Cognitive function is defined as the ability to deal meaningfully with information from the surrounding world. It includes mental activities associated with thinking, learning, and memory. It is a mental process of acquiring knowledge including aspects like awareness, perception, reasoning, and judgment . Patients with epilepsy are at an increased risk for cognitive deficits. Memory difficulty is the most frequent subjective complaint in patients with epilepsy and is also identified by objective measures. The vulnerable neuropsychologically affected areas are attention, short-term memory, and cognitive information processing . In addition, the changes in EEG peak frequency observed in quantitative occipital EEG are correlated with subjective cognitive complaints . Also, the P300 component of event-related potential (ERP) is impaired in patients with epilepsy and correlates with the degree of cognitive impairment encountered in neuropsychological testing . P300 is considered as a “cognitive” neuroelectrical phenomenon because it is generated in psychological tasks when subjects attend and discriminate stimuli that differ from one another on some dimensions. P300 is an objective, noninvasive, and clinically relevant method for evaluation of mental processing. P300 latency increases as the dementia symptoms increase, whereas P300 amplitude is depressed in all levels of dementia . The hippocampus, thalamus, and frontal cortex are the possible locations of the P300 generators, the structures important for learning and memory.
The cognitive aspects of epilepsy will be discussed within the context of (1) its relation to invariant and dynamic variables, (2) the pathophysiologic mechanisms underlying cognitive impairment in epilepsy, and (3) The vulnerability of immature brain to the cognitive adverse consequences of epilepsy.
Relationship of Cognition to Invariant and Dynamic Variables in Epilepsy
Determining the frequency of cognitive dysfunction due to epilepsy is difficult to estimate. Community-based studies reported that approximately 26.4–30.0% of children with epilepsy when first diagnosed have evidence of subnormal global cognitive function or mental retardation with inferior academic achievement . Problems in attention and memory are observed in about 30% of newly diagnosed and untreated epileptic patients with single or several seizures of cryptogenic origin .
Cognitive issues in epilepsy are associated with a number of invariant and dynamic factors. The invariant variables include genetics, basic brain lesion , type of epilepsy , site and side of brain lesion [15,18,37,38], etiology of epilepsy , and age at onset [16,30,39,40], together with the duration of epilepsy . The dynamic variables include uncontrolled seizures in epileptic mother , seizure frequency and severity , ictal as well as interictal transient focal or long-lasting electroencephalographic (EEG) epileptic discharges [19,20], adverse effects from antiepileptic medications , and psychosocial variables [23,24]. In some patients with epilepsy, many of these factors are intercorrelated and independently contributed, making it difficult to clearly delineate the relative contribution of any given factor (e.g., cognitive deficits in epilepsy occur regardless of patients' age, type, and duration of epilepsy or associated diseases).
The limited studies suggest that the offspring of mothers with epilepsy may have an increased risk of problems including prematurity, low birth weight, brain malformation, dysmorphic features, and cognitive deficits [42,43]. Hereditary predisposition to abnormal brain activity has been accounted for 30–50% of phenotypic IQ variance of children born to mothers with epilepsy [44,45]. Koch et al.  found abnormal spike activity in children born to mothers with epilepsy. The case reports clearly documented that maternal prolonged seizures and status epilepticus (SE) are serious hazards for both the mother and the fetus; however, the results of cohort studies, in which mainly mothers with generalized tonic–clonic seizures (GTCS) were included, were controversial [46,47]. Adab et al.  in their retrospective study found that verbal IQ in children of women with epilepsy was greatly affected by the number of seizures experienced during pregnancy, with significant reduction in IQ being observed in children (17% of all) who were exposed to more than four GTCS. Uncontrolled maternal GTCS increase the risk of fetal perinatal anoxia, placental abruption, premature labor, intracranial hemorrhage, or even death. These risks are high if seizures progress to SE. In addition, the offspring of mothers of epilepsy are exposed to teratogenicity from AEDs  and the adverse socio-familial conditions associated with having a chronically ill mother .
Cognitive and behavioral functioning in patients with epilepsy is an important area in various age groups. The earlier studies reported that seizure onset before the age of 14 years is a risk factor for cognitive decline. In controlled studies, significant neuropsychological impairment has been demonstrated in children and adolescents with chronic epilepsy . However, recent studies indicated that negative effect on cognition, even progressive cognitive deterioration, might occur in older adults with chronic partial or generalized seizure disorders. In some studies, adults with epilepsy and prior to treatment with AED exhibited poor performance on some cognitive tasks, especially tests of visual motor tasks, motor coordination, mental flexibility, and memory [40,49]. Epilepsy could possibly accelerate common age-associated changes, leading to uncertain and understudied outcome in old age .
Some studies found greater cognitive problems in patients with generalized seizures than in patients with partial seizures ; others found it vice versa. Complaints of memory difficulties are common among patients with temporal lobe epilepsy (TLE), where memory-related brain structures are directly involved in seizure activity. TLE is associated with more memory impairments than extratemporal epilepsies, and both have more memory impairments than those associated with generalized epilepsy [38,52]. Frontal lobe epilepsy is associated with performance deficits in executive functioning . However, most recent case–control and longitudinal studies revealed that patients with generalized as well as localization-related epilepsies may develop poor performance on tests of memory function, as well as on measures of intelligence, language, and executive functions, suggesting that cognitive dysfunction is not limited to limbic-related tasks presented in the hippocampus, amygdala, or piriform cortex but extends to involve diverse brain areas [54–56].
The nature and localization of epilepsy are also important determinants of the extent and nature of cognitive deficits. Patients with secondarily generalized seizures showed greater impairment in concentration and mental flexibility than patients with complex partial seizures . Problems of delayed recall of words were observed in newly diagnosed patients with partial seizures prior to medication . TLE is associated with cognitive decline in confrontational naming, visual memory, verbal memory, and motor speed . TLE affects declarative memory systems (i.e., episodic memory including contextual, autobiographic information, and semantic memory including abstract knowledge) , whereas nondeclarative learning (e.g., procedural learning) appears more or less unaffected. Episodic memory relies on hippocampal functioning . Semantic performance is definitely linked to speech-dominant hemisphere because it is expressed by speech-associated tasks (e.g., semantic fluency, naming, and vocabulary). Verbal-oriented problems are specifically involved in left-sided epileptogenic foci. Left TLE especially impairs verbal episodic memory (e.g., word list learning), long-term verbal associations, learning of semantically related verbal information, speed of learning, and delayed memory, with deficits in consolidation of verbal information . Visuoconstructive memory dysfunction has been found in patients with right TLE . Silva et al.  found that epileptic patients with mesial temporal injuries had a low cognitive performance in attentional span, memory, speech, and daily problems resolution, whereas patients without injury showed a more compensated cognitive performance, except mild attentional alterations.
Some cross-sectional cohort studies reported association of cognitive deficits with smaller hippocampal volume in TLE . Hippocampal volume reduction has been linked with the longer duration of epilepsy and is considered a marker as well as a predictor of cognitive decline in patients with epilepsy. However, recent quantitative magnetic resonance imaging (MRI) volumetric studies confirmed the presence of volumetric abnormalities in both temporal and extratemporal regions, consistent with the generalized cognitive compromise associated with early-onset localization-related epilepsy syndromes such as TLE. The abnormalities were identified in amygdale, fornix, entorhinal cortex, parahippocampus , thalamus and basal ganglia , cerebellum , and whole brain volumes . Hermann et al.  reported reduction in total cerebral white matter volume, increased total CSF, and reduced gray matter volume, both ipsilateral and contralateral to the side of temporal seizure onset. In a prospective study done by Liu et al. , a longitudinal follow-up study of 122 patients with chronic epilepsy, in which serial MRI scans were obtained 3.5 years apart, new focal or generalized neocortical volume loses were identified in 54% of patients with chronic epilepsy and 39% of newly diagnosed patients. Seidenberg et al.  reported bilateral thalamic volume reduction in chronic unilateral TLE. Thalamic atrophy was significantly correlated with performance in memory and non-memory cognitive domains. Rzezak et al.  found frontal lobe dysfunction in children with TLE, with worse performance in those with mesial TLE, early onset, longer duration of disease, and use of polytherapy. The authors suggested that temporal lobe epileptogenic activity affects the extratemporal regions that mediate attentional and executive functions. Guimarães et al.  did a comprehensive neuropsychological assessment in a population of children with TLE including IQ, forward digit, Trail-Making Test For Children part B, Wisconsin Card Sorting Test, block design, Boston naming test, verbal fluency, and Wide Range Assessment of Memory and Learning, including visual learning, verbal memory, visual memory, delayed recall of verbal learning, delayed recall of stories, and recognition of stories. The authors found that TLE presented with several neuropsychological deficits, despite normal IQ. The authors concluded that dysfunction of cerebral areas other than temporal lobe, particularly the frontal lobes, might be present in TLE. In support, generalized reduction of cerebral volume has also been observed in children with mixed seizures, as well as focal temporal and frontal lobe epilepsy, which are proportionately associated with delayed neurodevelopment . The extensive networks and interconnections between cortical regions are considered a contributing factor for the demonstrated widespread and remote cerebral atrophy from the putative epileptic focus. Functional MRI studies revealed that retrieval from working memory is associated with activation of dorsolateral frontal cortex. Other cortical and thalamic brain areas are also activated including the anterior cingulate cortex, which is associated with executive function, and the posterior parietal cortex, which is associated with attention . The results of volumetric quantitative MRI studies are in accordance with generalized reduction in neurospsychological function including intelligence, language, visuoperception, memory, and executive function in the same group of the studied patients .
Cross-sectional and longitudinal studies of cognitive change in epilepsy suggest that a longer duration of epilepsy is associated with decline in many areas of cognition . Cognitive impairments are more prevalent in symptomatic and cryptogenic compared with idiopathic epilepsy .
Mood state in epileptic patients may be an additional factor that negatively affects cognitive functions. Epileptic patients who are depressed may suffer a double burden of cognitive deficits . Seizures occurring at school or work can result in poor self-perception and reduced social interaction. Stigma resulting from epilepsy and learning problems may lower the parental and teacher expectations. Decreased expectations can negatively affect the academic effort and consequently the performance. Scholastic underachievement, intellectual impairment, lower educational levels, and potential mental retardation are the long-term consequences in children with epilepsy, whereas low functional status, less educational levels, low rates of employment, and poor quality of life (QOL) are the long-term consequences in adults with epilepsy [23,24].
The Pathophysiologic Mechanisms Underlying Cognitive Impairment in Epilepsy
The mechanism of cognitive impairment in epilepsy is complex. Negative effects on cognition may occur in the presence or absence of clinically manifest seizures, convulsive or nonconvulsive SE that occur during awakening or during sleep, and may occur due to focal or generalized EEG epileptic discharges without epileptic symptomatology . Cognitive deficits associated with epilepsy and EEG epileptic discharges may be transient [66,67], persistent , or progressive [6,69].
The underlying pathophysiologic mechanisms of cognitive dysfunction due to epilepsy itself will be discussed under the following topics: (1) cognitive impairment with ictal or clinically manifest EEG paroxysms, (2) cognitive impairment with brief interictal or subclinical EEG paroxysms, (3) cognitive impairment with long-lasting EEG activity, and (4) progressive cognitive deterioration in epilepsy.
Cognitive Impairment with Ictal or Clinically Manifest EEG Paroxysms
Three interrelated forms of memory impairment have been recently described in association with manifest seizures : (1) transient epileptic amnesia, in which the main manifestation of seizures is recurrent episodes of amnesia; (2) accelerated long-term forgetting, in which newly acquired memories fade over days to weeks, and (3) remote memory impairment, in which there is loss of memories for personal or public facts or events from the distant past. Accelerated long-term forgetting and remote memory impairment are common with transient epileptic amnesia in patients with TLE, but have also been reported in other forms of epilepsy.
With manifest epilepsy and during paroxysmal epileptic activity, transient disruption of cognitive processing has been attributed to the following: (1) the involvement of a neuronal circuitry in epileptic spiking, rendering the same neurons unavailable for normal physiological processes, (2) antidromic corticothtalmic backfiring, which would collide and annihilate any incoming information through orthodromic thalamocortical pathways, and (3) prolonged membrane hyperpolarization following paroxysmal depolarization shift mediated by recurrent postsynaptic inhibitory mechanisms that elelctrophysiologically correspond to the after-coming slow wave [33,70]. The presence of slow EEG activity in the same regions showing abundant spike wave has been interpreted as reflecting increased cortical inhibition mediated by hypersynchronous GABAergic inhibitory postsynaptic potentials. This increment of cortical inhibition might temporarily alter normal physiological processing of cognitive disruptions . High seizure frequency disrupts the first encoding state of the memory process and specifically disrupts attention, concentration, and working memory. However, in individual cognitive performance, even single seizures can generate long-term attentional slowing in the post-ictal period, which exists for at least 24 hours. A singleGTCS may have a lasting negative effect on attention for about 30 days .
Cognitive Impairment with Brief Interictal Subclinical EEG Paroxysms
The phenomenon of association between transient cognitive deficits and transient EEG epileptiform (generalized or focal) discharges that are not accompanied by obvious clinical events is defined as a state of transient cognitive impairment (TCI) . It is found in about 50% of patients and is regarded as subclinical or interictal . These brief subclinical EEG paroxysms or TCI may cause deficits that usually pass unrecognized by standard memory tests; however, sensitive methods of observation, such as continuous psychological testing, commonly show brief episodes of impaired cognitive function during such discharges. TCI was first demonstrated during 3 cycles/second generalized spike-and-wave discharges . Sirén et al.  found that the duration of generalized 3-Hz spike-wave discharges and the clinical absence of seizures were negatively correlated with the performance on the visual memory tasks. TCI was also demonstrated in many cases of benign childhood epilepsy with centrotemporal spikes, a disorder once thought to have no adverse psychological effects . TCI is not simple inattention. The effects of TCI are material and site specific, that is, lateralized discharges are associated with deficits of functions mediated by the hemisphere in which the discharges occur (e.g., left-sided focal spiking frequently produces errors in verbal tasks, whereas right-sided discharges are often accompanied by impairment in handling nonverbal material). Conversely, specific tasks can activate or suppress focal discharges over the brain regions that mediate the cognitive activity in question. In patients with benign childhood epilepsy with centrotemporal spikes, deficits in IQ were found to be significantly correlated with the frequency of EEG spikes but not with the frequency of seizures . Autistic features observed in come children with epilepsy have been suggested as a consequence of apparently subclinical spikes interfering with specific cerebral processes .
The studies pointed out that TCI may contribute to abnormalities in psychological test profiles that adversely affect the patient's psychosocial functioning in daily life such as educational skill, learning tasks, disorders of attention, behavior, sleep disruption, and motor dysfunction . An important practical issue is to determine whether patients with TCI have impaired psychosocial function, and if so, whether drug treatment is desirable or effective. Together with our personal experience in the field, uncontrolled reports and some preliminary randomized controlled trials of antiepileptic treatment of TCI have suggested that suppression of discharges by AEDs is associated with significant improvement in psychosocial function .
Cognitive Impairment with Long-Lasting EEG Activity
Recently, the mechanism of cognitive impairment of some specific epileptic syndromes with continuous spikes and waves during sleep (CSWS) has been explored . Landau–Kleffner syndrome (LKS) and the syndrome of CSWS represent a spectrum of epileptic conditions that share many common features including: (1) onset during childhood, (2) deterioration of cognitive functions that were normally acquired in the past, (3) continuous spike-and-wave discharges during slow wave sleep, (4) pharmacological reactivity, (5) regression of the neuropsychological symptoms when the EEG abnormalities improves (spontaneously or after drugs such as corticosteroids), and (6) the absence of obvious structural lesion detected by CT or MRI scan [76,77]. The cognitive deficits of children with CSWS are long lasting, present for months or years, and complete recovery is unusual. The pathophysiology of cognitive deficits CSWS and LKF is complex and different from that described with TCI as some patients with CSWS or LKS may have a completely normal awake EEG, whereas cognitive deficits are present in the awake state when interictal epileptiform discharges are rare or absent. Recently, positron emission tomography (PET) studies using [18F]-fluorodeoxyglucose (FDG) during acute and recovery phases of CSWS in a group of children with epilepsy showed that increased glucose metabolism at the epileptic focus was associated with hypometabolism in distant connected areas and both hypermetabolism and hypometabolism resolved at the recovery phase of CSWS [78,79]. An altered effective connectivity between focal hypermetabolism (centro-parietal regions and right fusiform gyrus) and widespread hypometabolism (prefrontal and orbitofrontal cortices, temporal lobes, left parietal cortex, precuneus, and cerebellum) was found at the acute phase of CSWS, and it markedly regressed at recovery, whether spontaneously or with corticosteroids . The parietofrontal altered connectivity observed in patients with hypermetabolism is interpreted as a phenomenon of remote inhibition of the frontal lobes induced by highly epileptogenic and hypermetabolic posterior cortex .
Progressive Cognitive Deterioration in Epilepsy
Many animal and human studies reported progressive cognitive decline and behavioral impairment in developing and mature brains with epilepsy [6,39,69,80]. Persistent and progressive cognitive dysfunctions are the result of progressive structural brain damage as a long-term consequence of uncontrolled epilepsy, for example, hippocampal sclerosis in complex partial and generalized epilepsy [39,69]. In TLE, a specific stereotypical pattern of pathology occurs in the hippocampus, amygdale, entorhinal region, piriform cortex, and mesdiodorsal thalamus, the areas primarily involved in memory processing. In complex partial and generalized epilepsy, a characteristic pattern of hippocampal sclerosis occurs . Loss of neural density in the left mesial temporal regions (i.e., CA3 of the hippocampus) and right hippocampal structures can explain the verbal and nonverbal memory impairments in patients with epilepsy . The progressive damaging effect of epilepsy is also confirmed by neuroimaging follow-up studies. A growing number of multiparametric MRI follow-up and prospective longitudinal imaging studies in TLE indicate that progressive atrophy after the first SE evolves over a prolonged period of time, weeks, months, or even years, in the hippocampus, amygdala, thalamus, and piriform cortex . Using quantitative MRI, Briellmann et al.  reported a hippocampal volume loss by almost 10% in 24 patients with mild TLE studied over a period of 3.5 years. Fuerst et al.  reported hippocampal volume loss in 12 patients with intractable TLE studied over 3.5 years. Liu et al.  reported progressive cortical volume loss in patients with neocortical epilepsy. Repeated seizures in kindling models of limbic epilepsy induce a sequence of complex activity-dependent neurodegenerative changes including neuronal synchronization, abnormal neuronal plasticity, sprouting, gliosis, and delayed hippocampal neurodegeneration. This type of neuronal plasticity or persistent epileptogenesis may then contribute to the appearance of adverse cumulative neurological deficits involving learning, memory, emotional, and behavioral changes as the number of seizures increases . Animal studies have shown that behavioral changes are in parallel to the changes in brain connectivity, dendritic morphology, excitatory and inhibitory receptor subunits, ion channels, and neurogenesis. Human neuropsychological studies indicate that hippocampal N-methyl-D-aspartate (NMDA) receptors are necessary for mediating repetition/recognition effects of limbic ERPs to continuous word recognition paradigms as well as for intact verbal memory performance . These changes occur even in the absence of overt cell loss. Recent studies revealed that abnormalities in intracellular functions of specific neurons occur after exposure to multiple seizures . Unfortunately, the current AEDs are unable to prevent progressive brain damage due to epileptogenesis.
The Vulnerability of Immature Brain to the Cognitive Adverse Consequences of Epilepsy
Normally, biological development and organization of the brain in human are very rapid in utero and start to slow down in the second year of postnatal life . Although the gross organization is nearly complete by 2 or 3 years of age, maturation may continue through adolescence and beyond . The period of infancy is characterized by peak hippocampal and cortical regional development, as well as myelinogenesis, dendritogenesis, and synaptogenesis in the brain, and changes in these processes underlie the deficits in spatial learning and memory processes . Many of the human studies on cognition and behavior have focused on infants, preschool, and school-age children. There is a developmental component to the relation between poor seizure control and mental performance. The presence of epilepsy and its treatment during a period of maximal white-matter growth could affect the development of white matter. The studies examined the effects of electroconvulsion-induced seizures in rats at various developmental stages that revealed that seizures in early development selectively impaired myelin accumulation in proportion to their effect on brain growth . It was found that some myelin specific lipids (such as cerebroside and proteolipid protein) were reduced by about 11–13% in immature epileptic rats . Executive functions, mainly under frontal lobe control, seem to be particularly vulnerable to epileptic EEG activity during the period of maturation; their disruption possibly interferes with the normal development of learning processes . Adults rats experiencing kainic acid (KA)-induced seizures on specific days during early postnatal development revealed the presence of a long-term loss of hippocampal plasticity, as manifested by a reduced capacity in long-term potentiation (LTP), which has been suggested to underlie memory formation, reduced susceptibility to kindling, and impaired special learning. Seizure activity incrementally causes an indiscriminate and widespread induction of LTP, consuming and reducing the overall hippocampal plasticity available for information processing .