Epilepsy & Behavior 31 (2014) 117–122

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Review

Temporal lobe epilepsy in children: Executive and mnestic impairments Patricia Rzezak a,b,⁎, Kette D. Valente a,c, Michael S. Duchowny d,e a

Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, SP, Brazil c Laboratory of Clinical Neurophysiology, Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil d Brain Institute and Department of Neurology, Miami Children's Hospital, Miami, FL, USA e Department of Neurology, Wertheim College of Medicine, Florida International University, Miami, FL, USA b

a r t i c l e

i n f o

Article history: Received 11 November 2013 Revised 29 November 2013 Accepted 2 December 2013 Available online xxxx Keywords: Epilepsy Memory Attention Executive function

a b s t r a c t The current definition of epilepsy emphasizes the importance of cognitive impairment for a complete understanding of the disorder. Cognitive deficits have distinct functional manifestations that differentially impact the daily life experiences of children and adolescents with epilepsy and are a particular concern as they frequently impair academic performance. In particular, memory impairment and executive dysfunction are common disabilities in adults with temporal lobe epilepsy but are less easily recognized and studied in the pediatric population. This review focuses on the consequences of early-onset temporal lobe epilepsy for the development of memory and executive function and discusses current theories to explain these deficits. © 2013 Elsevier Inc. All rights reserved.

1. Introduction

2. Memory and temporal lobe epilepsy in childhood

Temporal lobe epilepsy (TLE), particularly if caused by mesial temporal sclerosis (MTS–TLE), is the most common form of pharmacoresistant epilepsy in adults referred to tertiary centers [1]. Memory deficits are common in this population and are well documented on neuropsychological evaluation. This relationship is not surprising given the importance of the hippocampus and related temporolimbic structures for memory consolidation. However, the frequent cooccurrence of executive deficits [2–4] is unexpected and implicates more widespread cortical involvement, an association subsequently confirmed by structural and functional neuroimaging studies [5–7]. Similar neurocognitive impairments are less easily recognized and studied in the pediatric population. Children with temporal lobe epilepsy have less specific findings as they frequently exhibit cognitive symptoms implicating involvement beyond the temporal lobes or mesial temporal lobe structures. Early age at seizure onset is associated with widespread propagation of discharges that negatively impact neurodevelopmental processes including synaptogenesis and apoptosis. “Epileptogenic noise” [2] induced by recurrent seizures is also likely to play an important role. This review focuses on the consequences of early-onset temporal lobe epilepsy on the development of memory and executive function.

2.1. Episodic memory

⁎ Corresponding author at: Centro de Medicina Nuclear, 3° andar, LIM-21, Rua Dr. Ovídio Pires de Campos, s/n, postal code 05403-010 São Paulo, SP, Brazil. Fax: +55 11 26618193. E-mail addresses: [email protected] (P. Rzezak), [email protected] (K.D. Valente), [email protected] (M.S. Duchowny). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.12.005

Because of the high frequency of pathological changes in memoryrelevant brain structures, episodic memory disorders represent the single most important cognitive comorbidity in patients with TLE [8]. The episodic memory system is devoted to personally experienced events and allows individuals to be consciously aware of earlier experiences in certain situations and at certain times. Thus, information stored in episodic memory relates to past experiences in subjective space and time [9]. Approximately 70–80% of patients with pharmacoresistant TLE evidence verbal or nonverbal memory impairment [10]. This remarkably high incidence of memory impairment is related to the loss of structural integrity of the temporal lobe and the dynamic but potentially reversible influence of seizures and pharmacotherapy on brain function [8]. In comparison to adults, children with TLE are a unique population in which to study memory impairment as the impact of lesion and epileptogenic activity can be investigated in the absence of long-lasting epilepsy or drug exposure [11]. However, studies of episodic memory in childhood TLE are limited. Possible reasons include lack of episodic memory consolidation before age six years [12], decreased sensitivity of neuropsychological measures for detecting early subtle impairments [13], and the limited pediatric pool of longitudinal pre- and postoperative neuropsychological data [14]. It is known, however, that similar to adults, children with focal dyscognitive seizures arising from the temporal lobe manifest prominent memory deficits [15]. In older children and adolescents with TLE, memory impairment negatively impacts daily functioning [16], while

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in school-age children with TLE, memory impairment contributes to learning difficulties. Memory disturbance is therefore a critical factor in school underachievement [17,18]. These specific observations suggest that primary temporal lobe disturbance rather than chronic seizure burden or medication is primarily responsible. Standardized memory tests reveal that both verbal episodic memory and nonverbal episodic memory are impaired in children with TLE [11,16,19–21]. Only one study reported no difference in verbal and nonverbal performance compared to healthy controls [22], but this sample consisted of children with later epilepsy onset and a lower incidence of MTS–TLE. Furthermore, the investigators employed memory tests that were neither age-specific nor sufficiently sensitive for children with TLE. 2.2. Semantic memory —a neglected aspect of memory impairment Studies of patients with neurodegenerative disorders underscore the importance of the temporal lobe for semantic memory [23,24]. Semantic memory registers and stores knowledge about the world in its broadest sense and makes it available for retrieval. Thus, semantic memory enables individuals to represent and mentally operate with regard to situations, objects, and relations in the world that are otherwise unavailable to the senses [9]. Semantic memory involves stored knowledge of concepts, facts, and attributes that are acquired from but no longer defined by specific circumstances [25]. Only three studies have evaluated semantic memory competence in children with TLE [11,16,26]. All demonstrated semantic memory deficits. In a homogeneous group of children with MTS–TLE, impairments were documented in category fluency, object naming, word definition, and sentence repetition [11]. These cognitive functions are all based on semantic memory. A similar relationship was found in adults with TLE on tasks of object naming [27–29], category fluency [30,31], word definition [32], and attribute knowledge [29]. Deficits in semantic memory competence were further confirmed in a larger but more heterogeneous cohort of 66 children and adolescents with TLE [16]. While object naming and word definition were impaired compared to age-matched healthy controls, there were no differences between patients with left and right TLE. Moreover, this study revealed a double dissociation between semantic and episodic memory in some children with unilateral TLE—either impaired episodic and preserved semantic memory or preserved episodic and impaired semantic memory. Finally, Cormack and associates [26] used a nonspecific test of semantic memory (Verbal Paired Association Learning —Wechsler Memory Scale) to document semantic memory impairment in children with hippocampal sclerosis and dysembryoplastic neuroepithelial tumors. 3. Beyond memory impairment in children with temporal lobe epilepsy 3.1. Executive dysfunction in children with temporal lobe epilepsy Executive function refers to those abilities related to self-directed behaviors. This complex cognitive system is here understood as relating to metacognitive capacities that allow an individual to perceive stimuli from his or her environment, respond adaptively, flexibly change direction, anticipate future goals, consider consequences, and respond in an integrated manner. All are utilized to achieve a specific goal [33]. Thereafter, it is necessary to plan and sequence behaviors, simultaneously attend to different sources of stimuli and solve problems, resist distraction, control inhibition, and sustain behaviors for prolonged periods. Thus, successful executive function requires an intact complex cognitive network that includes perception, attention, and working memory. Patients with executive dysfunction (ED) often find it difficult to complete productive activities or socially adjust [34]. Executive dysfunction was first demonstrated in adults with TLE [2,3], but it was subsequently shown that patients with unilateral TLE

also exhibit impaired set-shifting [4,35–37], decision-making [38], and working memory [39,40]. Corcoran and Upton [3] postulated that hippocampal lesions alone could explain ED by compromising its role as a comparator of actions. Alternatively, Hermann and collaborators [2] proposed that ED resulted from ongoing epileptogenic activity that propagated to extratemporal regions responsible for executive functionality (“epileptogenic noise”). These competing theories are now regarded to be complementary as limbic and extralimbic structures can interact and generate unexpected cognitive impairment in patients with epileptogenic activity outside of temporal lobe memory centers. Neuroimaging studies in TLE have correlated executive performance to diminished left dorsal prefrontal cortex and left hippocampal volumes [41] and shown that ED is associated with extratemporal hypometabolism [42]. Takaya and associates [43] extended these findings by demonstrating that ED is associated with prefrontal hypometabolism in patients with TLE and high seizure frequency. Thus, adult ED is now viewed as a more global disorder of network functionality involving dysfunction at multiple cortical sites. Only five of 16 neurocognitive studies evaluated ED as a dependent variable in children and adolescents with TLE [52–56]. Executive function has been included in broader neuropsychological evaluations of cognition [19,22,44–46], and children and adolescents with TLE have also been compared with patients with other types of epilepsy including idiopathic generalized epilepsy, benign childhood epilepsy with centrotemporal spikes [47], generalized epilepsy with absence seizures [48,49], and frontal lobe epilepsy (FLE) [48–51]. Despite different sample sizes, age ranges, etiologies, and a wide range of cognitive tasks, ED was found in most of these study populations [19,44–50,52–56]. While children with FLE exhibit poorer executive function performance compared to children with TLE [51,57], this finding only indicates that the manifestations of ED are less pronounced in children with TLE. Patients with FLE would be expected to evidence more severe ED as the prefrontal cortex has a primary role in executive functioning [58]. But although ED is a core cognitive symptom in patients with FLE, children with TLE manifest a less specific but more widespread pattern of ED [50]. Other studies report no significant differences in executive functioning between children with TLE and healthy controls [22]. However, their study samples included few patients with hippocampal atrophy. As the hippocampus has a pivotal role in executive function [3], such an omission could lead to significant bias. Moreover, in these studies, executive functions were only assessed through tasks of sustained attention and mental tracking. The first study investigating ED in children and adolescents with TLE [52] employed a single cognitive task – the Wisconsin Card Sorting Test (WCST) – showing that children and adolescents with MTS–TLE had poorer performance in a subdomain of executive functions compared to patients with other TLE etiologies, patients with FLE, and healthy volunteers. The WCST assesses abstract reasoning and the ability to shift cognitive strategies in response to environmental changes. It also provides objective measures of overall ability and specific sources of difficulty —e.g., inefficient initial conceptualization, perseveration, failure to maintain set, and inefficient learning [59]. However, other domains of executive functioning including inhibitory control, planning, working memory, and mental tracking were not investigated. Abnormal domains of executive functions recently documented in early-onset TLE include focused attention [19,46,53–56], alternating attention [19,53–56], selective attention [54–56], concept formation and abstraction [19,44,46,52,54–56], working memory [45], and mental tracking of information [19,46,53–56]. Rzezak and collaborators [56] further proposed that all executive function subdomains in children with TLE are not impaired equally and emphasized the importance of a comprehensive battery for studying complex cognitive functions. By carefully assessing different aspects of executive functioning in children and adolescents with TLE, certain subdomains are now recognized to be more impaired.

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Using an even broader evaluation of executive function examining highly selective aspects of attentional processing, concept formation and abstraction, and mental tracking, Rzezak and colleagues [56] showed that the incidence of ED in children and adolescents with TLE is increased from 77.14% to 94.29%. Thus, evaluations utilizing the WCST alone are unlikely to provide a valid estimate of the incidence of ED. 4. Mesial temporal sclerosis: does etiology matter? The definitive characterization of TLE during infancy and early childhood is challenging because of the high frequency of developmental etiologies that are extensive and therefore unlikely to be limited to one lobe [60]. A high incidence of developmental pathologies and benign tumors is reported in all series of patients with severe epilepsy in early life [60–62]. The most frequent etiologies of TLE in most series are cortical dysplasia and low-grade tumors represented by dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma. Temporal lobe epilepsy–mesial temporal sclerosis is frequently described in surgical series of older children with TLE [63,64] and rarely occurs in isolation in early life [60,62,64,65]. 4.1. Memory functions As already mentioned, the hippocampus plays an essential role in the consolidation of new memories and is integral to long-term episodic memory functioning. There is now a large body of evidence showing that children and adolescents who present with MTS–TLE already evidence impaired verbal and nonverbal memory performance [11]. Episodic memory deficits are also found in children and adolescents with TLE caused by other etiologies including tumors, cysts, and cortical dysplasia [15,16,19–21]. However, while mesial temporal lesions are not the only cause of episodic memory dysfunction, they are overrepresented in children and adolescents with mesial temporal pathology. Cormack and colleagues [26] compared episodic memory performance of children with MTS–TLE and DNETs (lateral temporal lesions) and documented poorer memory performance in the group with MTS–TLE. Semantic memory impairments in TLE are related to a lack of integrity of lateral temporal structures [66–69]. However, the lateral temporal neocortex may function exclusively as a node within a more complex memory network as semantic performance has been linked to hippocampal integrity in adults [70,71]. Davies and colleagues [71] observed significant naming deficits in patients with hippocampal sclerosis indicating that the hippocampus and its connections are important for retrieving names from the lexicon held in cortical areas. Two studies investigated the contribution of mesial temporal structures to semantic memory in children [11,26]. Both found that similar to adults, children with mesial temporal lesions evidenced semantic memory impairment. Moreover, poor episodic/semantic memory contributed to deficient semantic memory performance in children [26]. As superior performance on the Verbal Paired Associates Test could be related to either episodic or semantic memory systems, future studies comparing children with MTS–TLE to children with other etiologies must utilize highly specific tests of semantic memory. 4.2. Executive functions Children with symptomatic TLE have deficient executive function compared to healthy volunteers [55]. Thus, both mesial and lateral temporal lesions can affect cognitive competence and implicate more widespread neural network disturbances. However, patients with hippocampal atrophy are still more impaired than those with other etiologies [52], unless the lesion involves other mesial temporal structures. Unfortunately, it is difficult to fully explore this issue in detail as small sample sizes reduce statistical power.

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An important unresolved question is whether single or dual temporal lobe pathology differentially impairs executive functioning. To answer this question, Bigel and Smith [44] administered the WCST to patients aged 6 to 18 years with TLE due to single or dual pathologies. Although dual pathology was hypothesized to cause greater cognitive dysfunction, no differences were noted. This outcome suggests that the absolute number of lesions is not critical for ED. Performance on executive function tests of children and adolescents with TLE has been compared to children with idiopathic generalized epilepsy and benign childhood epilepsy with centrotemporal spikes [47], generalized epilepsy with absence seizures [48,49], and FLE [48–51]. These comparisons revealed greater attentional deficits in children and adolescents with TLE compared to all groups except the group with FLE [47–49]. The collected evidence therefore confirms that seizure etiology is an important determinant of cognitive functioning and that the temporal lobes play a critical role in executive and memory functions (episodic and semantic). However, pathological substrate is also important as children with MTS–TLE exhibit poorer performance than children with TLE caused by other etiologies. 5. Right versus left: are impairments lateralized? Adults with left hippocampal lesions show verbal episodic memory decline [72–74], whereas right-sided lesions are associated with impaired visual episodic memory [75,76]. The relationship between laterality of hippocampal pathology and memory deficit is greater in patients with left TLE (verbal memory deficit) than those with right TLE [73,77]. The relationship between laterality and cognitive impairment is known as a “material-specific memory deficit”. A similar relationship between memory deficit and lateralization of seizure onset in childhood is less clear. Three separate investigations produced conflicting results revealing either a significant relation between verbal memory deficit in left TLE and visual memory deficit in right TLE [15,78], visual memory impairment only in right TLE [44], or no relationship between laterality and memory impairment [11,19,79–81]. The absence of a clearly definable pattern of material-specific memory deficits in childhood may be related to the effects of epileptogenic activity in early life which disrupt the development of memory system lateralization [79]. With regard to temporal lobe surgery, material-specific semantic memory deficits involving the classification of figures and names are recognized in adults after left temporal lobectomy [82]. However, nonoperated patients with left TLE also evidence impaired verbal recall, semantic cues and verbal production of categories [83], picture naming and semantic judgment [29], and semantic knowledge [28]. Patients with right TLE may also show impaired semantic memory compared with healthy adults [69,70]. Children with left MTS–TLE exhibit poorer naming ability compared to children with right MTS–TLE [11]. However, both groups show similar performance for other semantic memory abilities such as word definition and sentence repetition. A comparison of children with left and right TLE revealed no difference in semantic memory, word definition, or object naming [16]. The comparative impact of right and left TLE on executive functioning has received relatively less attention. There is presently no documentation that right temporal lobe epilepsy is detrimental to executive functions in children [44,45]. 6. TLE as an evolutionary disorder Developmental cognitive processes emerge from interactions between neural preorganization and environmental constraints, anticipated and selected by the neural organization. The resulting new neural organization interacts, in turn, with new features of the environment. In children, the situation might be more complex [84].

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An early epileptogenic process occurring during a phase of maximal brain plasticity may result in the development of a complex and extended epileptic network. Consequently, the epileptic activity might become a factor in development, in a similar sense to the way that normal activity generated by the brain itself and by the environment are factors of cognitive development. The pathological epileptic process interferes with normal cerebral development. Neural plasticity is greater than it is in adults (e.g., production of growth factors is more important). Greater plasticity, however, does not mean adaptive plasticity. Because fewer networks are functionally specialized in infants and young children, the constraints between networks are weaker so that abnormal interactions between networks are more likely [85]. Hermann et al. [86,87] suggest that structural damage to the brain associated with temporal epilepsy differs, according to whether the first seizures occurred in adulthood or in childhood. Onset during childhood has a more widespread structural effect on the brain than onset during adulthood. According to Hermann et al. [87], there is a volumetric reduction of white matter in the whole brain and the corpus callosum [86], which is greater in individuals with early rather than with late epilepsy onset. In individuals with early-onset epilepsy, the white matter volumetric reductions were found to be significantly associated with lower cognitive performances in some, but not all, cognitive domains [86,87]. Epilepsy duration rather than chronological age or age at epilepsy onset is now recognized as a major determining factor in the interindividual IQ variability in adult patients with TLE. Epilepsy duration exceeding two decades is associated with poorer cognitive abilities suggesting that refractory TLE induces a slow but progressive intellectual decline. Epilepsy-related adverse events and chronic antiepileptic medications presumably further exhaust the compensatory capacity of brain networks to adapt to recurrent epileptogenicity. However, a higher baseline cognitive reserve can delay the of clinically-apparent [88]. Hippocampal dysfunction may also be important, as hippocampal neuronal density, hippocampal volume, and glucose metabolism are reduced in patients with chronic temporal lobe seizures [89–92]. Helmstaedter and collaborators [93] performed longitudinal neuropsychological assessments in a large cohort of medically and surgically treated adult patients with chronic TLE and found that 50% of medically treated and 60% of surgically-treated patients showed a significant decline in memory function. Surgically induced seizure-free patients recovered memory function, whereas those with seizure persistence did not. Memory outcome was better in patients with higher baseline performance. The relationship between epilepsy duration and baseline cognitive functioning is more complex when epilepsy begins in childhood. In a retrospective study of 382 adult patients with TLE divided into three age cohorts, there were no differences in neuropsychological performance among cohorts and no specific intercohort differences in IQ, memory, or language competence [94]. Although epilepsy duration is an important determinant of cognitive function in adults, the cognitive profile of adults with childhood-onset TLE was established in childhood and remained stable over the adult lifespan. High-resolution MR imaging studies have confirmed this process by revealing reduced brain tissue volumes particularly affecting the white matter in children with diminished cognition [87]. 7. Early surgical intervention: does cognitive impairment improve after excisional procedures? Resective surgery is increasingly advocated for children with medically intractable temporal lobe epilepsy (TLE) [14,62,65]. Satisfactory seizure control is obtained in approximately 60–80% of cases [14,63,65], but most surgical candidates are older than age 12 years. In contrast, cases operated before age 5 years are rare [60,61,65,95], and a majority of the surgical procedures consist of extratemporal and multilobar resections and hemispherectomy [60,61,65,95].

Surgical outcome studies in children provide little information about specific memory functions before and after surgery [20]. Most surgical series include patients with heterogeneous etiologies including developmental tumors and dysplasias, whereas MTS–TLE is less common in childhood. Therefore, a higher proportion of pediatric procedures consist of individually tailored neocortical resections rather than standard procedures such as anterior temporal lobectomy or amygdalohippocampectomy. In a series of 22 children comparing temporal and extratemporal lobe epilepsy, Sherman and colleagues [96] identified four children in the surgical sample who had significantly higher-than-expected postsurgical IQ scores. Significant postoperative changes in memory were also observed in 9 of 20 children undergoing temporal lobectomy [22] —five improved and four deteriorated. Improvements occurred predominantly in visual memory and verbal learning, whereas deterioration occurred across all memory tests except verbal learning. Of note, no patients who deteriorated were seizure-free after surgery, whereas most children who improved or remained unchanged were seizure-free. Jambaque and colleagues [20] assessed 20 children undergoing temporal lobectomy and found that poor memory performance before surgery often improved one year postresection. Surgery significantly improved attention and working memory scores, immediate verbal episodic memory tests, and naming tests performance. Attention improved for both concentration and reaction time. Cognitive functioning does not improve uniformly after surgery, and patients with an earlier age at seizure onset and nonseizurefree status may remain unchanged or even deteriorate over time. It is now recognized that only successful surgical treatment improves cognitive prognosis and facilitates school performance in children with unilateral TLE [20]. In a large prospective study of intellectually normal children ages 6 to 14 years (mean IQ ≥ 70), Fastenau and colleagues [97] administered neuropsychological and academic achievement tests after a first recognized seizure and identified cognitive deficits in attention, executive function, memory, and language. However, school performance was unaffected, suggesting that there may be a window for timely treatment early in the disorder. Considering these data, the current approach towards children with epilepsy emphasizing treatment beyond pure seizure elimination seems not only valid but also mandatory.

8. Conclusions Children with TLE are a unique population in which to study memory impairment as the impact of lesion and epileptogenic activity can be investigated in the absence of long-lasting epilepsy or drug exposure. It is known that similar to adults, children with TLE present prominent episodic memory deficits. The few studies that investigated semantic memory showed that this population also have evidence of impairment in this memory domain. Mesial and lateral temporal lesions can affect cognitive competence and implicate more widespread neural network disturbances. Therefore, it seems reasonable that children with symptomatic TLE have deficient executive function. However, there are some gaps in our knowledge because of small sample sizes and heterogeneous groups regarding etiology and lesion location —mesial and lateral. There is insufficient evidence for episodic and semantic memory indicating material-specific deficits as documented for dominant hemisphere and verbal memory in adults. Future studies addressing this aspect and other memory types, such as implicit and prospective memory, would be of interest. In addition, several aspects of executive functions remain unknown, such as decision-making abilities and impulse control. Although cognitive domains in children with TLE need a better understanding with a more refined approach, the importance of early epilepsy surgery remains undeniable in order to improve cognitive prognosis and provide better quality of life.

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Acknowledgments This work was supported by a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the State of São Paulo; grant nos. 12/09025-3 and 13/11361-4), as well as by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; grant no. 307262/2011-1). Conflict of interest We state that there are no conflicts of interest.

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