Premotor: The larger area of frontal tissue anterior to the motor strip that acts as motor association cortex including supplementary motor area (medial BA 6), supplementary eye fields (BA 6), and parts of Broca’s area (BA 44).

Prefrontal: The vast prefrontal regions may be further subdivided into the following three topographically segregated groups (4): (i) dorsolateral cortex (BA 46 and rostromedial BA 9), (ii) most of orbitofrontal cortex (BA 11 and rostral BA 12), and (iii) paralimbic zones (the ventral and medial part of the frontal lobe including the anterior cingulate cortex (BA 23, 32), the paraolfactory gyrus (BA25), and posterior orbitofrontal regions (BA 11–13).

Clinicians typically refer to prefrontal cortex lesions as the cause of "frontal lobe syndromes." Of great significance in discussion of the neural basis of prefrontal cognitive and behavioral functions are the connectivity patterns of frontal cortex with other brain areas. Information comes to prefrontal structures via reciprocal connections with unimodal association cortex of all sensory modalities and the posterior heteromodal association cortices through three major white matter bundles: superior and inferior occipitofrontal fasciculi and the superior longitudinal fasciculus (5). The prefrontal lobes also have connections with three limbic systems (6): (1) corticolimbic regions (including subiculum, entorhinal area, and parahippocampal structures); (2) subcortical limbic regions (such as thalamic and hypothalamic nuclei); and (3) visceral-endocrine peripheral nervous system (via a series of ill-defined pathways in spinal cord and lower brain stem). Nauta (7) stressed that the prefrontal cortex is the only area in the nervous system that receives and integrates information from both the somatosensory and the limbic-sensory systems, a factor of tantalizing significance in the study of the influence of epilepsy on cognition and behavior.

Few subjects have proven as elusive and fascinating as the behavioral and cognitive consequences of injury to prefrontal cortex. The recognized personality changes following frontal lobe lesions are of two main types (8). In one type, that of being "disinhibited," harkening back to the classic case of Phineas Gage, the patient displays dramatic impulsivity, loss of judgment, an inability to foresee the consequences of one’s actions, increased motor activity, and a puerile, jocular affect. In a second type, best described as "abulic," the patient shows apathy, lethargy, emotional blunting, little sexual interest, loss of initiative, and poor planning. Clinical experience has suggested that the "dis-

inhibited" profile is more commonly associated with lesions in orbitofrontal and medial frontal areas (those containing paralimbic cortex), and the "abulic" profile is more likely associated with dorsolateral frontal lesions. In both situations, the dissociation between relatively intact cognitive function and impaired comportment can be striking.

The neuropsychology of the frontal lobes in health and disease is adequately reviewed in many texts (1–3, 6, 8). The emphasis of most recent reviews of frontal lobe neuropsychology has been placed on the concept of working memory, the attentional system that enables mental manipulation of information held "on line" for brief periods (9). The system has been divided into two general components: short-term storage and a set of "executive processes." Prefrontal cortex largely mediates both components. Short-term storage involves active maintenance of a limited amount of information for a matter of seconds. Executive processes are postulated to operate on the contents of working memory. Used now as an umbrella term for a diversity of functions, executive processes include (i) focusing attention on relevant information and inhibiting irrelevant information, (ii) switching focused attention between tasks, (iii) planning a sequence of subtasks to accomplish a goal, (iv) monitoring and updating the contents of working memory to determine the next step in a sequential task, and (v) coding representations in working memory for time and place of appearance. Tests commonly used as indicators of frontal network integrity include: digit span, the Wisconsin Card Sorting Test (WCST), verbal fluency, Trails A and B, Stroop, and sequencing tasks like the Tower of London.

FACTORS RELATED TO COGNITIVE
AND BEHAVIORAL DISORDERS
IN EPILEPSY

The study of cognitive and behavioral comorbidity in epilepsy is inherently complicated by the many known and suspected risk factors that can influence the observed clinical manifestations. Much effort has been expended to organize the risk factors into a conceptual framework such that an isolated variable, i.e., frontal lobe function, might be assessed in a methodologically rigorous fashion. Hermann and colleagues (10, 11) have proposed three broad potentially interactive categories to organize the multiplicity of risk factors: (1) neurobiological factors, including the neuropathology/ etiology of the epileptogenic region, sei-

zure variables including focus, type, age of onset, laterality of onset, duration of epilepsy, seizure control, and interictal epileptiform activity; (2) psychosocial factors, including chronic illness-related, epilepsyspecific issues, developmental, and demographic; and (3) iatrogenic, including specific medication effects, mono- or polytherapy, alterations in brain neurotransmitter concentrations, and metabolic effects.

Neuropsychology. General Intelligence Measures

Allowing for numerous methodological constraints, several generalizations about cognitive function in epilepsy appear consistent in the literature. Patients with well-controlled epilepsy rarely demonstrate significant impairment in general intellectual functioning as assessed by IQ tests (12–14). However, numerous studies have confirmed greater cognitive impairments (as assessed by IQ testing) in patients with generalized (especially secondarily generalized) versus partial seizures (13, 15), earlier onset and longer duration of epilepsy (16, 17), greater seizure frequency (18, 19), and episodes of status epilepticus (17). Theories regarding the nonspecific, nefarious neurological influence of long-standing, frequent seizures have been posited to account for these so-called "diffuse" cognitive concomitants of epilepsy in these high-risk subgroups.

Much of the work on the cognitive effects of epilepsy have used general intelligence or IQ measures such as the Wechsler Adult Intelligence Scale (WAIS). While many of the subtests of the WAIS may reflect frontal lobe function, the WAIS was not designed to provide specific information for separating frontal lobe function from more widespread disturbance (1). The contribution of the frontal lobes to "general intelligence" or IQ has sparked controversy for decades. A recent PET study by Duncan et al. (20), correlating Spearman’s g, or general intelligence factor, to a fairly discrete region of lateral frontal cortex in one or both hemispheres continues the debate.

The VA Cooperative Study of Smith et al. (12) controlled for medication effects by administering a neuropsychological test battery to 618 newly diagnosed epilepsy patients before the administration of any antiepileptic drug (AED). General intellectual ability as measured by the WAIS was without significant difference between patients and controls. However, the patients with epilepsy did not perform as well as controls on measures of attention/concentration and psychomotor speed (digit symbol, discriminative reaction

time, verbal fluency)—all highly correlated with specific frontal network activity.

Executive Function Testing

The WCST assesses problem solving, mental flexibility, and the perseverative tendencies found in frontal lobe dysfunction and has been used several times in studying epilepsy populations. Hermann et al. (21, 22) found perseverative tendencies in WCST in more than 50% of patients with unilateral temporal epilepsy, regardless of lateralization (to be discussed in further detail below). The Trails Test assesses psychomotor speed, sequencing, and cognitive flexibility. Dikmen and Matthews (18) found deficits in Trails in epilepsy patients to mirror those of generalized intellectual impairment; that is, those patients in high-risk groups (early age at onset, long seizure duration, high seizure frequency) had more severe impairments than those in lower-risk groups. Deficits were found more frequently for Part B of Trails (involving cognitive flexibility) than for Part A (involving more psychomotor speed and sequencing). Similar deficits in cognitive flexibility and response inhibition were shown with the Stroop test (17), especially in patients with a higher frequency of generalized seizures and episodes of status.

Medication Effects

In the past 20 years, numerous studies have investigated the cognitive effects of AEDs and extensive reviews are available (23). Controversial methodological issues have surrounded many early reports of the adverse cognitive effects of these medications, including the conflation of various cognitive variables with motor performance and accuracy (24). Recently a series of well-controlled randomized double-blinded crossover studies by Meador et al. (25, 26) in patients and healthy volunteers have demonstrated adverse cognitive effects (predominantly in concentration, attention, and psychomotor abilities) for all of the older AEDs tested, but no clinically significant differences among phenytoin, carbamazapine, and valproic acid monotherapy. The beneficial effects of reducing seizures largely offset the adverse cognitive effects. Factors that may increase the occurrence of cognitive side effects include increased AED dosage, higher AED blood levels, and polytherapy.

Data on the cognitive effects of the newer AEDs are incomplete. There is some evidence that gabapentin, tiagabine, vigabatrin, and lamotrigine have fewer cog-

nitive side effects than the traditional AEDs (27). Topiramate, however, may be a significant exception. While one of the most potent of the new drugs, topiramate has the commonly reported side effects of impaired concentration and memory, slowed thinking, and word-finding difficulties (28). Kellet et al. (29) recently reported cognitive or behavioral side effects in almost 50% of 174 patients studied taking topiramate. The mechanism of these specific (frontal?) behavioral changes has not yet been elucidated (30).

Neuropsychiatry

Patients with epilepsy have a significantly increased incidence of mental pathology compared with a normal population (31). Psychopathology in epilepsy can be manifested in psychiatric disorders such as depression, anxiety, psychoses, and aberrant personality traits. However, the incidence of psychopathology among patients is only slightly increased or the same as compared with the incidence in patients with chronic medical or neurological illness (32). Many variables have been purported to increase the risk of psychopathology among epilepsy patients including gender, psychosocial factors, focality on brain imaging, and seizure-related variables (seizure type, frequency, duration, age of onset, status epilepticus) (31). The association of temporal lobe epilepsy and increased incidence of psychopathology has been recognized since the report of Gibbs in 1951 (33). Recent investigations using functional imaging studies suggest that even among patients with temporal lobe seizure foci, frontal lobe dysfunction appears to play a crucial role in the neuropsychiatric dimensions of epilepsy (34 –36).

TEMPORAL LOBE EPILEPSY, THE
FRONTAL LOBES, AND BEHAVIOR

A diverse spectrum of ictal and interictal behaviors are displayed by epilepsy patients with seizures originating in the temporal lobe. This diversity reflects the numerous anatomical and functional specializations of the temporal lobe as well as within its limbic and paralimbic components.

Ictal Phenomenology

The ictal phenomena of TLE can be divided into broad categories such as motor, sensory, autonomic,

experiential, emotional, cognitive, and psychiatric (37). The anatomical substrates of these varied ictal manifestations have been firmly established by stimulation and ablation studies in animals and humans. The roles of inferior and lateral regions in the temporal lobes in auditory and visual function are well known. More medial temporal structures belong to the limbic system and are involved in learning, memory, affect, and hormonal balance. The left temporal lobe typically appears more involved with verbal processing, whereas the right temporal lobe is more specialized for processing nonverbal information (38). Autonomic responses such as changes in pupillary size, pulse rate, blood pressure, micturition, and salivation have been induced by stimulation of the temporal lobe or its limbic components. The precise localization of the psychic and emotional manifestations of temporal lobe seizures has been debated between the temporal neocortex itself and the limbic regions. Gloor et al. (39) determined that almost half of experiential, hallucinatory, or emotional phenomenology is associated with discharges restricted to the amygdala, hippocampus, and parahippocampal gyrus, whereas only 3% is restricted to the neocortical part of the temporal lobe. More recent data involving "dream" states are less localizing: Bancaud et al. (40) found the amygdala involved (as the stimulated structure or as the site of ictal afterdischarge) in 73% of cases, the anterior hippocampus in 83%, and the temporal neocortex in 88%.

Interictal Phenomenology

Less well-established clinicoanatomical correlations have been described for the interictal or long-term, persistent behavioral alterations associated with TLE. TLE is quite unlike the lesion model of focal brain damage that gave rise to classic neuropsychological paradigms. Indeed, identification of the temporal lobe as the origin of seizures in a given patient says little specific about the patient’s behavior. Several methodological issues have complicated study in this area including controversy regarding reliable measurements of behavior, selection of adequate comparison control groups, and precise definitions of epilepsy subpopulations (31). The behavioral heterogeneity of TLE is increasingly being recognized as a consequence of a complex neurobiology involving fixed (neuropathologic) factors (i.e., side of origin, presence or absence of hippocampal sclerosis) as well as multiple highly variable neurophysiological factors (i.e., discharge spread or metabolism) (41). The frontal lobes as

a preferential route of propagation are being frequently implicated as having a significant role in the behavioral variability of TLE (22, 42).

Neuropsychology: Language. Patients with TLE are particularly vulnerable to dysfunction of language and memory. Word-finding difficulty or even clinical anomia can occur in patients with left temporal seizures (43). Anomia and other language impairments may account for some of the verbal memory deficits associated with left temporal lobe seizures (43, 44). As a central feature of language, naming is deranged in virtually all aphasic syndromes and is notoriously poorly localizing (45). Word-finding difficulties in isolation have been found to correlate with diffuse regions (frontal and temporal) of the dominant (typically left) hemisphere. A recent PET study (46) found that the greatest metabolic depression in left TLE patients was in left inferior frontal and superior temporal regions (corresponding to Broca’s and Wernicke’s areas, respectively). Language impairments correlated with the metabolic deficits in the two regions.

Memory. Several studies have demonstrated that patients with left TLE have fixed long-term deficits on tests of verbal list learning, cued recall, and semantic encoding, whereas patients with right TLE may do poorly on tests of nonverbal memory (44, 47, 48). Much of this literature has been derived from studies with patients who have undergone unilateral temporal lobectomy (38, 49). Other work has not found significant differences in memory performance comparing nonsurgical candidate TLE patients with patients with other epileptic syndromes or normal controls (41, 50). More recent studies have demonstrated a subgroup of patients with left TLE with a form of accelerated long-term forgetting of verbal material (normal retention of new information over hours to days but amnesia for information from more remote periods) (51). This accelerated forgetting may reflect the disruptive effects of seizures on the long-term consolidation of new information, and the potential contribution of the frontal lobes to this process is presently under investigation.

Attempts at further honing the diverse manifestations of TLE on a neuropathological basis have yielded equivocal results concerning the possible contribution of the frontal lobes. With hippocampal sclerosis its defining characteristic, the syndrome of mesial temporal lobe epilepsy (MTLE) seems to represent a highly localizable neuropathology, and indeed, diffuse neuropsychological impairment is considered a contraindication to the syndrome (52). Studying a group of patients with EEG, MRI, and histopatholog-

ically confirmed diagnoses of MTLE, Hermann et al. (53) demonstrated diffuse cognitive impairment (in intelligence, academic achievement, language, and visuospatial function) but interestingly not related to performance in the more specific frontal lobe activities of attention, concentration, and executive function. Lateralizing effects were noted exclusively for verbal memory impairments in patients with left MTLE. They hypothesized that the widespread cognitive impairment is not attributable to the consequences of hippocampal sclerosis per se, but more likely associated with the neurobiological effects of early onset of seizures, increasing years of intractable seizure activity, and prolonged exposure to AEDs.

Other studies have demonstrated that a substantial proportion of patients with TLE perform outside of normal limits on the WCST (21, 22, 54, 55). Attempts at stratifying the TLE population into pathological subgroups have found that performance on the WCST is independent of the indices of hippocampal integrity (22). This has been used to bolster a "nociferous cortex" hypothesis whereby executive dysfunction seen in TLE patients is not due to functional compromise of the epileptogenic temporal lobe or hippocampus, but is attributable to the noxious influence of epileptogenic cortex on extratemporal regions.

Electrophysiological and functional imaging studies. Attribution of the functional disturbance predicted by the nociferous cortex hypothesis to the frontal lobes, in particular, has been supported by a series of electrophysiological and functional imaging studies. Invasive EEG procedures have demonstrated preferential spread of ictal activity from the mesial temporal lobe to the ipsilateral frontal region (42) and preferential propagation of interictal spikes from mesial temporal to mesial and orbitofrontal regions (56). Interictal studies of cerebral metabolism using PET and cerebral blood flow using SPECT have revealed regions of physiological abnormality beyond the epileptogenic temporal lobe (57, 58).

Henry et al. (59), using PET, found regional hypometabolism in 25 of 27 patients with TLE, and the affected extratemporal regions included ipsilateral thalamus (63%), basal ganglia (41%), and frontal (30%), parietal (26%), and occipital (4%) regions. These regions of extratemporal hypometabolism correlate with specific patterns of neuropsychological performance in patients with TLE (58, 60). Several studies have suggested that the frontal lobes are subject to hypometabolism/hypoperfusion and neuropsychological deficits in patients with TLE, albeit less consistently than the temporal lobes (58, 61).

Jokeit and colleagues (62) investigated 96 TLE patients by FDG-PET and found prefrontal metabolic asymmetries more frequently in patients with left TLE (21 left, 6 right) and a history of secondarily generalized seizures. Comparing TLE patients with and without prefrontal asymmetry, the study (62) revealed that those patients with prefrontal metabolic asymmetry were impaired in intelligence and frontal lobe measures (performance IQ, verbal IQ, Trails A and B, and constancy of word list learning). The deficits as measured by psychomotor speed were pronounced, whereas deficits in specific "frontal lobe tests" were less marked. The question of intellectual deterioration or dementia in chronic TLE has been studied (63, 64). Controlling for many related variables, Jokeit and Ebner (64) found that patients with a long history of intractable TLE were at higher risk of generalized cognitive impairment than patients with a shorter duration of TLE. Education, as in Alzheimer’s disease, demonstrated some protective effects, but the duration effect persisted even in those patients who became seizure free after temporal lobectomy.

Neuropsychiatry: Psychosis. The relationship between TLE and psychosis, especially persistent interictal psychosis, is laden with methodological controversy (24, 31). Gudmundsson (65), in a survey on the frequency of mixed psychosis in epilepsy patients in Iceland, found prevalence rate for males of 6% and for females of 9%. The frequency of psychopathology was greater (50%) for those with TLE, compared with those without (25%) (24, 65). Many studies have commented on the distinguishing characteristics of TLE patients with schizophreniform psychosis when contrasted with idiopathic schizophrenia (66, 67). The psychoses of epilepsy are characterized by a preservation of warm affect and personality with a predominance of visual rather than auditory hallucinations. Formal thought disorder, incoherent thought, emotional withdrawal, and negative symptoms are less common in interictal psychosis than in schizophrenia.

Evidence of structural changes in medial temporal lobe regions in patients with schizophrenia have fueled direct comparisons of these patient groups (68, 69). Gold et al. (70) recently compared the neuropsychological performance of patients with TLE with that of patients with schizophrenia to address the possibility of an overlapping temporal dysfunction model to account for similar behavioral and cognitive disorders in the two groups. The schizophrenia patients demonstrated a degree of attentional impairment in both auditory (WAIS-R attentional factor) and visual (Digit Symbol, Trails) tasks that was not observed in the TLE

group. The WCST was more ambiguous: the TLE patients demonstrated an equivalent degree of perseveration as compared with schizophrenics and performed below that reported for normal control populations. Overall, the schizophrenia patients demonstrated a pattern of deficits more consistent with widespread dysfunction of working memory (a widely distributed system within the frontal lobes), whereas the TLE patients had more impairments in verbal memory and semantic knowledge (attributed mainly to the left temporal lobe).

Depression. The incidence of depression is higher in patients with TLE than in patients with other neurological or medical disorders (24, 31, 65). Depression may be temporally related to seizures as a prodrome, as an ictal or postictal affect, or as a chronic interictal mood disturbance. Factors that increase susceptibility to depression in TLE include the reaction to chronic illness with its associated life problems and limitations imposed on functional status as well as dysfunction in brain regions involved in emotional regulation (31, 71).

A consistent relationship between the laterality of seizures and depressive symptoms has been elusive. Many observers have found a higher prevalence of depression among patients with left-hemisphere complex partial seizures than among patients with righthemisphere seizure foci (36, 72, 73). These findings are consistent with reports of increased rates of depression in patients with anterior left-hemisphere strokes (74). However, some studies have noted a right-sided association between seizure foci and depression (75), while others have shown no clear relationship to mood (76, 77).

Functional imaging has shed light on the widespread perfusion changes seen in association with TLE, especially in limbic frontal regions, and several investigations have attempted to correlate localized hypometabolism with interictal depression. Bromfield et al. (36) using FDG-PET found that patients with left temporal foci were more likely than patients with right temporal foci to exhibit depressive symptoms by self-report, and the neurophysiological correlate appeared to be hypometabolism in the inferior frontal lobes bilaterally. A more recent study using SPECT by Schmitz et al. (35) confirmed that in patients with left temporal foci, the higher the self-reported ratings for depression, the lower the perfusion in frontal areas bilaterally.

Personality. The association of specific personality traits with TLE has generated a vast and controversial literature (78, 79). Among those traits frequently rec-

ognized are deepened emotionality, humorlessness, hyposexuality, anger, religious interests, philosophical preoccupations, paranoia, moralism, obsessional thoughts, circumstantiality, viscosity, and hypergraphia. Based on a literature review, Bear and Fedio composed the Temporal Lobe Epilepsy Inventory consisting of 18 traits and found an increased frequency of all 18 traits in patients with TLE compared with normal or neurological controls (80). Differences in personality traits between right and left TLE were also found. Patients with right-sided TLE displayed more emotional traits and exhibited "denial" or "polished" their self-image, whereas those with left temporal foci exhibited more ideational traits and "tarnished" their self-images. Subsequent studies did not support consistent lateralized personality changes in TLE (79).

Using frontal and temporal depth electrodes as well as the self-rating questions of the Bear–Fedio Inventory, Weiser et al. (81) demonstrated increased hypergraphia, religiosity, and altered sexual content in patients with left temporolimbic foci, increased hypermoralism and humorlessness in patients with rightsided foci, and a nonlateralizing association of circumstantiality in temporolimbic foci. Interestingly, he noted a nonsignificant increase in all Bear–Fedio Inventory behavioral traits in patients with frontal foci.

Few pathophysiological mechanisms have been posited to account for the personality changes seen in TLE. Mayeux et al. (43) suggested that circumstantiality and verbosity might be secondary to the anomia frequently demonstrated by patients with left TLE. Relations found in TLE patients between depressed mood and frontal hypoperfusion and between obsessionality and frontal hyperperfusion add to the accumulating data supporting a prominent role for frontal brain regions in the regulation of mood and behavior in TLE (35, 36).

FRONTAL LOBE SEIZURES AND
EPILEPSY

Ictal Phenomena

The diverse spectrum of ictal and interictal behavioral phenomenology of patients with seizures emanating from the frontal lobes has received far less attention than that of the temporal lobes. While 600,000 people are estimated to be affected by FLE in the United States (82), several unique diagnostic dilemmas have historically complicated its study (83). The EEG can be normal in either the ictal or interictal

state (84). Frontal lobe seizures spread widely and rapidly and have a tendency to manifest interictal discharges bilaterally, further complicating accurate localization of epileptiform foci (85). The behavioral manifestations of frontal lobe seizures can be quite bizarre and are often mistaken for pseudoseizures (86). Neuroimaging studies are often unrevealing (87).

Despite great clinical heterogeneity and wide propagation, seizures whose discharges originate in different "zones" of the frontal lobes have distinct characters. Several investigators have characterized the semiology of seizures from specific frontal foci (88 –90).

1. Motor cortex (BA 4). Typical focal motor seizures arising from the motor cortex consist of either isolated, brief myoclonic jerks or proceeding with a jacksonian march (88). The high incidence of onset of focal motor epilepsy in the lips, fingers, and toes is probably related to the disproportionately high cortical representation of these parts.

2. Premotor cortex (BA6). Usually brief and clustering at night, seizures from the SMA may be associated with vocalization or preservation of consciousness. Speech arrest, contraversive head movement and eye deviation, contralateral arm abduction, and external rotation and flexion at the elbow ("fencer’s posture") are believed to be virtually pathognomonic for an SMA focus (88, 90).

3. Prefrontal cortex. (i) dorsolateral. Dorsolateral seizures are not well characterized in the literature owing to rapid discharge spread in multidirectional pathways (91). Nevertheless, the most frequent inaugural sign is contralateral tonic deviation of the eyes which precedes the adversion of the head. Clonic facial contractions are often seen. Often masked by motor signs, visual hallucinations and illusions have been reported consisting of dimming or intense brightening of gray or dull colors and occasional immobile geometric images (88). Seizures may also begin with an obsessive thought (forced thinking) which may be acted out (forced acts) (91).

(ii) orbitofrontal. The semiology of orbitofrontal seizures is also not well characterized. Discharges emanating from the orbital cortex may remain silent until they spread to adjacent deep temporal structures (such as the amygdala), lateral temporal cortex, or other frontal structures (mainly the cingulate) (92). These regions may be responsible for the associated autonomic signs, olfactory hallucinations, and oroalimentary automatisms sometimes attributed to orbitofrontal seizures.

(iii) paralimbic (anterior cingulate). Ictal discharges involving the anterior cingulate region (BA

24) can produce dramatic manifestations in motor function and affective behavior (93). Cingulate seizures may alter the level of attention and consciousness, often manifested as an arrest of motor and verbal activity, mimicking absence seizures. Contralateral or bilateral tonic or clonic movements can occur in the extremities as can sudden loss of muscle tone (head nods). Autonomic phenomena such as pallor, tachycardia, mydriasis, forced urination, and apnea are frequent. Florid emotional outbursts consisting of intense fright and facial expressions of fear associated with shouts and aggressive verbalizations are frequently reported. In some cases, ictal or possibly postictal automatisms with aggressive behavior have led to a psychiatric hospitalization or imprisonment (88).

Many aspects of the diverse manifestations of frontal seizures are explained by straightforward anatomicophysiological correlations: SMA seizures are similar to local stimulation effects, dorsolateral frontal adversive seizures are readily understood, and the aphasic aspects of frontal seizures have a strong experimental grounding. Niedermeyer (90) postulates a relationship between 3/second spike-wave absences of the frontal lobe and suspension of "working memory". Niedermeyer (90) further remarks that anatomicophysiological correlation for other frontal seizure types "seems to be quite far-fetched," the domain of future epileptologists and neurophysiologists.

Interictal Phenomena

Neuropsychology. Few studies have explicitly studied the performance of patients with FLE on neuropsychological measures (94 –98). This has been attributed to numerous non-epilepsy- and epilepsy-related factors. The elusive psychometrics of frontal lobe function, the unique stages of frontal lobe development, and the functional heterogeneity of frontal lobe regions are all well recognized as complicating study of this issue (95). The particularly rapid propagation of epileptic activity in frontal seizures may potentially disrupt functions associated with other cortical regions and obfuscate clinicoanatomical correlations.

In a series of studies, Upton and Thompson (95–97) have attempted to clarify some of these issues. Subdividing patients with FLE into specific frontal regions affected (based on EEG monitoring, seizure semiology, and neuroimaging), they used an extensive neuropsychological battery of both executive and motor skills, both assessed to be dependent on frontal lobe integrity (95). Overall, they reported their results to be "slightly disappointing" insofar as only 2 of 26 vari-

ables were impaired dependent on the location of epileptic foci in the frontal lobe. Upton and Thompson cited the very lack of observable neuropsychological differences between frontal region subgroups in FLE as evidence in support of a "system" model of cortical organization, whereby one brain region alone is insufficient for successful completion of many tasks. A subsequent study controlling for various seizure-related variables such as etiology, seizure type, seizure frequency, and duration similarly yielded few significant results (97). Age of onset for developing FLE does appear to be a relevant variable for differential impairment on certain cognitive tasks (especially those involving a primary motor skill component) (96).

Comparison of neuropsychological functions in patients with frontal versus temporal lobe epilepsy. Few studies have compared directly performance on varied neuropsychological measures between patients with FLE and patients with TLE. Helmstaedter et al. (99) tested 38 patients with TLE (17 right, 21 left) and 23 patients with FLE (17 right, 6 left) on a broad range of tests selected to address specialized frontal subfunctions. The test battery included digit and visual memory span, word and figural fluency, the visual–verbal test, a maze, a letter cancellation test, the Stroop, and a Luria motor sequencing task. All patients were left hemisphere dominant for language by WADA testing. The FLE patients had a higher seizure frequency than the TLE cohort, but were otherwise matched for age, sex, IQ, lesion by MRI, age of onset, and duration of epilepsy.

When compared with TLE patients, the FLE patients demonstrated significantly poorer performance on nearly all the tasks presented, fluency tests being the notable exception. No group differences were found with respect to the lateralization of focus or the presence or absence of focal cerebral lesions. The authors explored the possibility of whether the chosen tests were not independent of each other, that is, whether the overall poorer performance of the FLE group could be attributed to one underlying "central executive" dysfunction. A factor analysis of the tests did not support a unitary frontal hypothesis and indicated that four distinct subfunctions were assessed by the battery: speed and attention for timed tests, motor coordination (Luria sequencing), memory span, and response maintenance and inhibition. Only motor control and response inhibition differentiated significantly between FLE and TLE patients. Functions of speed/attention were equally impaired in FLE and TLE.

Cluster analysis to subgroup patients on factor scores yielded three clusters suggesting three patterns of cognitive impairment. Cluster I reflected mainly impaired performance with motor coordination; Cluster II was associated exclusively with poor performance on tests of speed/attention; and Cluster III reflected poor performance preferentially on tasks involving response inhibition. Cluster II appeared mainly in TLE patients (79%), whereas Clusters I and III were associated with FLE (82%). Nine patients with FLE, however, displayed the pattern seen in the TLE patients.

Overall, the study provided evidence that impaired motor programming and coordination along with impaired response inhibition characterize more than two-thirds of patients with FLE. Helmstaedter et al. surmise that the deficits in attention and fluency, commonly observed in both the FLE and the TLE study populations, were attributable "to the strong frontal interconnections between frontal and temporal/temporomedial structures and irradiating epileptic dysfunction."

Neuropsychiatry. Systematic studies of interictal behavior in patients with FLE are lacking. Numerous case reports describe wide-ranging interictal behavioral abnormalities. Devinsky et al. (100) stated that seizure activity originating in the prefrontal area might give rise to brief feelings of acute embarrassment (the "opposite" of the disinhibited prefrontal syndrome). A thirteen year old girl with frontal lobe seizures was described by Boone et al. (101) as demonstrating reversible behavioral changes including sexual disinhibition, loss of concern for personal hygiene, physical and verbal aggression, and pressured and tangential speech accompanying interictal electrophysiological abnormality located in anterior frontal lobe areas. Attention deficit disorder has been described in association with orbitofrontal epilepsy (102). Patients with anterior cingulate seizure foci can develop interictal psychosis, aggression, sociopathic behavior, sexual deviancy, irritability, obsessive–compulsive disorder, and poor impulse control (93). In a study using invasive electrodes for localization and lateralization, Weiser (81) found a nonsignificant increase in all Bear–Fedio Inventory behavioral traits in the group with FLE (see above for more on the frontal lobes and personality).

CONCLUSIONS

The specific contributions of the frontal lobes to behavior and cognition in epilepsy continue to elude

simple characterization. Several generalizations regarding the frontal lobes and behavior in epilepsy may be made:

Patients with well-controlled epilepsy rarely demonstrate significant impairment in general intellectual functioning as assessed by IQ tests. However, numerous studies have confirmed greater cognitive impairments (by IQ) in patients with generalized versus partial seizures, earlier onset and longer duration of epilepsy, greater seizure frequency, and more frequent episodes of status. Specific executive function testing in undifferentiated epilepsy patients has found deficits in tasks of psychomotor speed, sequencing, and cognitive flexibility to mirror those of generalized intellectual impairment.

Controversial methodological issues surround reports of the adverse cognitive effects of antiepileptic drugs, including the conflation of various cognitive variables with motor performance and accuracy.

Patients with TLE are particularly vulnerable to dysfunction of language and memory. Numerous patients with TLE have impaired performance on WCST, independent of hippocampal integrity. Functional imaging has demonstrated regions of extratemporal hypometabolism correlating with specific patterns of neuropsychological performance: left inferior frontal hypometabolism with language dysfunction, and prefrontal asymmetry with impairment in intelligence and frontal lobe measures.

Executive dysfunction in TLE patients supports a "nociferous cortex" hypothesis whereby functional compromise is due to the noxious influence of epileptogenic cortex on extratemporal regions. Invasive EEG and functional imaging studies have supported attribution of the functional disturbance predicted by the nociferous cortex hypothesis to the frontal lobes.

Functional imaging has demonstrated bilateral frontal hypometabolism to be correlated with self-reported rates for depression in patients with left TLE.

Clinical neuropsychological batteries have been unable to distinguish frontal regional subgroups (based on EEG, seizure semiology, and neuroimaging) in FLE populations. Age of onset of FLE does appear to be a relevant variable for differential impairment on certain cognitive tasks.

A single study directly comparing patterns of frontal- executive cognitive impairment in TLE versus FLE found the former to be associated with impaired performance on tests of cognitive speed and attention whereas the latter to be associated with impaired performance on tests of motor programming and response inhibition.

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