REVIEW Behavioral Aspects of Frontal Lobe Epilepsy Christoph Helmstaedter, Ph.D.1 University Clinic of Epileptology Bonn, Sigmund Freud Strasse 25, D-53105 Bonn, Germany Received February 24, 2001; accepted for publication August 15, 2001 There is growing interest in disorders of behavior, personality, and mood associated with focal epilepsies, though the neuropsychological and behavioral or psychiatric aspects of epilepsy have usually been treated separately. The causes of behavioral disorders in patients with focal epilepsies are multifactorial, though the positive effects of seizure control on behavior suggest that state dependency is a major contributing factor. Patients with temporal lobe epilepsy manifest depression, anxiety, neuroticism, and social limitations, as well as impaired memory. By contrast, studies of cognitive function in patients with frontal lobe epilepsy show executive dysfunctions in response selection/initiation and inhibition, as well as cognitive impairment, hyperactivity, conscientiousness, obsession, and addictive behaviors. 2001 Academic Press Key Words: frontal lobe epilepsy; cognition; seizure semiology; behavior; personality; quality of life. To date, neurobiologists interested in behavior and epilepsy have focused primarily on temporal lobe epi- lepsy (TLE) and mesial temporal lobe epilepsy (mTLE), in particular, mostly because TLE accounts for the ma- jority of patients with focal epilepsies seen at epilepsy referral centers. For example, in the Bonn series of pa- tients with pharmacoresistant epilepsies, approximately 80% had TLE. Another reason is that patients with mTLE often constitute a well-defined cohort with respect to underlying pathology (hippocampal sclerosis), a fre- quent history of febrile convulsions, an early onset of epilepsy, and memory problems as the prominent neu- ropsychological impairment. Further, the affected cere- bral structures and epileptogenic regions associated with TLE are usually circumscribed, and the structural pa- thology can be readily characterized by quantitative MRI (T2 relaxometry and volumetry) or histopathological ex- aminations of resected specimens. Thus, frequency of occurrence, homogeneity of phe- notypic expression, and well circumscribed and quanti- fiable pathology provide ideal prerequisites for the study of the functional and behavioral correlates of TLE. Ac- cordingly, great progress has been made in recent years with respect to the neuropsychological and cognitive aspects of TLE. Additionally, studies have led to a redis- covery of the role of the temporal lobes in emotion and psychiatric symptoms. The conditions for studying frontal lobe epilepsy (FLE) are quite different. FLE, despite the size of the frontal lobes, is less frequent than TLE. In our own series, patients with FLE represent about 15% of the patients with pharmacoresistant epilepsies. Further, the site and type of the underlying pathology are very heterogeneous. Finally, ictal and interictal clinicoelec- tric manifestations of FLE are infrequently localizable because multiple connections to most other brain ar- eas enable fast and widely distributed propagation of epileptic activity. The functional correlates of frontal pathology in epilepsy are thus less well understood. FRONTAL LOBE: ANATOMY, FUNCTION, AND ASSOCIATED BEHAVIOR DISORDERS Based on its cytoarchitectonic structure, the frontal lobe is traditionally divided into two parts, each with 1 To whom correspondence should be addressed. Fax: 49 (0) 228 287 6294. E-mail: C.Helmstaedter@uni-bonn.de. Epilepsy & Behavior 2, 384­395 (2001) doi:10.1006/ebeh.2001.0259, available online at http://www.idealibrary.com on 1525-5050/01 $35.00 Copyright 2001 by Academic Press All rights of reproduction in any form reserved.384 important functional characteristics. The posterior part controls motor movement and is subdivided into a premotor area and a motor area, which control prep- aration for movement and actual execution of move- ment, respectively. The anterior part, the prefrontal cortex, is especially important for higher mental func- tions, such as anticipation and planning, initiative, judgment, and in the control of mood, will power, and the determination of personality (1, 2). The prefrontal cortex can be further subdivided into the dorsolateral cortex and the orbitofrontal cortex, though this is sim- plistic because the orbitofrontal cortex is a heteroge- neous area connected with a wide range of other pre- frontal, limbic, premotor, sensory areas in addition to subcortical nuclei (3). Damage of the dorsolateral prefrontal cortex is typ- ically associated with impairment of executive func- tions and working memory, whereas damage of the orbitofrontal cortex leads to impairment of the choice of behavior, the establishment of emotional valences, and the evaluation and balancing of the past and future consequences of a given behavior (4­6). Studies in common marmosets suggest a dissociation between the lateral and the orbital medial divisions of the prefrontal cortex according to which the former selects and controls actions on the basis of higher-order rules and the latter controls different behavior on the basis of lower-order rules (7). The significance of the orbito- frontal cortex for social and interpersonal behavior in humans was again demonstrated by the recent report of two patients, one with a traumatic brain injury at 15 months of age and the other with a frontal tumor resected at 16 months of age, who both showed severe impairment of social and moral behavior (8). Traditionally, behavioral dyscontrol in epilepsy has been attributed to dysfunction of temporolimbic struc- tures. Evidence for the involvement of the amygdala in aggression comes from human and animal stimu- lation studies, from the effects of antiepileptic drugs on activating and inhibiting aggression, and, recently, from direct correlations of amygdala volumes with aggression in patients with mesial epilepsy (9­12). Aggression associated with involvement of the amyg- dala appears to be defensive rather than offensive in nature (13). Disinhibition phenomena or a loss of impulse con- trol as observed in patients with frontal lesions sug- gests the importance of frontal regions in the genesis of impulsive aggressive behavior. The orbitofrontal cortex, as the border zone between the frontal lobe and the limbic system, links the frontal and limbic compo- nents involved in disorders of behavioral control. The anterior cingulate gyrus, which is also strongly con- nected to the amygdala, has also been associated with deviant social behavior and pathological affective states when damaged (14). Attributing antisocial and aggressive behavior to frontal lobe damage is not new. A prominent and often-cited example is the historic case of Phineas Gage, who after an accident with a severe frontal brain injury changed from a well-behaved man into an irre- sponsible and convention-neglecting person (15, 16). One new concept, brought out by the case reports of Anderson et al. (8), is that patients with frontal lobe damage not only may display severe behavioral dis- orders but also may neglect the moral aspects of their behavior, depending on the age at which the damage occurred (17). Consequently, the orbitofrontal cortex seems important both for behavior control and for the acquisition of social and interpersonal rules of con- duct. It is important to note that irresponsible, aggres- sive, and sociopathic behaviors can occur irrespective of intellectual abilities, which are often well preserved in frontal lesions. The orbitofrontal cortex and medial prefrontal cor- tex are believed to play a central role in addictive behavior, attention deficit­hyperactivity disorder, and negative emotion and major depression, respectively (18­21). Davidson and co-workers further propose a key role of the prefrontal cortex in the regulation of emotion in violent subjects and those predisposed to violence (22). Damasio proposed the "somatic marker" hypothe- sis as a theoretical basis for the role of the prefrontal cortex in the interplay of cognition and emotion (23). This hypothesis posits that responses to external stim- uli do not rely on either conditioning processes or cognition alone, but on somatic "marker signals" or autonomic response sets, which determine the con- scious/unconscious connection between stimulus conditions, feelings, and behavior. EPILEPSY AND ASSOCIATED BEHAVIOR DISORDERS Case reports of behavioral and personality disor- ders in patients with severe brain lesions raise the question of whether there might be parallels in the behavior of patients with seizures arising from the same brain regions. With the exception of rare cases of ictal aggression, postictal confusional states, or psy- chosis (24), behavior and personality disorders ob- served in patients with frontal lobe epilepsy appear to 385Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved. be less dramatic than found in the published case reports. Furthermore, as with TLE, one can hardly expect to find the prototypical "frontal epileptic per- sonality" or "Wesensa¨nderung," respectively. Person- ality is by definition more trait than state dependent. In patients with epilepsy, it is particularly difficult to determine whether a given behavior has trait charac- teristics or not. Concluding that abnormal behaviors have persisted requires follow-up observations over long time intervals, which generally are not reported in the literature. Several epilepsy-related variables can account for reversible changes in cognitive abilities and mood states (see Table 1). Finally, despite the long history of patients becoming seizure free from epi- lepsy surgery, it is still not clear whether seizures are necessary for the development of epilepsy-related be- havior and mood disorders. Behavior in patients with epilepsy should be defined by state as it relates tem- porally to seizure events, e.g., ictal, postictal, or inter- ictal. Recent findings with regard to seizure prediction by nonlinear measures of complexity loss as recorded by intracranial EEG suggest that the preictal period should also be considered (25). Accordingly, patients may report a prodrome consisting of increased dys- phoric mood and cognitive problems well before their seizures begin. Finally, the observation of behavior problems following successful treatment with epi- lepsy surgery or antiepileptic drugs implies that an additional state that should be evaluated is that of seizure freedom associated with treatment. Epileptic activity can affect brain areas distant from the epileptogenic zone, causing cognitive and behav- ior problems (26). Notwithstanding seizures and in- terictal epileptic activity one must also differentiate the underlying pathology(ies) and when they oc- curred (which could influence effects on brain matu- ration and the development of cognition and person- ality). We must also consider the effects of chronic antiepileptic medications, which may have positive or negative psychotropic side effects (27). Antiepileptic drugs can have different effects in patients with le- sional epilepsy compared with nonlesional patients, and they may act differently dependent on seizure control (28). Thus, the effects of underlying pathology, seizures, and pharmacological treatment must be con- sidered individually and as they may interact in a given patient. FRONTAL LOBE EPILEPSY: NEUROPSYCHOLOGY AND EVIDENCE OF SPECIFIC BEHAVIORAL DISORDERS The development of neuropsychology in frontal lobe epilepsy is probably best reflected by Brenda Milner's description of her evaluation of Penfield's patient K.M., the frontal counterpart of the temporal patient H.M. This patient had a penetrating head in- jury in 1928, developed seizures, and underwent sur- gery of the anterior parts of both frontal lobes. Surgery successfully controlled the seizures and led to im- proved behavior as well as improved IQ. However, when reevaluated with the newly developed Wiscon- sin Card Sorting test in 1962 he showed severe impair- ment in flexible categorical thinking and concept for- mation while the IQ still was average (see Milner (29)). This case exemplifies how much outcome interpreta- tion depends on test sensitivity and test selection. Since that time surprisingly few attempts have been made to comprehend the cognitive characteristics of patients with frontal lobe epilepsy in group studies (26). Unfortunately, most data from Milner's era stem from operated patients and thus tell us more about frontal lobe lesions than about frontal lobe epilepsy. Furthermore, most earlier studies focused on single functions more or less following a rather monistic view of a frontal "central executive" (30). Major im- pairments indicated by these studies are problems in concept formation, response inhibition (31), estima- tions (32), conditional associative learning (33, 34), and profit from information provided in advance in choice reaction tasks (35). Focusing on memory Delaney et al. TABLE 1 Factors Affecting Cognitive and Mood States in Epilepsy States of epilepsy Preictal Ictal Postictal Interictal (seizure free after successful surgery) Seizures Frequency Generalization Nonconvulsive status epilepticus Epileptic dysfunction Local versus distant effects Lesion For example, alien tissues versus migration and developmental disorders (confounded with different ages at lesion/epilepsy onset) Extent, location, lateralization AED Positive versus negative psychotrophic effects Individual incompatibility Drug-induced encephalopathy Intoxication 386 Christoph Helmstaedter Copyright 2001 by Academic Press All rights of reproduction in any form reserved. found no differences in measures of memory when nonoperated patients with unilateral frontal lobe foci were compared with healthy controls (36). The first of our own studies found that deficits in attention are the most significant problem in patients with frontal lobe epilepsy (37). Later systematic group studies in nonresected pa- tients with FLE followed the theoretical suggestion of different frontal subfunctions (38) and met the re- quirements of the manifold frontal lobe pathology by the use of a broader range of tests. These addressed different aspects of attention, motor coordination, psy- chomotor speed, fluency, response inhibition, concep- tual formation and shift, as well as planning, guessing, and estimating. Between 1996 and 1999 Upton and co-workers pub- lished a series of five articles reporting different find- ings on neuropsychology in the their sample of 74 subjects with frontal lobe epilepsy (39­43). Using a test battery with different measures of executive func- tions and motor skills they came to the conclusion patients with frontal lobe epilepsy show a deficit pat- tern similar to that found in frontal lobe dysfunction in general (39). As compared with patients with tempo- ral lobe epilepsy, frontal patients show poorer motor cordination, guessing, estimation, and response inhi- bition. Similarly, we found in 23 patients with frontal lobe epilepsy that cognitive problems could be diag- nosed with a broad range of 10 "frontal" tasks with about double as many test parameters. The great num- ber of test parameters, however, turned out to be highly redundant and could be statistically reduced to four relatively independent functional areas: "psy- chomotor speed/attention," "motor coordination," "working memory," and "response inhibition." These four factors explained 70% of the total variance. When compared with patients with temporal lobe epilepsy, those with frontal lobe epilepsy were characterized by prominent impairment in motor skills and response inhibition (44). Problems in speed/attention and working memory were frequent but they appeared rather nonspecific since they were also observed in the temporal lobe group. This, however, does not neces- sarily contradict the assumption that these are frontal functions. An imaging study by Jokeit et al. showed in this respect that in patients with temporal lobe epi- lepsy, prefrontal metabolic asymmetries are evident that are associated with "frontal lobe measures" and intelligence (45). In another of our own studies we addressed the cognitive consequences of frontal lobe surgery. We evaluated 33 patients pre- and postoperatively. First, we were able to confirm the impairment pattern of impaired motor skills and response inhibition. Second, we showed that frontal surgery does not cause con- siderable additional damage as far as eloquent cortex (SMA, motor and language area) is spared. However, when surgery included resection of the SMA the most prominent neuropsychological symptom besides neu- rological deficits directly after surgery was a SMA deficiency syndrome (impairment of initiation) with aphasia (speech arrest and transcortical aphasia) (46). Additional psychomotor slowing was observed in lo- bectomies as compared with lesionectomies. Looking closer at clinical variables that might ex- plain the impairment pattern in nonresected patients, no consistent picture emerges. According to Upton and Thompson seizure frequency and the duration of epilepsy have an effect on performance but this ap- pears to be a nonspecific effect rather than a consistent finding over different tests (41). With the exception of motor skills, which were spared in early right-sided FLE, no systematic effect of the assumed influence of the age at the onset of epilepsy on cognitive develop- ment could be concluded from their data (42). The impact of having epileptic seizures on cognition can well be demonstrated by our postoperative findings indicating that in seizure-free patients adjacent func- tions recovered after surgery. Comparable release ef- fects have been also reported after temporal lobe sur- gery (47). However, one should not go so far as to conclude that all deficits are due to epileptic dysfunc- tion and thus reversible as has been suggested by Boone et al. in a single case report in 1988 (48). In summary, from the neuropsychological findings in FLE, it appears that indeed different frontal sub- functions can be differentiated. Nevertheless, the mea- sures that characterize FLE have in common the de- mand of adequate response selection and initiation, and response inhibition. This holds for tests that ex- plicitly assess interferences and response inhibition but also for tests of motor skills or working memory. Ending up again with a unique central executive func- tion, one may hypothesize that the particular problem in FLE is the impairment of response selection/initia- tion/inhibition with varying emphasis depending on different functional areas. Which area is affected then depends on the type and localization of the underly- ing lesion, including the possibility that symptoms are overshadowed by spreading epileptic dysfunction. It is important to mention that the development of appropriate test instruments for the assessment of frontal lobe dysfunction is not yet complete and still represents a challenge for neuropsychologists. Most 387Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved. psychometric tests that allow quantification of test behavior provide patients with a clear structure for behavior, i.e., with test instructions, rules, time con- straints. This enables the patient to behave in an or- dered way and real problems with behavior organiza- tion arising from frontal pathology are easily over- looked. If provided with more degrees of freedom and demands on spontaneous interactions with complex situations, the same patient would otherwise reveal deficits. A possible solution to this dilemma could be to design tasks that evoke spontaneous behavior and decisions that are up to the subject, as has been done by Bechara et al. with the gambling task (49), by Gold- berg et al. with their cognitive bias task (50), or by Upton and Thompson with their twenty questions task (43). ICTAL BEHAVIOR IN FRONTAL LOBE SEIZURES: "POSITIVE" AND "NEGATIVE" PHENOMENA Like others before, we recently analyzed seizure phenomena in patients with frontal lobe epilepsy by video-EEG monitoring. The main purpose was to get hints from seizures for differential diagnosis. On the other hand seizures can be studied in terms of tran- sient dysfunctions, which are more or less circum- scribed and point to certain cerebral structures. Sei- zure semiology, preserved functions, as well as im- paired functions can tell us something about the cerebral functional organization of cognition and con- sciousness. We studied "positive phenomena" in terms of seizure semiology and "negative phenom- ena" in terms of impairment when patients were neu- ropsychologically tested during their seizures (51­53). Ictal phenomena in frontal seizures are mostly pos- itive phenomena (see Table 2). On the one hand, this means a nearly 1:1 relationship between discharges and motor excitation when direct access to motor neu- rons is possible in primary motor area seizures, for example. On the other hand, this means release and disinhibition of complex behaviors and behavior chains when precentral areas are involved. Examples are posturing and contraversive movements in SMA and premotor seizures, and explosive, bizarre, and emotional unstable behaviors in prefrontal seizures including its mesial parts. Negative phenomena like loss of consciousness are commonly observed in sei- zures with mesial propagation and secondary gener- alization. For frontal seizures one can thus conclude that the prominent feature is impairment of executive control in terms of a pathological "hyperexcitation or disinhibition." Neuropsychological examination of the cognitive impairment during seizures can provide additional insight into the ictal event. We performed ictal testing in 116 patients, most of whom were candidates for epilepsy surgery. These patients underwent ictal ex- aminations that included examination of orientation reflexes (verbal, nonverbal, tactile), expressive/recep- tive language (commands, naming repetition), non- verbal reception/expression (commands and imita- tion), and, finally, awareness and memory (interroga- tion after the seizure). Testing was performed by the video-EEG monitoring staff and started as soon as possible after seizure onset. Functions were tested hi- erarchically according to their complexity and testing was continued until the seizure ended. About half of the patients had implanted strip or depth electrodes for invasive EEG recordings. Table 3 shows the im- pairment pattern that results when distribution of ictal EEG activity at the time of testing is considered. In comparison to lateralized and bilateral temporal lobe seizures, frontal lobe seizures are characterized by prominent impairment of orientation reflexes and ex- pressive speech, which are typical frontal functions. Receptive speech is often preserved. Patients can try, for example, to follow body commands even when they appear involved in excessive motor activity. In contrast to left and bitemporal seizures in particular, consciousness (awareness of any kind) and memory TABLE 2 Ictal Frontal Seizure Semiology (N 15) Localization Positive symptoms Motor area Nearly 1:1 manifestation of seizure activity in myoclonic and tonic or clonic motor activity SMA Tonic posturing Premotor Contraversive head and eye movements Prefrontal (including cingulate gyrus) Explosive and complex motor automatisms (including vocalizations) Bizarre and hysterical behaviour Mood change Negative symptoms Mesial propagation and secondary generalization Loss of consciousness Impaired executive control: "pathological exitation and disinhibition" 388 Christoph Helmstaedter Copyright 2001 by Academic Press All rights of reproduction in any form reserved. for the test situation during the seizures are mostly preserved. A very interesting behavior and neuropsychological pattern of impairment can be observed in patients with frontal nonconvulsive status epilepticus. It is im- portant to note that in contrast to grand mal status, which is the repetition of the same seizure, the nature of frontal nonconvulsive status and frontal seizures is completely different. In contrast to frontal lobe sei- zures, seizure semiology of nonconvulsive status is dominated by negative seizure phenomena. Without EEG recording, the epileptic nature of this state is easily overlooked and patients appear somehow strange since they are slowed, dysphoric, morose, and adverse. When neuropsychologically examined dur- ing the seizure we found in five cases consistently generally reduced activity, fluctuating orientation, re- flexive and no self-initiated behavior, perseverations, intrusions, apractic signs, problems to shift between tasks, impaired working memory on a higher cogni- tive level, and emotional instability (see Table 4). In 1997 we already described a single patient with a nonconvulsive status epilepticus who showed a gen- eralized EEG pattern but focal cognitive deficits when neuropsychologically tested during this state. Today, with better diagnostic tools we would probably be able to reinterpret this case also as frontal nonconvul- sive status (54). In contrasting frontal seizures with frontal noncon- vulsive status one could interpret the latter rather in terms of an impaired executive control by pathological "hyperinhibition." Impressive recovery to normal be- havior can be observed in these patients when the status is successfully ended by injection of diazepam. This is thus one form of state-dependent cognitive impairment. Another form can be seen in postictal impairment. Because they often do not lose consciousness during frontal lobe seizures, patients are accordingly quickly reoriented postictally. Figure 1 shows the course of verbal memory and decision times in pre- and postic- tal memory testing after frontal lobe seizures as com- pared with left/right temporal seizures and repeated testing in healthy controls. After lateralized temporal lobe seizures, material-specific memory impairment can be observed for at least 1 hour after complete reorientation. What is shown for left temporal patients in verbal memory in Fig. 1 has its counterpart for right temporal patients in figural memory. As for frontal lobe seizures it is remarkable that there is no postictal deterioration in memory nor significant slowing of reaction times. However, when seizures secondarily generalize, lasting memory impairment can be ob- served also following frontal seizures (55). We can conclude so far that from frontal lobe sei- zures, a dysexecutive syndrome results with mostly preserved awareness and consciousness, reflexive but not self-initiated behavior, and a seizure semiology dominated by a state of hyperexcitation and disinhi- bition or hyperinhibition. This would confirm the im- pression from neuropsychological findings that the major problem in FLE is appropriate response selec- tion/initiation and inhibition of behavior. A further TABLE 4 Ictal Symptoms in Frontal Nonconvulsive Status Epilepticus (N 5) Performance Impairment Motor functions (including speech) Generally reduced activity Rarely automatisms (fumbling etc. . . .) Orientation Fluctuating Executive functions (including language) No self-initiated directed actions Increased perseverations Intrusions Apraxia signs in object use and imitation Reasoning Problems with concept formation and shift (color/ form, etc.) Working memory Impaired only when complex mental information processing is required Emotion Emotional instability (dysphoric) Impaired executive control: "pathological inhibition" TABLE 3 Negative Ictal Symptoms in Focal Epilepsy (N 116) Location of seizure activity Frontal N 29 Right temporal n 21 Left temporal n 38 Bitemporal N 28 % Impaired when tested ictally Orientation reflex 62 10 18 57 Receptive speech (commands) 48 15 59 93 Expressive speech 77 11 47 76 Memory 31 0 46 100 Consciousness 33 12 39 100 389Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved. differentiation according to lesions or foci within par- ticular sites of the frontal lobes can be suggested but has not yet been proven. From a neuropsychological point of view it is still difficult to decide whether one central executive function or different executive func- tions should be assumed. As already mentioned a compromise is favored at the moment, which suggests that the frontal subfunctions are constituted by similar processes of response selection/initiation and inhibi- tion in different domains and modalities of behavior, respectively. BEHAVIORAL CORRELATES OF FRONTAL LOBE EPILEPSY If we propose problems with behavior selection/ initiation and inhibition as a functional complex that is affected mainly in frontal lobe epilepsy, the obvious question is whether or not this dysfunction has a correlate in personality and behavior. With respect to this question we applied several self-rating scales to a group of 95 patients with either frontal (n 18) or mesial (n 77) temporal lobe epilepsy. Epilepsy groups were matched regarding sex, age at onset of epilepsy (mean, 11 years), and duration of epilepsy (mean, 24 years). The BPSE "ac- tivity subscale" was used to assess frequencies of ac- tivities (56), depression and anxiety were assessed by the Beck Depression Inventory (BDI) (57) and the Zung Self Rating Anxiety Scale (SAS) (58), and per- sonality was assessed by the Neo Five Factor Inven- tory, a German version of the NEO personality inven- tory (59). Quality of life in epilepsy was assessed by a German modified QOLIE-10 (English version: Cramer et al. (60)), and finally we evaluated education and employment to add some objective data. Group comparisons considering localization and lateralization of epilepsy revealed only slight differ- ences (Table 5). Patients with M-TLE as a trend showed poorer mood and significantly increased anx- iety scores; they described themselves more active at home, less active with respect to outdoor cultural ac- tivities, and less open for experiences than patients with FLE. It is important to note that, when compared with normative data for healthy control subjects, the result regarding outdoor cultural activities must be interpreted in the context that patients with FLE are more active than the controls and patients with M- TLE. Furthermore, when compared with normal data for a healthy control group, the neuroticism score of patients with M-TLE and the conscientiousness score of patients with FLE appeared elevated. As regards quality of life, patients were categorized as having poor QOL when they showed scores below the 25% percentile. As shown in Fig. 2 patients with TLE generally tended to report poorer QOL than pa- tients with FLE. Impaired mood, memory problems, FIG. 1. Preictal baseline measures and postictal course of verbal memory and decision times in patients with frontal and left or right temporal lobe epilepsy. The bars indicate performance of healthy subjects when tested repeatedly in the same intervals. 390 Christoph Helmstaedter Copyright 2001 by Academic Press All rights of reproduction in any form reserved. and social limitations correspond well to the features of TLE found with the other instruments in this eval- uation. Our current approach to behavioral problems and personality in patients with focal epilepsies is less led by classification systems, which may be useful in id- iopathic psychiatric disorders. As already mentioned in the Introduction there is a long history of person- ality research in epilepsy and up to now no consistent features are discerned. So far this has been explained by the multifactorial determination of psychiatric problems in patients with symptomatic epilepsies. As far as psychometric approaches are concerned, previ- ous studies of temporal lobe epilepsy mostly used the MMPI (61) or, more specifically, the Bear­Fedio Inven- tory (62, 63). It is our daily experience that commonly used psychiatric scales or psychological personality inventories largely fail to reflect objectively what seems to the examiner clearly to be an epilepsy-related change in personality or a behavior disorder. At the moment we are evaluating our own clinical personality inventory, which was empirically designed according to a collection of behavioral problems per- ceived by the clinical psychological staff at the Univer- sity Hospital of Epileptology, Bonn, Germany (64). For preliminary analysis the questionnaire was consecu- tively applied to 59 patients with TLE, 17 patients with FLE, 9 patients with parieto-occipital epilepsy, and 44 healthy subjects. It consists of 82 questions concerning 15 different behavioral domains. The answer style is a six- step frequency of occurrence rating with 1 "occurs not at all" and 6 "occurs very frequently." Second-order factor analysis resulted in six factors, which were inter- preted as follows: (1) "organic personality change" with patients reporting communication problems, emotional lability, being indetermined, and suspectibilty to inter- ference, perseverations, and hypoactivity; (2) "depressed mood," including depressive mood, reduced vitality, anxiety, and insensitivity; (3) "addiction and obsession" including addiction to legal and illegal substances, com- pulsion, and obsession; (4) "extraversion" comprising sociability, curiosity, and self-determined behavior; (5) "aggression" comprising aggression, sensation seeking, nonadaptive behavior, and violence; (6) "hyperactivity and adaptivity." When clinical data as well as sex are taken as independent variables some interesting results emerge (Fig. 3). The data indicate that problems in the respective areas are evident in 20 to 30% of the patients. Organic personality changes are preferentially seen in left ep- ilepsies of either origin, as well as in women rather than men. Addiction and obsession are more frequent in right epilepsies and frontal epilepsies in particular. Depressed mood is preferentially seen in patients with hippocampal sclerosis, a finding that is in line with one of our recent publications (65). All patients and patients with parietal epilepsies in particular show FIG. 2. Quality of life in FLE as compared with M-TLE. Values 25% percentile were considered as reflecting perception of impaired QOL. Asterisks indicate significant group differences in 2 testing. TABLE 5 Scale Group Mean SD Significance Mood (BDI SAS) Depression FLE 7.6 7.3 n.s. M-TLE 11.1 9.0 Anxiety FLE 29.7 7.9 * M-TLE 35.9 7.4 Activities (BPSE: activity subscale) Home activities FLE 25.3 4.9 * M-TLE 27.8 5.7 * Social activities FLE 20.2 5.3 n.s. M-TLE 18.7 6.1 Cultural activities FLE 16.3 6.5 * M-TLE 12.8 5.4 Personality (NEO FFI) Neuroticism FLE 21.4 5.4 n.s. M-TLE 24.7 7.4 n.s. Extraversion FLE 26.2 4.3 n.s. M-TLE 26.0 6.2 Open for experiences FLE 28.6 6.6 * M-TLE 25.1 5.3 Agreeableness FLE 31.6 4.6 n.s. M-TLE 30.2 4.2 Conscientiousness FLE 34.9 5.6 n.s. M-TLE 33.2 5.3 Note. *P 0.05. 391Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved. reduced extraversion. Aggressive behavior seems more frequent in left epilepsies, and patients with FLE show increased hyperactivity and adaptivity, which may parallel the finding of increased outdoor/cultural activities and openness for experiences. It is important to note that these results are preliminary and that larger control groups and validation studies are still required. However, the data indicate that the often- cited depressive mood is not the only behavioral prob- lem in patients with focal epilepsy and that apart from this there are specific behavioral aspects that appear related to localized and lateralized lesions/or epileptic dysfunctions. Although no differences between patients with FLE and TLE could be observed it is worth reporting the results with respect to organic personality change scale in more detail. As shown in Fig. 4 for selected items, about 20% of the patients report that they offend others, between 20 and 35% of the patients report problems with reception, misunderstandings, or that they were per- ceived as perseverative or circumstantial, and 50% re- port that their behavior irritates others. This is similar to the "epileptic personality" and, taken together with the depressed mood, one might as well think of the dyspho- ric and paroxysmal mood disorder as has been proposed from a more psychiatric point of view (66). ACADEMIC ACHIEVEMENT AND EMPLOYMENT IN FRONTAL LOBE EPILEPSY It is well known that patients with frontal lesions may show unimpaired cognitive functions but never- theless fail on everyday demands of job and career because of behavioral problems, unsteadiness, concen- tration problems, increased susceptibility to interfer- ence, and problems with timing and planning. Subjec- tive data may not reveal behavioral problems because patients with frontal lobe lesions have been reported to underestimate their impairments. With school achievement and employment, however, we have in- direct markers, which allow us to infer to what extent patients are adapted to everyday life. As indicated in Table 6 it is not the group with FLE but that with M-TLE that is less educated, and the job situation is comparable in both groups. TRAIT OR STATE The above data suggests that patients with frontal lobe epilepsy have behavioral disorders that appear FIG. 3. Results obtained with the clinical personality inventory. *P 0.05. **P 0.01. FIG. 4. Items extracted out of the "organic personality change" scale of the clinical personality inventory. Bars represent the per- centages of patients with focal epilepsies reporting increased prob- lems in communication and interpersonal contact. 392 Christoph Helmstaedter Copyright 2001 by Academic Press All rights of reproduction in any form reserved. very mild as compared with those reported in patients with frontal mass lesions. With respect to mood dis- orders they appear less affected than patients with temporal lobe epilepsy and they also show better ac- ademic achievement. The finding that hyperactivity, addiction, and obsession might be behavioral features of FLE is of great interest and can be discussed as reflecting frontal dysfunction in general and as being in line with the behavior observed in neuropsycholog- ical examination and during seizures. The question that remains is how consistent the behavior in focal epilepsies is over time. We cannot yet conclusively answer this question on the basis of long-term follow-up observations. The impact of epilepsy and seizures on behavior, however, can be estimated by comparisons of patients who after surgery still have seizures and those who are com- pletely seizure free. We therefore analyzed data from operated and nonoperated patients who participated in a long-term follow-up study, which was originally designed to show the cognitive development of these patients over time (67). At the long-term follow-up visit we also assessed depression by use of the Beck Depression Inventory and quality of life by use of a German modified QOLIE-10. For the present purpose we extracted from the total database only the data for patients with temporomesial epilepsy and hippocam- pal sclerosis as compared with those with frontal lobe epilepsy. Fifty-seven patients had mesial temporal lobe epilepsy with hippocampal sclerosis (27 had sur- gery, 20 were treated conservatively) and 30 patients had frontal lobe epilepsy (16 had surgery, 14 were treated conservatively). Taking depression and quality- of-life measures as the dependent variables in a mul- tivariate analysis with consideration of surgery, local- ization, and lateralization of epilepsy as independent variables and age and follow-up interval (mean, 56 months, 2­10 years) as covariates, seizure outcome turned out to be the only significant predictor. Only 14% of the seizure-free patients in contrast to 51% of those who still had seizures showed elevated depres- sion scores greater than the cutoff score of 12 points. It should be noted that 14% is much less than the usually reported 30% of patients with focal epilepsy and de- pressive mood, and that 51% clearly exceeds this num- ber. Comparably, 45% of the seizure-free patients re- ported good quality of life with QOLIE, as compared with only 11% of the patients who continued to have seizures. Although these are not follow-up data and depression and quality of life represent only two fac- ets of the whole range of behavior, these data show quite impressively what a difference the presence or absence of seizures can make. The finding parallels recent findings in children who after successful epi- lepsy surgery showed marked improvement in behav- ior disorders (68). Long-term follow-up studies on personality and behavior disorders are thus needed to complete our understanding of the interaction be- tween brain damage, epilepsy, and behavior. CONCLUSION We can conclude that in frontal lobe epilepsy "fron- tal dysfunctions" characteristically become evident in cognition, seizures, and behavior. The main common feature of the behavioral problems in FLE is behavior control in terms of response selection/initiation and inhibition. The domains in which these problems be- come apparent may vary with clinical conditions. Fol- lowing our own findings hyperactivity, conscientious- ness, obsession, and addiction can be seen as behav- ioral correlates of frontal lobe dysfunction in frontal lobe epilepsy. Depression, anxiety, neuroticism, cog- nitive (memory) impairment, and social limitations, in contrast, seem to be features of mesial temporal lobe epilepsy. However, methodological difficulties re- garding the adequacy of the clinical measures in use as well as confounding effects of lesions, epileptic dys- function, AED, and psychosocial status do not yet allow further distinctions as they are made for exam- ple in neurobiological models about the frontal lobes TABLE 6 Academic achievement level Employment Employed No regular school Lowa (Hauptschule) Medium (Realschule) Higha (Gymnasium) FLE (n 18) 17% 22% 22% 39% 68% M-TLE (n 83) 10% 54% 21% 15% 59% a 2 , significant difference. 393Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved. and behavior. Full-blown personality disorders are very rare in FLE and symptoms appear rather mild as compared with patients with mass lesions. As regards the state/trait discussion in epilepsy, the effects of seizure control indicate that a major component of the observed behavioral problems is indeed state depen- dent. However, follow-up evaluations are needed to understand the contribution of lesions and epileptic dysfunctions to behavior disorders and to demon- strate to what extent these are reversible. REFERENCES 1. Raine A, Lencz T, Bihrle S, LaCasse L, Coletti P. Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder. Arch Gen Psychiatry 2000; 67:119­27. 2. Bechara A, Damasio H, Damasio AR, Lee GP. Different contri- bution of the human amygdala and ventromedial prefrontal cortex to decision making. J Neurosci 1999;19/13:5473­81. 3. Cavada C, Compan~y T, Tejedor J, Cruz-Rizzolo RJ, Reinoso- Suárez F. The anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cereb Cortex 2000;10:220­42. 4. Sarazin M, Pillon B, Giannakopoulos P, Rancurel G, Samson V, Dubois B. Clinicometabolic dissociation of cognitive functions and social behavior in frontal lobe lesions. Neurology 1998;51/ 1:142­48. 5. Bechara A, Damasio H, Damasio AR. Emotion, decision mak- ing and the orbitofrontal cortex. Cereb Cortex 2000;10:295­307. 6. Rolls ET. The orbitofrontal cortex and reward. Cereb Cortex 2000;10:284­94. 7. Roberts AC, Wallis JD. Inhibitory control and affective pro- cessing in the prefrontal cortex: neuropsychological studies in the common marmoset. Cereb Cortex 2000;10:252­62. 8. Anderson SW, Bechara A, Damasio H, Tranel D, Damasio AR. Impairment of social and moral behavior related to early demage in human prefrontal cortex. Nat Neurosci 1999;2(11): 1032­37. 9. Trimble MR, Van Elst LT. On some clinical implications of the ventral striatum and the extended amygdala. Investigations of aggression. Ann NY Acad Sci 1999;877:638­44. 10. Azouvi P, Jokic C, Attal N, Denys P, Markabi S, Bussel B. Carbamazepine in agitation and aggressive behavior following severe closed head injury: results of an open trial. Brain Inj 1999;13:797­804. 11. Bearn RG, Gibson RJ. Aggressive behavior in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia 1998;39:280­2. 12. Van Elst LT, Woermann FG, Lemieux L, Thompson PJ, Trimble MR. Affective aggression in patients with temporal lobe epi- lepsy: a quantitative MRI study of the amygdala. Brain 2000; 123(2):234­43. 13. Kalynchuk LE, Pinel JP, Treit D. Characterization of the defen- sive nature of kindling-induced emotionality. Behav Neurosci 1999;113(4):766­75. 14. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behavior. Brain 1995;118:279­306. 15. Harlow JM. Recovery from passage of an iron bar through the head. Mass Med Soc Publ 1868;2:327­46. 16. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science 1994;20/264(5162):1102­5. 17. Dolan R. On the neurology of morals. Nat Neurosci 1999;2/11: 927­9. 18. London ED, Ernst M, Grant S, Bonson K, Weinstein A. Orbito- frontal cortex and human drug abuse: Functional imaging. Cereb Cortex 2000. 19. Rubia K, Overmeyer S, Taylor E, et al. Functional frontalization with age: mapping neurodevelopmental trajectories with fMTI. Neurosci Biobehav Rev 2000;24/1:13­9. 20. Northoff G, Richter A, Gessner M, et al. Functional dissociation between medial and lateral prefrontal cortical spatiotemporal activation in negative and positive emotions: A combined fMRI/MEG study. Cereb Cortex 2000;10:93­107. 21. Drevets WC, Raichle E. Positron emission tomographic imag- ing studies in human emotional disorders. In MS Gazzaniga (Ed.) The Cognitive Neurosciences. Massachusetts, The MIT Press 1996, 1153­62. 22. Davidson RJ, Putnam KM, Larson CL. Dysfunction in the neural circuitry of emotion regulation--A possible prelude to Violence. Science Jul 28 2000: 591­4. 23. Damasio AR. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos Trans R Soc Lond B Biol Sci 1996;351:1413­20. 24. Marsh L, Krauss GL. Aggression and violence in patients with epilepsy. Epilepsy Behav 2000;1(3):160­8. 25. Elger CE, Lehnertz K. Seizure prediction by non-linear time series analysis of brain electrical activity. Eur J Neurosci 1998 Feb;10(2):786­9. 26. Shulman MB. The frontal lobes, epilepsy, and behavior. Epi- lepsy Behav 2000;1:384­95. 27. Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia 1999;40(suppl. 10):65­70. 28. Helmstaedter C, Wagner G, Elger CE. Differential effects of first antiepileptic drug administration on cognition in lesional and nonlesional patients with epilepsy. Seizure 1993;2:125­30. 29. Milner B. Aspects of human frontal lobe function. In: Jasper HH, Riggio S, Goldman-Rakic PS, eds. Advances in Neurol- ogy. Vol. 66 New York Raven Press, 1995:67­84. 30. Baddeley AD, Hitch G. Working memory. In Bower GA, ed. Recent advances in motivation and learning, Vol 8, Academic Press, New York, 1974:47­90. 31. Milner B. Some effects of frontal lobectomy in man. In Warren JM, Akert K, eds. The frontal granular cortex. McGraw-Hill, New York 1964, 313­34. 32. Smith ML, Milner B. Differential effects of frontal-lobe lesions on cognitive estimation and spatial memory. Neuropsycholo- gia 1984;22(6):697­705. 33. Petrides M, Milner B. Deficits on subject-ordered tasks after frontal and temporal lobe lesions in man. Neuropsychologia 1982;3:249­62. 34. Petrides M. Deficits on conditional associative learning tasks after frontal- and temporal lobe lesions in man. Neuropsycho- logia 1985;5:601­14. 35. Alivisatos B, Milner B. Effects of frontal or temporal lobectomy on the use of advance in information in a choice reaction time task. Neuropsychologia 1989;27:495­503. 36. Delaney RC, Rosen AJ, Mattson RH, Novelly RA. Memory function in focal epilepsy: A comparison of non-surgical, uni- lateral temporal lobe and frontal lobe samples. Cortex 1980;16: 103­17. 394 Christoph Helmstaedter Copyright 2001 by Academic Press All rights of reproduction in any form reserved. 37. Kemper B, Helmstaedter C, Elger CE. Kognitive Profile von pra¨chirurgischen Patienten mit Frontal- und Temporallappe- nepilepsie. In: Scheffner D ed. Epilepsie '91. Einhorn Presse Verlag, Reinbeck, 1992, 345­50. 38. Stuss TD, Benson T. The Frontal Lobes. Raven Press, New York, 1986. 39. Upton D, Thompson PJ. General neuropsychological charac- teristics of frontal lobe epilepsy. Epilepsy Res 1996;23(2):169­ 77. 40. Upton D, Thompson PJ. Epilepsy in the frontal lobes: Neuro- psychological characteristics. J Epilepsy 1996;9(3):215­22. 41. Upton D, Thompson PJ. Neuropsychological test performance in frontal-lobe epilepsy: the influence of aetiology, seizure type, seizure frequency and duration of disorder. Seizure 1997; 6(6):443­7. 42. Upton D, Thompson PJ. Age at the onset and neuropsycholog- ical function in frontal lobe epilepsy. Epilepsia 1997;38:1103­ 13. 43. Upton D, Thompson PJ. Twenty question task and frontal lobe dysfunction. Arch Clin Neuropsychol 1999;14/2:203­16. 44. Helmstaedter C, Kemper B, Elger CE. Neuropsychological as- pects of frontal lobe epilepsy. Neuropsychologia 1996;34(5): 399­406. 45. Jokeit H, Seitz RJ, Markowitsch HJ, Neumann N, Witte OW, Ebner A. Prefrontal asymmetric interictal glucose hypometab- olism and cognitive impairment in patients with temporal lobe epilepsy. Brain 1997;120(12):2283­94. 46. Helmstaedter C, Gleißner U, Zentner J, et al. Neuropsycholog- ical consequences of epilepsy surgery in frontal lobe epilepsy. Neuropsychologia 1998;36(4):333­41. 47. Hermann BP, Wyler AR, Richey ET. Wisconsin card sorting test performance in patients with complex partial seizures of temporal lobe origin. Clin Exp Neuropsychol 1988;10:467­76. 48. Boone KB, Miller BL, Rosenberg L, Durazo A, McIntyre H, Weil M. Neuropsychological and behavioural abnormalities in an adolescent with frontal lobe seizures. Neurology 1988;38: 583­6. 49. Bechara A, Damasio H, Tranel D, Anderson SW. Dissociation of working memory from decision making within the human prefrontal cortex. J Neurosci 1998 Jan 1;18(1):428­37. 50. Goldberg E, Podell K. Adaptive decision making, ecological validity, and the frontal lobes. J Clin Exp Neuropsychol 2000 Feb;22(1):56­68. 51. Scherrmann JM, Elger CE. Generation of seizure phenomena in the frontal and temporal lobe. Epilepsia 1999;40(Suppl. 7):102. 52. Lux S, Helmstaedter C, Kurthen M, Hartje W, Elger CE. Local- izing value of ictal neuropsychological deficits in focal epilep- sies. Epilepsia 2000;41(Suppl. 7):153. 53. Helmstaedter C, Bauer J, Hoppe C, Elger CE. Dysexecutive symptoms in frontal lobe seizures and frontal nonconvulsive status epilepticus. (in preparation). 54. Bauer J, Helmstaedter C, Elger CE. Nonconvulsive status epi- lepticus with generalized `fast activity.' Seizure 1997;6(1):67­ 70. 55. Helmstaedter C, Elger CE, Lendt M. Postictal courses of cog- nitive deficits in focal epilepsies. Epilepsia 1994;35:1073­8. 56. Helmstaedter C, Elger CE. Cognitive-behavioral aspects of quality of life in presurgical patients with epilepsy. J Epilepsy 1994;7:220­31. 57. Beck AT, Rush AJ, Shaw BF, Emery G. Kognitive Therapie der Depression. Urban und Schwarzenberg, Mu¨nchen 1981. 58. Zung WWK. A Rating Instrument for anxiety disorders. Psy- chosomatics 1971;12:371­9. 59. Costa PT, McCrea RR. Revised NEO Personality Inventory (NEO PI-R) and the NEO Five Factor Inventory. Professional Manual. Odessa FL; Psychological Assessment Resources, 1992. 60. Cramer JA, Perrine K, Devinsky O, Meador K. A brief ques- tionnaire to screen quality of life in epilepsy the QOLIE-10. Epilepsia 1996;37:577­82. 61. Rose KJ, Derry PA, McLachlan RS. Neuroticism in temporal lobe epilepsy: assessment and implications for pre- and post- operative psychosocial adjustment. Epilepsia 1996;37(5):484­ 91. 62. Bear D, Levin K, Blumer D, Chetham D, Ryder J. Interictal behaviour in hospitalized temporal lobe epileptics: relation- ship to idiopathic psychiatric syndromes. JNNP 1982;45:481­8. 63. Devinsky O, Najjar S. Evidence against the existence of a temporal lobe syndrome. Neurology 1999;53(2):S13­S25. 64. Helmstaedter C, Gleißner U, Elger CE. Clinical personality scales (CPS) in focal epilepsy: preliminary results. Epilepsia 2000;42/(7 Suppl.):236. 65. Quiske A, Helmstaedter C, Lux S, Elger CE. Depression in patients with temporal lobe epilepsy is related to mesial tem- poral sclerosis. Epilepsy Res 2000;39(2):121­5. 66. Blumer D. Dysphoric disorders and paroxysmal affects: recog- nition and treatment of epilepsy related disorders. Harv Rev Psychiatry 2000;8/1:8­17. 67. Helmstaedter C, Kurthen M, Lux S, Johanson K, Quiske A, Schramm J, Elger CE. Long-term clinical, neuropsychological, and psychosocial follow-up in surgically and nonsurgically treated patients with drug-resistant temporal lobe epilepsy. Nervenarzt 2000;71/8:629­42. 68. Lendt M, Helmstaedter C, Kuczaty S, Schramm J, Elger CE. Behavioural disorders in children with epilepsy: early im- provement after surgery. JNNP 2000;69:739­44. 395Behavioral Aspects of Frontal Lobe Epilepsy Copyright 2001 by Academic Press All rights of reproduction in any form reserved.