seems most frequent. ADHD is defined as symptoms of inattentiveness and/or hyperactivity and impulsivity inappropriate for age and gender, to a degree sufficiently significant to cause impairment in daily functioning (Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR, 2000). The attention deficits in these children are thought to be attributable to an inability to ignore irrelevant stimuli (Auclair et al., 2005). Combined with a tendency to respond impulsively, ADHD is likely to develop in children with FLE (Riva et al., 2002; Hernandez et al., 2003; Prévost et al., 2006). The prevalence of ADHD in children with FLE has not been systematically studied, although a prevalence of up to 67% has been reported in a case series (Prévost et al., 2006). The majority of these children exhibited typical ADHD, whereas a minority exhibited oppositional behavior, impulsivity, or anxiety as a comorbidity of FLE (Prévost et al., 2006). Other studies have described psychotic as well as autistic features in children with FLE (Fohlen et al., 2004; Sinclair & Snyder, 2008).
The risk factors for these behavioral disturbances are not fully understood. Seizure frequency and poor seizure control have been proposed as risk factors associated with attention difficulties and inability to inhibit impulsive responses, as these disturbances improved with adequate seizure control (Jambaqué & Dulac, 1989; Lendt et al., 2002; Riva et al., 2002; Derry et al., 2008). The efficacy of seizure control in these cases suggests that a functional disturbance of the brain regions involved in the regulation of attention and behavior is responsible for the induction of these symptoms.
Even if the behavioral disturbances seem FLE-related, it needs to be emphasized that no systematic studies have investigated whether these behavioral disturbances are more prevalent in children with FLE than in the normal population. Regardless of whether they are FLE related, these behavioral disturbances interfere with the children’s school performance, which may be aggravated by cognitive deficits. In a previously discussed case series, all children with FLE and attention deficits with or without hyperactivity required special academic support (Lassonde et al., 2000).
Given the impact of these behavioral disturbances and their seemingly high prevalence, there is a need for studies of the etiology of FLE-associated behavioral disturbances. Various hypotheses now exist. First, functional anatomic relationships have been considered; the high prevalence of similar psychiatric changes among patients with primary frontal and primary temporal epileptogenic zones has been related to the intimate connection of the frontal and temporal limbic systems (Blumer et al., 1998). Second, cognitive and behavioral problems can be the result of the epilepsy-related factors, including the age of onset of seizures, the number of seizures, the occurrence of secondary generalized seizures, and the location and extension of the epileptic focus (Fohlen et al., 2004). Third, the association between psychosis or ictal fear and FLE has been related to the reciprocal connections between amygdala, orbitofrontal, and anterior cingulated regions and between the frontal and temporal lobes through the uncinate fasciculus and the superior longitudinal fasciculus (Mega et al., 1997). Fourth, aggressive behavior has been related to activation of limbic structures and loss of frontal suppression of limbic activity. Spreading of discharges from primary foci to other frontal, temporal, or limbic structures may be another explanation (Sumer et al., 2007). Separately, the epileptic activity may impact on the normal maturation of the brain; in epilepsy of early onset this disturbed maturation may explain specific deficiencies (Fohlen et al., 2004).
Response to Antiepileptic Drug Treatment
Treatment failure is a significant problem in epilepsy, including FLE. Treatment failure is defined as recurrent seizure(s) after the intervention has been adequately applied (Kwan & Brodie, 2009). Drug-resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen, and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan et al., 2010). Seizure freedom is defined as freedom from seizures, for a minimum of three times the longest preintervention interseizure interval or 12 months, whichever is longer (Kwan & Brodie, 2009).
Most studies investigating treatment outcome in children with FLE assess outcome after epilepsy surgery in children with drug-resistant FLE. These studies have been performed in tertiary reference centers or centers for epilepsy surgery and are, therefore, subject to selection bias (Kral et al., 2001; Lawson et al., 2002; Lendt et al., 2002; Nolan et al., 2004).
In epilepsy in general, regardless of localization, young age at seizure onset, a history of status epilepticus, the presence of underlying pathology, changes in type of epilepsy during the clinical course, and neonatal seizures have been identified as risk factors for therapy resistance (Ohtsuka et al., 2000). Specific causes of therapy resistance in FLE remain elusive. Drug target availability and drug delivery are among the many aspects that warrant additional study.
Pediatric FLE, even if cryptogenic in nature, is frequently complicated by impairment of cognitive function, behavioral disturbances, and therapy resistance. Cognitive impairment generally consists of impairment of executive functions and attention deficits, with consequences for school performance, although interindividual variability is high, and even “typical” temporal lobe impairments such as memory impairment are found. Risk factors remain controversial, although a young age at seizure onset has been associated with cognitive impairments during childhood.
The behavioral disorders show even stronger interindividual variability and might have a negative impact on existing cognitive impairment. ADHD is the most common disorder complicating pediatric FLE. AED therapy-resistance may be more frequent in children with FLE than in other types of epilepsy, although its causative mechanisms need further research.
The fact that all these complications occur at a young age is troublesome. The brain is at its most vulnerable in childhood, when neurologic disturbances such as FLE can impact on brain maturation and the acquisition of cognitive skills. FLE can impact on cognitive functioning in childhood, leading to learning disabilities. In turn, these disabilities may have a negative influence throughout life, in terms of social skills and level of education.
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