18 Aggression in Epilepsy (21).docx

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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 wellas controversial, aspect of this relationship is the association of epilepsy andaggressive or violent behavior (1,2,3,4,5,6,7). Many books, papers, and reviewshave addressed this topic because of its highly charged medical, legal, andsociological implications (8,9,10,11,12,13,14,15,16,17,18,19).

A comprehensive review of the neurobiology of aggression, violence, andimpulsivity is beyond the scope of this chapter (20,21,22), but it is pertinent tonote the increasing evidence that serotonin and the amygdala are involved withimpulsive and aggressive behaviors (22) and that electrical stimulation of limbicstructures 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 thecaudate nucleus, suggesting that hippocampal or amygdaloid kindling could beassociated with violent behavior even without clinical evidence of a seizuredisorder (26). Further, ictal discharges in amygdala, hippocampus, and septalregions have been observed with deep electrodes in several patients with epilepsyand nonictal episodic aggressive behavior, (30) as well as in others with ictalaggression (31,32).

The behavioral effects of electrical stimulation and the findings of epileptiformdischarges in patients with aggressive behavior do not, however, prove thataggression and epilepsy are related. As outlined by Herzberg and Fenwick, thereare three key questions to be answered (33):

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

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


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Is it the result of socioeconomic factors or medication?

This chapter first reviews the available data related to these three questions andthen outlines the measurement of aggressive behavior, discusses treatmentapproaches, and highlights legal considerations.

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Is the Association between Aggression and Epilepsy Due to Occurrence of theEpileptic Seizure Itself?

Using seizures as a marker in time, aggressive and violent behavior may beconsidered by their temporal relations to seizures.

Preictal Aggression

In some patients, the seizure prodrome (the minutes, hours, or even days leadingup 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 generallyconsidered rare. Papers in the literature typically include either cases in whichseizures were inferred from the history, or others in which seizures were directlyobserved by trained professionals or recorded with sophisticated monitoringtechniques.

Hindler reported the case of a 19-year-old nanny with a history of febrileconvulsions up to the age of 7 and a positive family history for focal epilepsy in ayounger 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


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of the mind becoming separated from the body, followed by intense feelings ofhate 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 babywere 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 generalizedepileptiform convulsion. An electroencephalogram showed epileptiformabnormalities and she was treated with anticonvulsant therapy with no further

abnormal experiences. Hindler concluded that the patient committed murderduring an epileptic attack and that she had an unusual form of reflex epilepsy.

One hundred and thirty-two prisoners with epilepsy (including 11 who wereconvicted 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 threereported 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 beenrarely reported (1,38,39,40). At the Montreal Neurological Institute, Gloorwitnessed few, if any, cases of spontaneous or electrically induced ictalaggression (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, ratherthan related directly to the seizure (40).

Rodin further reported 57 patients whose bemegride-induced psychomotorautomatisms were photographed while they were seated in a chair undergoingelectroencephalographic (EEG) testing (40). None of the patients becameaggressive during seizures, although two patients were observed to suddenlylunge forward and show a rather ferocious facial expression. In one case,

an unsuccessful attempt by the attending physician to keep the patient seated


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Nonconvulsive status epilepticus may present with psychiatric symptomatology,including psychotic features (44). A report nearly 40 years ago suggested thatabsence 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 anteriortemporal lobectomy and became seizure-free for at least 2 years. Ictal aggressionoccurred 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 neocorticalgliosis 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-calledresistive 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, withundirected 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 beginswithin several days of a cluster of complex partial or secondary generalizedseizures 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).


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Kanemoto et al. evaluated aggression in 30 patients with postictal psychosis and30 patients matched for gender, age, and age of seizure onset with postictalconfusion, but no postictal psychosis (54). All seizures had partial onset, and weredirectly observed and documented by trained professionals. A postictal psychosiswas diagnosed on the basis of hallucinations, delusions, thought disorder, andaffective changes that were clinically demarcated from seizures and the immediate postictal state. Violence was defined as well-directed, well-organized attacksagainst human beings because of irrational behavior that resulted in a severeinjury or a life-threatening situation,

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such as strangulation. Resistive violence as described in the preceding text wasanalyzed 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 postictalconfusion (p


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antiepileptic drug (AED) treatment. The authors concluded that interictal violencein their sample was not associated with epileptiform activity or other seizurevariables.

Herzberg and Fenwick (33) retrospectively reviewed the charts of patientsadmitted to the epilepsy unit of the Maudsley Hospital over a 10-year period witha diagnosis of TLE on discharge. Aggressive behavior was associated with malesex, early age of seizure onset, and a history of chronic behavioral difficulties. Norelationship 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 patientswith localization-related epilepsy and acute interictal psychosis. Violent attacksoccurred

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in association with 3 of 62 interictal psychotic episodes, which was significantlyless than the incidence of violent attacks that occurred in other patients during postictal psychoses (p


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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 ofSeizures or the Result of Socioeconomic Factors or Medication?

Several studies showed a high prevalence of head injury in violent patients withepilepsy, suggesting that brain damage is the more proximate cause of poorimpulse control and violent behavior, rather than seizures (67,72,73). Among 18incarcerated adolescent boys with definite or probable epilepsy, 16 (89%) hadhistories 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 withepilepsy 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 withepilepsy (76), and psychosis in nonepileptic patients is associated with violent

behavior, especially in conjunction with delusions (77,78,79). In an unselectedSwedish birth cohort followed up to the age of 30, men with schizophrenia andmajor affective disorders were four times more likely to commit a violent offensethan men with no mental disorder; among women with major mental disordersthere 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 significantlymore likely to meet the diagnostic criteria for a schizophrenic disorder comparedwith age- and sex-matched patients with epilepsy who were not violent (p


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Nakaji et al. (80) reported two pediatric patients with TLE and interictalaggression and rage attacks whose behavior and seizures significantly improvedafter resection of temporal lobe tumors, although the relative contribution of thetumors versus the seizures to the aggressive behavior in these patients cannot befully 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

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motor speed are associated with epilepsy in many patients (82) and maycontribute to violent behavior. In a Swedish study, intellectually handicapped menwere 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 andchronic behavioral disorders in patients with epilepsy who were violent (33).Mendez et al. (66) found that these patients were significantly more likely to bementally retarded compared with nonviolent age- and sex-matched patients withepilepsy (p


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Prolactin and cortisol are of particular interest. Low prolactin levels have beenlinked to psychosis (92,93), and an increase in the rate of metabolism of aradioactive dopa tracer has been demonstrated in the neostriatum of patients withlimbic seizures and psychosis (94). Leiderman et al. (95) studied the correlationsof neuroendocrine function with psychopathology, seizure variables, andneuropsychological function in 16 male patients with limbic epilepsy and found acorrelation between low prolactin concentrations and thinking disturbance on theBrief Psychiatric Rating Scale.

Cortisol concentrations may increase following seizures (96,97), and high serumcortisol concentrations are associated with fear-based defensive aggression inrhesus 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 nototherwise have an aggressive personality disorder. The patient's temper escalatesover 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 theirtemper was excessive under the circumstances.

The relationship of episodic dyscontrol to epilepsy is unclear (99,100) and theetiology is unknown, although epileptiform discharges in limbic structures may play a role (53). van Elst et al. (101) evaluated 50 patients with TLE, including 25with IED and 25 without IED, and found that IED was associated with left-sidedor bilateral EEG and magnetic resonance imaging (MRI) abnormalities, low

intelligence quotients (IQ) and high scores in depression and anxiety. These


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findings suggested to the authors that IED is associated with more distributed and predominantly bilateral or left-sided brain pathology. In support of thishypothesis, Juhasz et al. (102) found bilateral prefrontal and temporal neocortical brain glucose hypometabolism in 6 children with intractable partial epilepsy andaggressive behavior, and Woermann et al. (103) noted decreased frontal graymatter, 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 intracranialelectrodes, involved the right amygdala/hippocampal region plus

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the orbitomedial prefrontal cortex. Consistent with a contribution of extratemporalstructures to aggressive behavior, Hallak et al. (104) described a 28-year-old manwith a 21-year history of TLE and IED whose aggression continued after atemporal lobectomy despite the patient becoming seizure-free from the procedure.

In that case, olanzapine resulted in significant improvement of the aggressiveepisodes.

Socioeconomic Factors

Antisocial, violent behavior is often associated with a childhood history ofimpulsive behavior. Other contributing factors are living in a crowdedenvironment, disrupted and unstable home environments, accessibility of guns,

decline of cultural constraints, and violent role models, especially parents whoincorporate 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


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285 pediatric patients with refractory generalized and focal epilepsy who weretreated 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 aggressionwas observed in 30 patients (10.5%); for example, 2 patients with no prior historyof aggression attacked others violently. Dinkelacker et al. (108) studied 33 patients with epilepsy who became aggressive while taking LEV, representing3.5% of LEV-treated patients at their center. A previous history of aggressionappeared to be a risk factor. Although most of these patients displayed minorirritability or verbally aggressive behavior, nine patients became physicallyviolent, 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 associatedwith complete seizure control (forced normalization) (110) or because of sedationand 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 bymany AEDs and may last for day to weeks. Prominent symptoms includeabdominal pain, constipation, tachycardia, and seizures. Patients are oftendelirious and psychotic, and may exhibit aggressive or violent behavior.

Miscellaneous

Violent behavior may occur during a delirium, which is usually characterized byinattention, agitation, hallucinations, delusions, and restlessness. Delirium may bedue to drug (substance) and alcohol abuse or withdrawal in patients with orwithout a history of psychosis (77,114). Amphetamines, diet pills, cocaine, phencyclidine, opioids, and lysergic acid diethylamide (LSD) are particularly


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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 patientswith epilepsy, in part because of the problems inherent in assessing aggression inthis population (115,116). Even so, the Resentment-Aggression scale on theMinnesota Multiphasic Personality Inventory (MMPI)

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and the Aggression scale of the Bear-Fedio Inventory have been utilized forresearch 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 headinjury and dementia. The Behavior Rating Scale for Dementia was designed tomeasure 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 patientswith 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, acomputerized test designed to provoke aggressive behavior (122); the BarrattImpulsiveness Scale (123); the Agitated Behavior Scale (124), and several others(125,126,127,128,129,130,131).

Treatment Considerations


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Aggressive behavior is probably underreported to physicians for a variety ofreasons, including embarrassment, the desire to keep such behavior personal, anda lack of appreciation that it may be treatable. Most neurologists, in turn, do nottake sufficiently detailed histories of aggressive behavior. Therefore, theassessment of aggressive behavior must begin with heightened awareness by physicians, who should inform patients and families in a reassuring manner thataggressive behavior can occur in association with epilepsy for a number ofreasons, some of which are reversible. The physician should ask patients and theirfamilies specific and directed questions to determine whether the behavior inquestion is disruptive, destructive, or dangerous, and, therefore, necessary to beevaluated and addressed further. Aggressive behavior can be viewed along aspectrum; the point at which it requires evaluation and possible treatment willdepend on the individual circumstances and cultural setting.

In general, the appropriate treatment of aggressive or violent behavior in a patientwith epilepsy depends on the cause. Ictal aggression due to isolated seizures or

nonconvulsive status epilepticus responds to AED therapy. Postictal resistiveviolence 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 notnecessarily improve with complete seizure control (9,133). Controlled studies areunavailable, 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


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disorders and no evidence of EEG abnormalities (137). An open trial of CBZ, 400to 800 mg per day for 8 weeks, in ten nonepileptic patients with agitation andanger outbursts following closed head injuries reduced irritability anddisinhibition, and resulted in improvement on the Agitated Behavior Scale in eight patients (80%) (124). A placebo-controlled, double blind, randomized trial ofCBZ for treatment of agitation and aggression in 51 nursing home residents withdementia showed statistically significant efficacy for CBZ (mean serum level of5.3 g per mL) compared with that for placebo (138). CBZ may also be beneficial for agitation in patients with Alzheimer's disease whose behavior failsto improve with neuroleptics (139).

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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 foragitation in nonepileptic patients, including patients with Alzheimer's disease(141,142,143).

Psychoactive Drugs

Clozapine, an atypical antipsychotic agent that does not cause extrapyramidal sideeffects, reduces aggressive and violent behavior associated with a psychosis,including self-mutilating behavior (144,145). However, dose-related seizuresoccur in 3% to 5% of treated patients (51). Antidepressants may be useful for theinterictal 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


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epilepsy (115,146). No controlled studies were performed, behavioral outcomeswere 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 ofmurder, homicide, manslaughter, or disorderly conduct in 15 appellate cases (1).From 1977 through 1981, epileptic automatisms were used as part of adiminished legal responsibility or insanity defense against 12

charges of violent crimes, including 5 murder cases in 1979 (1). In one well- publicized case, a New York City policeman pleaded mental illness to acharge 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 neurologiststestified he did not have epilepsy. The jury found him not guilty, and he wascommitted 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 adanger to others.

Physicians may be called on to render an opinion whether a particular patientcommitted an aggressive or violent act in conjunction with a seizure. In 1981, a panel of epileptologists suggested five relevant criteria to determine whether aviolent crime resulted from an epileptic seizure (1):

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

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


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The presence of aggression during epileptic automatisms should beverified 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 habitualseizures.

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 determiningthat 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 newtechniques, such as neuroimaging studies, are expanding our understanding of theneurobiology of these behaviors (102,103). However, the practical limitations ofstudying epilepsy and violence and the methodological problems reported in the


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literature have hampered our understanding of the causal relationships betweenseizures and aggression, although, as observed by Devinsky and Bear (58), it

would be difficult to cite, either from case reports or a literature review, anothermedical or neurologic illness in which aggressive behavior is described soregularly. 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 areobserved in unnatural environments, such as hospital rooms, and seize undercircumstances that may be unusual for them, for example, in bed or in a lockedroom (33,47). Observers are generally trained professionals who are taught not toapply restraint during or after seizures. These factors probably influence theincidence 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 postictalviolence that involves a series of organized purposeful behaviors, if it exists,could ever be electrographically confirmed. Although the current evidence arguesagainst the possibility of goal-directed ictal aggression, absence of proof is notnecessarily 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 biasthe likelihood of documenting aggressive behavior. Similarly, studies of interictalaggression generally rely on specific cohorts, such as incarcerated prisoners orsubjects at detention centers or group homes, rather than a random sampling of patients with epilepsy in the community, and the reliability of medical informationand data acquisition varies substantially between studies.


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Etiology of seizures/epilepsy syndrome/EEG findings Nature of auras and ictal automatismsPostictal behavior/psychosisTemporal relationship between aggression and seizuresActivity that the patient was engaged in at start of seizureSeizure medications taken; evidence of neurotoxicity

Other medical variables Drug or alcohol abuseHead injury/brain pathologyIntelligence quotientConcomitant cognitive and psychiatric disorders Neuroendocrinological function

Psychosocial variables Socioeconomic statusHistory of violence before onset of seizuresFamily background/structure

Coping skills

EEG, electroencephalogram.

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