18 Aggression in Epilepsy

Steven C. Schachter Epilepsy is a model for brainbehavior relationships because seizures affect behavior, and behavior affects seizures. One particularly interesting, as well as controversial, aspect of this relationship is the association of epilepsy and aggressive or violent behavior (1,2,3,4,5,6,7). Many books, papers, and reviews have addressed this topic because of its highly charged medical, legal, and sociological implications (8,9,10,11,12,13,14,15,16,17,18,19). A comprehensive review of the neurobiology of aggression, violence, and impulsivity is beyond the scope of this chapter (20,21,22), but it is pertinent to note the increasing evidence that serotonin and the amygdala are involved with impulsive and aggressive behaviors (22) and that electrical stimulation of limbic structures in animals elicits aggressive or attack behaviors (23,24,25,26,27,28,29). Rats with an electrically kindled amygdaloid seizure focus (but no spontaneous seizures) are more aggressive than control rats or those with a kindled focus in the caudate nucleus, suggesting that hippocampal or amygdaloid kindling could be associated with violent behavior even without clinical evidence of a seizure disorder (26). Further, ictal discharges in amygdala, hippocampus, and septal regions have been observed with deep electrodes in several patients with epilepsy and nonictal episodic aggressive behavior, (30) as well as in others with ictal aggression (31,32). The behavioral effects of electrical stimulation and the findings of epileptiform discharges in patients with aggressive behavior do not, however, prove that aggression and epilepsy are related. As outlined by Herzberg and Fenwick, there are three key questions to be answered (33):

Is the association between aggression and epilepsy due to occurrence of the epileptic seizure itself?

Is it due to the associated brain damage that may be the cause of seizures?

Is it the result of socioeconomic factors or medication?

This chapter first reviews the available data related to these three questions and then outlines the measurement of aggressive behavior, discusses treatment approaches, and highlights legal considerations. P.307

Is the Association between Aggression and Epilepsy Due to Occurrence of the Epileptic Seizure Itself? Using seizures as a marker in time, aggressive and violent behavior may be considered by their temporal relations to seizures. Preictal Aggression In some patients, the seizure prodrome (the minutes, hours, or even days leading up to a seizure) consists of predictable changes in psychological functioning and behavior, including the development of irritability, anxiety, and aggression (34,35). Ictal Aggression Directed, purposeful, aggressive, or violent behavior during seizures is generally considered rare. Papers in the literature typically include either cases in which seizures were inferred from the history, or others in which seizures were directly observed by trained professionals or recorded with sophisticated monitoring techniques. Hindler reported the case of a 19-year-old nanny with a history of febrile convulsions up to the age of 7 and a positive family history for focal epilepsy in a younger sister (36). The patient had a more recent history of 5- to 10-minute episodes of strange sensations resulting in a feeling of emptiness and a sensation

of the mind becoming separated from the body, followed by intense feelings of hate and aggression directed at the baby in her care. The episodes were triggered by the baby laughing and were only experienced while the nanny and the baby were alone. During one such episode, she swung the baby by the legs and the baby's head hit a cabinet and perhaps the floor, leading to a fatal brain injury. After she was incarcerated, her doctor observed her to have a generalized epileptiform convulsion. An electroencephalogram showed epileptiform abnormalities and she was treated with anticonvulsant therapy with no further abnormal experiences. Hindler concluded that the patient committed murder during an epileptic attack and that she had an unusual form of reflex epilepsy. One hundred and thirty-two prisoners with epilepsy (including 11 who were convicted of murder, attempted murder, rape, attempted rape, and armed violence) were asked if they had ever committed an offense in association with a seizure (37). None of the prisoners admitted to a history of ictal violence, although three reported being arrested for disorderly conduct immediately after a seizure and one had a seizure while a robbery was already in progress. Directed, purposeful ictal aggression during observed seizures has only been rarely reported (1,38,39,40). At the Montreal Neurological Institute, Gloor witnessed few, if any, cases of spontaneous or electrically induced ictal aggression (41). Similarly, Rodin witnessed several hundred spontaneous psychomotor seizures; only one seizure was accompanied by directed aggression, which Rodin concluded was goal directed and an expression of vengeance, rather than related directly to the seizure (40). Rodin further reported 57 patients whose bemegride-induced psychomotor automatisms were photographed while they were seated in a chair undergoing electroencephalographic (EEG) testing (40). None of the patients became aggressive during seizures, although two patients were observed to suddenly lunge forward and show a rather ferocious facial expression. In one case, an unsuccessful attempt by the attending physician to keep the patient seated

made the patient clench his fist, adopt a boxer-type stance, and appear imminently violent. The threatening behavior immediately ended once the patient was physically released, suggesting to Rodin a defensive reaction due to being restrained rather than active trouble-seeking. He postulated that P.308

the patient, if he were to be restrained during his confusional state, might react in a defensive manner that could be misinterpreted as a goal-directed assault. Because the EEG results were not provided, it is possible that this may have been a case of postictal resistive violence (see subsequent text). Ramani and Gumnit recorded focal seizures in 15 patients with epilepsy and significant histories of episodic aggressive behaviors (39). No patients showed ictal violent or aggressive behavior. Delgado-Escueta et al. reviewed the cases of 5,400 patients with epilepsy who underwent inpatient evaluation (1). They further studied 19 patients who were believed to have ictal aggression, including 3 previously reported patients (31,42). On the basis of a review of 33 seizures, the authors concluded that only one patient committed an aggressive act during a seizure that could have harmed another person (the patient attempted to scratch her psychologist's face). None of the other observed aggressive behaviors threatened the well-being of others, although some behaviors appeared hostile, such as assuming a karate posture and making striking motions, shouting, or spitting, or destroying inanimate objects such as curtains, chairs, and beds. Other anecdotal reports of aggressive ictal automatisms have documented behaviors such as flailing or chopping movements of the arms, spitting, biting, or physical assaults on nearby objects (32,42,43), which were generally stereotyped and nondirected.

Nonconvulsive status epilepticus may present with psychiatric symptomatology, including psychotic features (44). A report nearly 40 years ago suggested that absence status epilepticus may be associated with hostility, aggression, agitation, and impulsive behavior (45). Kutlu et al. (46) analyzed ictal behaviors during 282 recorded seizures in 48 patients with temporal lobe epilepsy (TLE) who subsequently underwent anterior temporal lobectomy and became seizure-free for at least 2 years. Ictal aggression occurred nearly twice as often in the 13 patients whose resected tissue showed pathological findings other than hippocampal sclerosis, such as tumors, cavernoma, and hamartoma, as in the 35 patients with hippocampal sclerosis. However, this difference was not significant when a patient with neocortical gliosis was excluded from the analysis. Postictal Aggression Several studies utilizing video EEG monitoring showed that violent behavior may result from attempts at physical restraint during the postictal period, the so-called resistive violence (1,43,47). For example, one patient exhibited angry facial expressions during ictal episodes and confused, nondirected, aggressive behavior postictally while attempting to free himself of the soft restraints (39). Another patient became greatly agitated during the postictal period, with undirected aggression, loud screaming, kicking and fighting against the restraints (47). Tassinari et al. (48) noted that late ictal and postictal biting behavior was usually precipitated by the intrusion of the examiner's hand near the patient's face. Violent behavior may occur during a postictal psychosis, which typically begins within several days of a cluster of complex partial or secondary generalized seizures and includes hallucinations, paranoia, and delusions (44,49,50,51,52). The fear that accompanies the delusions or paranoia may lead to violent behavior, which may be self-directed (53,54).

Kanemoto et al. evaluated aggression in 30 patients with postictal psychosis and 30 patients matched for gender, age, and age of seizure onset with postictal confusion, but no postictal psychosis (54). All seizures had partial onset, and were directly observed and documented by trained professionals. A postictal psychosis was diagnosed on the basis of hallucinations, delusions, thought disorder, and affective changes that were clinically demarcated from seizures and the immediate postictal state. Violence was defined as well-directed, well-organized attacks against human beings because of irrational behavior that resulted in a severe injury or a life-threatening situation, P.309

such as strangulation. Resistive violence as described in the preceding text was analyzed separately. In their study, violent attacks occurred in association with 13 out of 57 (23%) episodes of postictal psychosis, compared with 1 out of 134 episodes of postictal confusion (p <0.001). In eight postictal psychotic episodes, violent behavior occurred within 24 hours of the onset of postictal psychosis. Another four patients in the postictal group attempted suicide during their postictal psychosis, compared with none of the controls (p <0.005). On the other hand, four control patients displayed resistive violence during the postictal state compared with none of the patients with postictal psychosis. Interictal Aggression Blumer has described an interictal dysphoric disorder, characterized by marked irritability, with troublesome loss of control and often associated with intermittent depressive or euphoric moods, anergia, insomnia, anxiety, and fears (55,56). Interictal aggression has generally been studied in select groups of patients and prisoners with epilepsy. The results in these skewed populations suggest that impulsive, assaultive interictal behavior is seen in up to 56% of patients with TLE (57,58,59,60,61,62,63).

Of 100 children with TLE followed for a mean of 10 years, 36 had outbursts of unspecified catastrophic rage (64). Rage outbursts were associated with a history of head injury or cerebral infection, seizure onset under the age of 1 year, and a disordered home (defined as gross poverty, deceased mother before the proband was 10 years old, aggressive father, or psychosis or chronic neurosis in one or both parents). There was no relationship between seizure frequency and rage outbursts. Not all studies find a high incidence of interictal aggression. Rodin (40) reviewed the charts of 700 patients with epilepsy seen at a tertiary referral center over a 5year period and found that 34 (4.8%) had exhibited destructive-assaultive behavior. These aggression-prone patients tended to be young men of lower-thanaverage intelligence, with a history of behavioral difficulties dating back to school age, who had unspecified signs of diffuse organic disease. There was no association between seizure type or the location of onset and the likelihood of aggressive behavior. Hermann et al. later confirmed these findings (65). Ramani and Gumnit (39) studied 19 patients with epilepsy and significant histories of episodic aggressive behaviors for an average of 6.3 weeks as inpatients with video telemetry. Two patients exhibited repeated aggressive behavior. There was no apparent temporal relationship between the aggression and ictal EEG patterns in one patient, who ripped loose a kitchen sink. Upon admission, 13 patients were irritable and socialized poorly, but this behavior was said to improve in the supportive ward milieu. Mendez et al. (66) reviewed the records of 44 patients with epilepsy attending a university-affiliated neurology clinic who were referred for psychiatric evaluation because of violent interictal behavior (defined as the forceful infliction of injury or harm on persons or property). Most of the violent acts consisted of verbal or minor physical aggression. Compared with nonviolent age- and sex-matched patients with epilepsy, the violent patients did not differ on seizure variables such as type and frequency of seizures, auras, EEG findings, age of seizure onset, or

antiepileptic drug (AED) treatment. The authors concluded that interictal violence in their sample was not associated with epileptiform activity or other seizure variables. Herzberg and Fenwick (33) retrospectively reviewed the charts of patients admitted to the epilepsy unit of the Maudsley Hospital over a 10-year period with a diagnosis of TLE on discharge. Aggressive behavior was associated with male sex, early age of seizure onset, and a history of chronic behavioral difficulties. No relationship was found with specific EEG or computed tomography scan findings or a history of psychosis. Kanemoto et al. (54) studied the incidence of interictal violence in 33 patients with localization-related epilepsy and acute interictal psychosis. Violent attacks occurred P.310

in association with 3 of 62 interictal psychotic episodes, which was significantly less than the incidence of violent attacks that occurred in other patients during postictal psychoses (p <0.01). Among adolescent and adult prisoners, the prevalence of EEG abnormalities and epilepsy has been reported to be as high as 65% and 18%, respectively (16,37,67,68,69,70). Because the prevalence of epilepsy in prisoners may be similar to the prevalence of epilepsy in the underprivileged, lower socioeconomic communities from which prisoners typically originate (71), these studies do not necessarily prove that epilepsy is more frequent among prisoners. Several studies on prisoners have attempted to correlate epilepsy with violence. Lewis et al. (67) retrospectively reviewed records of incarcerated adolescent boys and found that the number of psychomotor symptoms correlated with degree of violence (as measured by a scale derived by the authors). By contrast, two other studies found that prisoners with epilepsy were not convicted of more

serious or more violent crimes than age- and race-matched nonepileptic prisoners (37,68,70). Is Aggression Due to the Associated Brain Damage that may be the Cause of Seizures or the Result of Socioeconomic Factors or Medication? Several studies showed a high prevalence of head injury in violent patients with epilepsy, suggesting that brain damage is the more proximate cause of poor impulse control and violent behavior, rather than seizures (67,72,73). Among 18 incarcerated adolescent boys with definite or probable epilepsy, 16 (89%) had histories of severe brain trauma and/or perinatal difficulties (67). In another study, head trauma was the probable cause of seizures in 45% of adult prisoners with epilepsy using rigorous diagnostic criteria (37). Another cause of violent behavior in patients with epilepsy is psychosis (74,75). Interictal psychosis and other psychopathology are increased in patients with epilepsy (76), and psychosis in nonepileptic patients is associated with violent behavior, especially in conjunction with delusions (77,78,79). In an unselected Swedish birth cohort followed up to the age of 30, men with schizophrenia and major affective disorders were four times more likely to commit a violent offense than men with no mental disorder; among women with major mental disorders there was a 27-fold increase (74). Among 18 incarcerated adolescent boys with definite or probable epilepsy, paranoid ideation and hallucinations were common and contributed to violent acts (67). In another series, patients with epilepsy who were violent were significantly more likely to meet the diagnostic criteria for a schizophrenic disorder compared with age- and sex-matched patients with epilepsy who were not violent (p <0.001) (66). Although not reaching statistical significance, violent patients were also twice as likely to be diagnosed with depression or bipolar disease, and an adjustment disorder. One patient impulsively killed someone with an automobile in association with paranoid ideation; a court-ordered neuropsychiatric evaluation concluded that the violence resulted from a paranoid schizophrenic state.

Nakaji et al. (80) reported two pediatric patients with TLE and interictal aggression and rage attacks whose behavior and seizures significantly improved after resection of temporal lobe tumors, although the relative contribution of the tumors versus the seizures to the aggressive behavior in these patients cannot be fully known. By comparison, Franzon et al. (81) described two patients who became very aggressive after surgical resection of left temporal lobe tumors. Cognitive and Behavioral Disorders Mild-to-severe cognitive deficits, especially in the domains of attention, memory, and P.311

motor speed are associated with epilepsy in many patients (82) and may contribute to violent behavior. In a Swedish study, intellectually handicapped men were five times more likely than men with no handicap to commit a violent offense; among intellectually handicapped women there was a 25-fold increase (74). Several studies have shown a high incidence of mental retardation and chronic behavioral disorders in patients with epilepsy who were violent (33). Mendez et al. (66) found that these patients were significantly more likely to be mentally retarded compared with nonviolent age- and sex-matched patients with epilepsy (p <0.01). In a retrospective study at a residential facility for patients with epilepsy, Bogdanovic et al. (83) found that the prevalence of aggression was 27.2% over 1 year, and the overall frequency was between 121 and 207 incidents per 100 persons per year. Neuroendocrinological Dysfunction Measurable hormonal changes accompany seizures, (84), epileptiform discharges (85,86), and AED therapy (87,88,89,90,91). Whether these hormonal changes are surrogate markers for neuronal dysfunction or related to specific behaviors is not known.

Prolactin and cortisol are of particular interest. Low prolactin levels have been linked to psychosis (92,93), and an increase in the rate of metabolism of a radioactive dopa tracer has been demonstrated in the neostriatum of patients with limbic seizures and psychosis (94). Leiderman et al. (95) studied the correlations of neuroendocrine function with psychopathology, seizure variables, and neuropsychological function in 16 male patients with limbic epilepsy and found a correlation between low prolactin concentrations and thinking disturbance on the Brief Psychiatric Rating Scale. Cortisol concentrations may increase following seizures (96,97), and high serum cortisol concentrations are associated with fear-based defensive aggression in rhesus monkeys (98). The relationships between postictal resistive violence, postictal fear, and postictal cortisol concentrations remain to be explored. Episodic Dyscontrol Episodic dyscontrol (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] classification 312.34, Intermittent Explosive Disorder [IED]) is characterized by episodic violent behavior in patients who do not otherwise have an aggressive personality disorder. The patient's temper escalates over minutes and is greatly out of proportion to the nature of the provocation, which is trivial, if any (53). The episodes generally occur in the presence of other people who are emotionally important to the patient and last for 20 to 30 minutes. Patients are unable to terminate the episode once it is in progress. Afterwards, patients are remorseful, regretful, or embarrassed, and they understand that their temper was excessive under the circumstances. The relationship of episodic dyscontrol to epilepsy is unclear (99,100) and the etiology is unknown, although epileptiform discharges in limbic structures may play a role (53). van Elst et al. (101) evaluated 50 patients with TLE, including 25 with IED and 25 without IED, and found that IED was associated with left-sided or bilateral EEG and magnetic resonance imaging (MRI) abnormalities, low intelligence quotients (IQ) and high scores in depression and anxiety. These

findings suggested to the authors that IED is associated with more distributed and predominantly bilateral or left-sided brain pathology. In support of this hypothesis, Juhasz et al. (102) found bilateral prefrontal and temporal neocortical brain glucose hypometabolism in 6 children with intractable partial epilepsy and aggressive behavior, and Woermann et al. (103) noted decreased frontal gray matter, especially on the left, in 24 patients with TLE and IED as compared to 24 patients with TLE but without IED. Interestingly, Tassinari et al. (48) reported a patient with ictal biting behavior whose ictal activity, as recorded by intracranial electrodes, involved the right amygdala/hippocampal region plus P.312

the orbitomedial prefrontal cortex. Consistent with a contribution of extratemporal structures to aggressive behavior, Hallak et al. (104) described a 28-year-old man with a 21-year history of TLE and IED whose aggression continued after a temporal lobectomy despite the patient becoming seizure-free from the procedure. In that case, olanzapine resulted in significant improvement of the aggressive episodes. Socioeconomic Factors Antisocial, violent behavior is often associated with a childhood history of impulsive behavior. Other contributing factors are living in a crowded environment, disrupted and unstable home environments, accessibility of guns, decline of cultural constraints, and violent role models, especially parents who incorporate physical punishment in their child-rearing practices (59,72,78,105). Iatrogenic Causes Aggressive or violent behavior may be due to corticosteroids, digitalis, L-dopa, isoniazid, anticholinergic drugs, antihistamines, antabuse, propranolol, indomethacin, bromocryptine, and sedatives (106). In patients with epilepsy, AEDs may cause aggressive behavior. In a multicenter observational survey of

285 pediatric patients with refractory generalized and focal epilepsy who were treated with add-on, open-label levetiracetam (LEV), aggression was noted in 44 patients (15.4%) and led to discontinuation in 23 (8.1%) (107). Frank aggression was observed in 30 patients (10.5%); for example, 2 patients with no prior history of aggression attacked others violently. Dinkelacker et al. (108) studied 33 patients with epilepsy who became aggressive while taking LEV, representing 3.5% of LEV-treated patients at their center. A previous history of aggression appeared to be a risk factor. Although most of these patients displayed minor irritability or verbally aggressive behavior, nine patients became physically violent, including two who required emergency psychiatric treatment. Topiramate (TPM) has been associated with aggressive behavior in children and adolescents, especially when there is a history of aggression before TPM treatment (109). AEDs may also precipitate aggression as a consequence of a psychosis associated with complete seizure control (forced normalization) (110) or because of sedation and disinhibition. Therefore, before initiating additional pharmacotherapy, reducing the dose of a sedating AED may be reasonable, particularly if seizures are well controlled. Another unusual cause of iatrogenic aggression due to AEDs is acute intermittent porphyria, which results from inherited abnormalities of the enzyme porphobilinogen deaminase (111,112,113). Acute attacks can be triggered by many AEDs and may last for day to weeks. Prominent symptoms include abdominal pain, constipation, tachycardia, and seizures. Patients are often delirious and psychotic, and may exhibit aggressive or violent behavior. Miscellaneous Violent behavior may occur during a delirium, which is usually characterized by inattention, agitation, hallucinations, delusions, and restlessness. Delirium may be due to drug (substance) and alcohol abuse or withdrawal in patients with or without a history of psychosis (77,114). Amphetamines, diet pills, cocaine, phencyclidine, opioids, and lysergic acid diethylamide (LSD) are particularly

likely to cause aggression. Other medical conditions to consider are hypoxemia, hypoglycemia, and thyrotoxicosis. Research Methodology: Instruments for Measuring Aggressive Behavior There is no widely used instrument for measuring aggressive behavior in patients with epilepsy, in part because of the problems inherent in assessing aggression in this population (115,116). Even so, the Resentment-Aggression scale on the Minnesota Multiphasic Personality Inventory (MMPI) P.313

and the Aggression scale of the Bear-Fedio Inventory have been utilized for research purposes in patients with epilepsy, as have several other tools (59,65,67,117). Many scales and inventories have been developed, validated, and used in studies of aggressive behavior in nonepileptic populations, such as patients with head injury and dementia. The Behavior Rating Scale for Dementia was designed to measure behaviors, including irritability and aggression, in patients with dementia (118). The Neurobehavioral Functioning Inventory addresses somatic, cognitive behavioral, communication, and social problems and has been used in patients with head injury (119,120). Other available instruments include the Buss-Durkee Hostility Inventory, which is completed by self-report, and includes the subscales Indirect Assault, Irritability, Verbal Assault, and Direct Assault (121); the Subtraction Aggression Paradigm, a computerized test designed to provoke aggressive behavior (122); the Barratt Impulsiveness Scale (123); the Agitated Behavior Scale (124), and several others (125,126,127,128,129,130,131). Treatment Considerations

Aggressive behavior is probably underreported to physicians for a variety of reasons, including embarrassment, the desire to keep such behavior personal, and a lack of appreciation that it may be treatable. Most neurologists, in turn, do not take sufficiently detailed histories of aggressive behavior. Therefore, the assessment of aggressive behavior must begin with heightened awareness by physicians, who should inform patients and families in a reassuring manner that aggressive behavior can occur in association with epilepsy for a number of reasons, some of which are reversible. The physician should ask patients and their families specific and directed questions to determine whether the behavior in question is disruptive, destructive, or dangerous, and, therefore, necessary to be evaluated and addressed further. Aggressive behavior can be viewed along a spectrum; the point at which it requires evaluation and possible treatment will depend on the individual circumstances and cultural setting. In general, the appropriate treatment of aggressive or violent behavior in a patient with epilepsy depends on the cause. Ictal aggression due to isolated seizures or nonconvulsive status epilepticus responds to AED therapy. Postictal resistive violence is avoided by limiting physical restraint during the postictal period when possible (42,132). Aggression or violence during a postictal psychosis is prevented by eliminating clusters of seizures and treated acutely with benzodiazepines and dopamine blockers, particularly haloperidol (11,44). Psychiatric hospitalization is recommended if the patient is at risk for impulsive, potentially self-injurious behavior. Interictal aggression is somewhat more complicated to treat because it does not necessarily improve with complete seizure control (9,133). Controlled studies are unavailable, but AEDs and psychoactive drugs have been used empirically. Antiepileptic Drugs AEDs have been used to treat aggressive and violent behavior in nonepileptic patients (134). Carbamazepine (CBZ) has been shown to be effective for episodic dyscontrol (135,136) as well as for violent behavior in patients with psychiatric

disorders and no evidence of EEG abnormalities (137). An open trial of CBZ, 400 to 800 mg per day for 8 weeks, in ten nonepileptic patients with agitation and anger outbursts following closed head injuries reduced irritability and disinhibition, and resulted in improvement on the Agitated Behavior Scale in eight patients (80%) (124). A placebo-controlled, double blind, randomized trial of CBZ for treatment of agitation and aggression in 51 nursing home residents with dementia showed statistically significant efficacy for CBZ (mean serum level of 5.3 g per mL) compared with that for placebo (138). CBZ may also be beneficial for agitation in patients with Alzheimer's disease whose behavior fails to improve with neuroleptics (139). P.314

Other AEDs may be beneficial. Valproate shows possible efficacy in the treatment of agitation, impulsive aggression, and episodic dyscontrol (53,140). There have been several reports of a beneficial effect of gabapentin and lorazepam for agitation in nonepileptic patients, including patients with Alzheimer's disease (141,142,143). Psychoactive Drugs Clozapine, an atypical antipsychotic agent that does not cause extrapyramidal side effects, reduces aggressive and violent behavior associated with a psychosis, including self-mutilating behavior (144,145). However, dose-related seizures occur in 3% to 5% of treated patients (51). Antidepressants may be useful for the interictal dysphoric disorder described by Blumer (55). Psychosurgery From the 1950s through the 1970s, amygdalectomies were recommended by some proponents for the treatment of aggressive behavior, including use in patients with

epilepsy (115,146). No controlled studies were performed, behavioral outcomes were not quantified, and selection criteria are not yet understood (11,53,116). Legal Considerations From 1889 through 1981, epilepsy was used as a defense against charges of murder, homicide, manslaughter, or disorderly conduct in 15 appellate cases (1). From 1977 through 1981, epileptic automatisms were used as part of a diminished legal responsibility or insanity defense against 12 charges of violent crimes, including 5 murder cases in 1979 (1). In one wellpublicized case, a New York City policeman pleaded mental illness to a charge of murder (147). A psychiatrist testifying for the defendant stated that the police officer shot and killed a 15-year-old boy, apparently without being provoked, either during a seizure or because of a psychosis associated with epilepsy. The defendant had no prior history of epilepsy, and neurologists testified he did not have epilepsy. The jury found him not guilty, and he was committed to a state hospital. Other psychiatrists and neurologists concluded he did not have epilepsy. He was subsequently released upon order from the court because there was no documented proof that he had mental illness and posed a danger to others. Physicians may be called on to render an opinion whether a particular patient committed an aggressive or violent act in conjunction with a seizure. In 1981, a panel of epileptologists suggested five relevant criteria to determine whether a violent crime resulted from an epileptic seizure (1):

The diagnosis should be established by at least one neurologist with special competence in epilepsy.

The presence of epileptic automatisms should be documented by the history and by closed-circuit television and EEG monitoring.

The presence of aggression during epileptic automatisms should be verified in a videotape-recorded seizure in which ictal epileptiform patterns are also recorded on the electroencephalogram.

Aggressive or violent act should be characteristic of the patient's habitual seizures.

A clinical judgment should be made by the neurologist, attesting to the possibility that the alleged crime was part of a seizure.

In 1989, Hindler suggested the following less stringent criteria for determining that a crime was committed during a seizure (36):

An unequivocal past history of epileptic attacks The crime is out of character with the accused person's previous personality

The crime is motiveless and unpremeditated EEG studies are compatible An altered state of consciousness during the event Total or partial amnesia for the crime

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Conclusions There are multiple determinants to violent and aggressive behavior, and new techniques, such as neuroimaging studies, are expanding our understanding of the neurobiology of these behaviors (102,103). However, the practical limitations of studying epilepsy and violence and the methodological problems reported in the

literature have hampered our understanding of the causal relationships between seizures and aggression, although, as observed by Devinsky and Bear (58), it would be difficult to cite, either from case reports or a literature review, another medical or neurologic illness in which aggressive behavior is described so regularly. Nonetheless, the available evidence suggests that seizures and the brain pathology that underlies seizures may give rise to aggression in some patients with postictal confusion who are restrained, patients with postictal psychosis, and some patients during the interictal period. Studies of ictal aggression have been limited by a number of factors. Patients are observed in unnatural environments, such as hospital rooms, and seize under circumstances that may be unusual for them, for example, in bed or in a locked room (33,47). Observers are generally trained professionals who are taught not to apply restraint during or after seizures. These factors probably influence the incidence and nature of seizure-related behavior (42). Recording seizures in patients with very violent behavior is technically difficult and ethically problematic. Therefore, it is unlikely that a case of ictal or postictal violence that involves a series of organized purposeful behaviors, if it exists, could ever be electrographically confirmed. Although the current evidence argues against the possibility of goal-directed ictal aggression, absence of proof is not necessarily proof of absence. Studies of ictal aggression are generally performed in tertiary referral centers with patients who are referred for evaluation of particularly severe or unusual seizures. Such patients also tend to have significant cognitive and behavioral disorders and psychosocial difficulties. The highly selected nature of this population may bias the likelihood of documenting aggressive behavior. Similarly, studies of interictal aggression generally rely on specific cohorts, such as incarcerated prisoners or subjects at detention centers or group homes, rather than a random sampling of patients with epilepsy in the community, and the reliability of medical information and data acquisition varies substantially between studies.

Many previous studies have lacked adequate control groups. Numerous confounding and interrelated variables must be considered in future studies of epilepsy and aggression (Table 18.1), including seizure type, specific auras, ictal automatisms, postictal behavior, whether the patient is already engaged in a threatening situation when the seizure begins, seizure medications, and fluctuations in serum concentrations. Other important variables are a history of violence before the onset of seizures, history of drug or alcohol abuse, intelligence level, brain injury/pathology, comorbid cognitive and psychiatric disorders, neuroendocrine function, and psychosocial variables, such as coping mechanisms, socioeconomic status, and family structure. In addition to adequate controls, studies must be sufficiently powered; otherwise, negative findings are inconclusive. Further, researchers must develop a practical taxonomy of aggressive behavior (IED is the only DSM-IV diagnosis that recognizes aggressive behavior), precise terminology (20), and tools for measuring aggressive and violent behavior in patients with epilepsy that are easy to complete and validate for this patient population. Well-controlled studies of aggression and epilepsy will better characterize the etiological factors that give rise to socially disruptive behavior and help establish more effective treatments. In addition, such studies will reduce the stigma of epilepsy, which is based in part on the misconception that violence and epilepsy are inextricably linked (11). P.316

TABLE 18.1 Variables That Should Be Controlled in Studies of Epilepsy and Aggression Seizure-related variables Seizure type(s) and age of onset

Etiology of seizures/epilepsy syndrome/EEG findings Nature of auras and ictal automatisms Postictal behavior/psychosis Temporal relationship between aggression and seizures Activity that the patient was engaged in at start of seizure Seizure medications taken; evidence of neurotoxicity Other medical variables Drug or alcohol abuse Head injury/brain pathology Intelligence quotient Concomitant cognitive and psychiatric disorders Neuroendocrinological function Psychosocial variables Socioeconomic status History of violence before onset of seizures Family background/structure Coping skills EEG, electroencephalogram.