Psychiatric complications in patients with epilepsy: a review

Epilepsy Research 49 (2002) 11 – 33 www.elsevier.com/locate/epilepsyres

Psychiatric complications in patients with epilepsy: a review Laura Marsh a,b,*, Vani Rao a a

Neuropsychiatry and Memory Group, Department of Psychiatry and Beha6ioral Sciences, School of Medicine, Johns Hopkins Uni6ersity, 600 N. Wolfe Street, Baltimore, MD 21287, USA b Di6ision of Psychiatric Neuro-imaging, Department of Psychiatry and Beha6ioral Sciences, School of Medicine, Johns Hopkins Uni6ersity, 600 N. Wolfe Street, Meyer 3 -166, Baltimore, MD 21287 -7362, USA Received 6 January 2002; accepted 15 January 2002

Abstract At least 50–60% of patients with epilepsy develop psychiatric disturbances, particularly mood, anxiety, and psychotic disorders. This article, aimed at the non-psychiatric clinician, reviews the differential diagnosis and treatment of psychiatric disturbances in epilepsy and focuses on the evaluation of psychiatric phenomena relative to the ictal state or the periictal and interictal periods. Pharmacological and non-pharmacological therapies are reviewed. A final section discusses potential interactions between antiepileptic and psychiatric medications. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy; Psychiatric disturbances; Depression

1. Introduction Epilepsy, like all conditions involving the brain, is associated with an increased co-occurrence of psychiatric illnesses. Most studies indicate that up to 50% of patients with epilepsy have psychiatric syndromes, with mood, anxiety, and psychotic disturbances being the most common (Torta and Keller, 1999; Lambert and Robertson, 1999). However, actual prevalence

* Corresponding author. Tel.: +1-410-502-6945; fax: + 1410-614-3676. E-mail address: [email protected] (L. Marsh).

rates for psychiatric illnesses in epilepsy patients are unclear, owing to differences in sampling and diagnostic strategies, and the heterogeneity of epilepsy syndromes. Nonetheless, the relative risk of an individual with epilepsy developing a psychiatric illness is compounded by multiple factors, including additional brain injury, the type and severity of the epilepsy syndrome, medication effects, psychosocial factors, and cognitive and temperamental (personality) attributes (Reynolds, 1981). Non-psychiatric clinicians have an integral role in the identification, assessment and management of any emotional or behavioral disturbance in the epilepsy patient, although

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specialized psychiatric care may be necessary. The first step is recognition that there is a psychiatric problem. As part of general care, patients with epilepsy should be educated that psychiatric symptoms can occur, and that proper recognition and treatment of psychiatric conditions will reduce their suffering and the morbidity associated with epilepsy (Marsh, in press). Often, however, pathological emotional changes and behavioral problems are regarded as ‘understandable’ reactions to difficult circumstances. In addition, stigma and misinformation deter patients from revealing symptoms or seeking psychiatric care. On initial assessment, there must be careful consideration of whether the psychiatric phenomena are direct expressions of the epileptic seizure (i.e. the ictal state), features of a periictal state (i.e. postictal or preictal/prodromal phases that are temporally associated with seizures, but are not manifestations of epileptic discharges), or a function of nonictal conditions or factors (the interictal period) (Fig. 1). Though, transition from one phase to the next can be ambiguous, most patients show consistent patterns from one seizure to the next. In addition, symptoms associated with ictal and peri-ictal states are transient and accompanied by other features of a typical seizure; nonictal psychiatric conditions tend to persist, and are sometimes chronic. Some patients have more than one disturbance, with independent psychiatric conditions during each of the different periods. Therefore, it is essential that psychiatric treatments target symptoms and syndromes according to their relationship to seizures. The first three sections of this review describe the clinical features, differential diagnosis, and treatment of ictal, periictal, and interictal psychiatric conditions; the major emphasis is on mood, anxiety, and psychotic disorders. Mood disturbances include depressive states and states with abnormal mood elevation, such as mania. Anxiety disorders include states of pathological anxiety as well as panic attacks. Psychotic conditions involve disorders with hallucinations (sensory perceptions in the absence of an external stimu-

Fig. 1. Timing of psychiatric disturbances in epilepsy.

lus), delusions (fixed false idiosyncratic beliefs), or disorganized speech (thought disorder) and behavior. A final section discusses interactions between anti-epileptic and psychiatric medications.

Table 1 Psychiatric disturbances during ictal, postictal, and interictal states Ictal

Postictal

Interictal

Anxiety Intense feelings of fear or horror Panic attacks Depressed mood Tearfulness Sexual excitement Paranoia Hallucinations Illusions Laughter Forced thoughts resembling Obsessions De´ ja` vu and other memory Experiences Confusion Aggression/violence

Confusion Depression Agitation Paranoia Hallucinations Mania Aggression/ violence

Major depression Adjustment disorders Dysthymic disorder Atypical depressive syndromes Medication-induced mood changes Mania Panic disorder Generalized anxiety disorder Obsessive-compulsi ve disorder Phobias Conversion disorder Medication-induced conditions Psychotic syndromes Aggression/violence

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2. Ictal psychiatric disturbances

2.1. Clinical features A number of affective and behavioral changes occur as direct manifestations of seizure activity (Table 1). Hughlings Jackson described the ‘dreamy state’, in which mental phenomena such as personal recollections, hallucinations and illusions occur during temporal lobe partial seizures (Critchley and Critchley, 1998). Later, temporal lobe electrical stimulation was shown to evoke diverse emotional, cognitive, and perceptual changes (Penfield and Perot, 1963; Halgren et al., 1978; Gloor et al., 1982). Usually, ictal psychiatric symptoms are associated with partial seizures, especially during simple partial seizures (i.e. the aura) when consciousness is retained. However, generalized seizures, either primary or secondary, are also associated with psychiatric disturbances. Ictal mood changes and other psychiatric phenomena may not be readily attributed to epileptic seizures, especially during simple partial seizures, as consciousness is not affected and seizures are usually brief (e.g. 10– 15 s). In some patients, several years may pass before the epileptic syndrome evolves and other phenomena suggest the diagnosis of epilepsy. Thus, misdiagnosis of epileptic syndromes as psychiatric conditions may be especially common when there are affective features or problematic or unusual behaviors (Wakai et al., 1994). For example, an adolescent with a history of attention deficit disorder had brief auras of epigastric discomfort accompanied by facial contortions that were regarded as tics before changes in consciousness led to the diagnosis of epilepsy. The key features of ictal psychiatric disturbances are the characteristics of a typical seizure. That is, the history should reveal that events are stereotyped, begin suddenly and without provocation, are brief (B1– 3 min), and end abruptly. With complex partial seizures, consciousness will be altered, though impairment or confusion may be subtle. There may also be staring, motor or oral automatisms, simple utterances or nonsensical speech, and undirected pacing. Such behaviors or emotions during the seizure will be out of

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context for the situation and unresponsive to psychiatric interventions. Electrographic epileptiform abnormalities and a postictal elevation in prolactin support the diagnosis of epilepsy. Documentation of electrical seizure activity during the psychiatric disturbance, usually with video-EEG monitoring, provides ultimate confirmation that the event is epileptic. In contrast to epileptic seizures, most psychiatric syndromes, including episodic states such as panic attacks or anger outbursts, are sustained and the behaviors are not stereotyped. However, there are exceptions to consider. The first is that ictal psychiatric symptoms can extend into the postictal state but the associated features will change. Second, is that emotional or psychologically stressful situations can precipitate or exacerbate epileptic seizures (Fenwick, 1991a). One in-patient with otherwise well-controlled epilepsy was noted to have her typical complex partial seizures during tense telephone conversations with her boyfriend. Important life events can also trigger increased seizure activity, as in cases of prenuptial seizures (McConnell et al., 1995). Additionally, there may be extreme distress related to mental, somatosensory, or autonomic experiences during a seizure, even after the ictal event has ceased. Several additional circumstances must be carefully considered to avoid mistaking epileptic seizures for a primary psychiatric condition, or vice-versa. Nonconvulsive partial status epilepticus can manifest as prolonged states of fear, mood changes, automatisms, or psychosis that resemble an acute schizophrenic or manic episode (Trimble, 1991). While usually confused, such patients may perform simple behaviors and respond to commands and questions. Absence status is associated with fluctuating states of arousal, blinking, staring, and myoclonic jerks. Though, psychotic or affective changes are unlikely, absence status or brief absence seizures can be attributed to an attention deficit disorder, as above. An EEG may be necessary to confirm the diagnosis of status epilepticus, especially when there is concomitant interictal psychopathology or in nonepileptic psychiatric patients on medications that lower the seizure threshold (Yoshino et al., 1997).

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Misdiagnoses of epilepsy are also made for transient emotional episodes and other states when they involve reduced responsiveness, such as catatonic states, severe depression, and delirium (Silberman et al., 1985).

2.1.1. Ictal anxiety Anxiety is one of the most common affective states during a seizure. Some patients feel anxious or fearful as a general reaction to the ensuing seizure or, more specifically, to ictal paranoia or other psychotic symptoms. In addition, up to 1/3 of patients with partial seizures report fear as a component of their typical aura (Engel, 1989). Ictal fear, an extreme feeling of unprovoked terror or panic as a discrete manifestation of epileptiform activity, is often described as ‘unnatural’. It may be associated with visual or auditory hallucinations and autonomic phenomena such as hyperventilation, tachycardia, flushing, gastrointestinal upset, or sweating (Betts, 1981). A 35-year-old woman with ictal fear plus motor automatisms described recurrent bouts of nausea since childhood, leading to characterization of her as ‘nervous’ and ‘somatically preoccupied’. Until epilepsy was diagnosed and treated in her late 20s, the patient regarded herself as chronically anxious. Careful assessment is required to distinguish ictal anxiety from interictal panic or other anxiety states, and both may be present in the same individual (Perrine, 1991; Genton et al., 1995). Panic attack-like phenomena can occur during simple or complex partial seizures, and, like interictal panic attacks, may involve depersonalization (the feeling that oneself is unreal) or derealization (the feeling that other people and the environment is unreal, as if one is watching cardboard characters on a stage) (Young et al., 1995; Alemayehu et al., 1995). Ictal fear tends be associated with right temporal foci, although left-sided and extratemporal foci are also reported (Hermann et al., 1992; Alemayehu et al., 1995). 2.1.2. Ictal depression Depressed feelings during seizures are less common than ictal anxiety; they were reported as part of the aura in 1% of one large sample of epilepsy patients, and were most common with temporal

foci (Williams, 1956). Reports of ictal crying (dacrystic epilepsy) are also rare (Luciano et al., 1993). When ictal dysphoria is reported, the mood state tends to come on suddenly, without environmental precipitants and has a prolonged duration relative to the usual aura or postictal state (Williams, 1956; Weil, 1959; Robertson, 1998). Depressed moods can also predominate during status epilepticus. Laterality of the seizure focus does not have an apparent effect on the development of ictal depression (Devinsky and Bear, 1991). Ictal sadness may involve the features of typical interictal depressive syndromes, such as feelings of pathological guilt, hopelessness, worthlessness, profound despair, and suicidal ideation. Mood congruent delusions and hallucinations may also be present. While some patients recognize the emotional state as out of context, others may not distinguish ictal emotions as separate from their usual emotions, especially during the actual seizure (Betts, 1981). Thus, ictal dysphoria can result in self-harm, including suicide. Furthermore, the intermittent depressive states can be misinterpreted as a reaction to a prevailing life circumstance (such as recurrent seizures) or as a feature of a primary mood disorder, such as major depression. Such assumptions and the failure to inquire about other epileptic phenomena associated with transient emotional states can lead patients mistakenly to seek psychotherapy or antidepressant treatment, which might actually exacerbate the epileptic phenomena.

2.1.3. Ictal psychosis Ictal psychotic phenomena include a variety of forms. Olfactory and gustatory hallucinations are often associated with partial seizures and less so with primary psychiatric disturbances. Ictal visual or auditory hallucinations typically involve poorly defined shapes or sounds, although there may be complex visual scenes or speech. Paranoid or grandiose thoughts also occur and may be frightening or lead to inappropriate behaviors. Although, most seizures are brief, nonconvulsive status epilepticus with delusions or hallucinations can be mistaken for a primary schizophrenia- or maniclike illness.

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2.1.4. Ictal 6iolence and aggression Ictal violence is extremely rare, although violent crimes are occasionally attributed to epileptic seizures (Sweet et al., 1969; Treiman, 1999). In one large clinical series, 19 of 5400 patients with epilepsy had aggressive behavior, and 13 had violence documented during the seizure (Delgado-Escueta et al., 1981). Mostly, this involved shouting, spitting, or spontaneous, nondirected, stereotyped movements that caused destruction to property. There was also occasional resistive violence, i.e. unintentional aggression that occurs when someone attempts to restrain or assist the patient during a seizure or postictally, but there was no evidence of directed violence during seizures. Like other psychiatric symptoms directly related to seizures, the patient’s usual ictal semiology should accompany the aggressive act. Video-EEG monitoring may be necessary to discern whether the violent behavior is related to seizure activity, but other general caveats hold (Treiman, 1986). First, although the aggressive act may appear orchestrated, the aggressive behavior should be poorly directed and not involve intricate skills or purposeful, detailed, or interactive behavior. Pushing and shoving are more typical, but can be misinterpreted as threatening or assaultive. Repetitive limb movements during a seizure or myoclonic jerks can also be mistaken for menacing gestures. Ictal automatisms can lead to inadvertent violent or destructive acts, such as throwing or losing control of an object that is being held at the onset of a seizure. While generalized seizures, either primary or secondary, may be associated with the violent act, directed aggression cannot occur during a convulsion. However, when consciousness is not affected, such as during simple partial or myoclonic seizures, behaviors will be directed and under conscious control. Violence can also occur postictally, as described below. 2.1.5. Other ictal affecti6e phenomena In general, positive emotions during seizures are infrequent compared with negative ones. However, sexual sensations, pleasant moods, religious feelings, euphoria, joy, and grandiose ideation have all been reported as manifestations of epileptic seizures. Ictal laughter (gelastic seizures)

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is usually a feature of an automatism, and patients tend to be unaware of their behavior. Observers, however, may report paroxysms of inappropriate and unprovoked laughter, which can be uproarious and contagious. Before other signs of an epileptic syndrome were apparent, one patient described receiving disciplinary action for gelastic seizures when they occurred in school. A number of conditions and epilepsy syndromes are associated with gelastic seizures (Shaibani et al., 1994). Ictal laughter may represent an emotional expression, e.g. mirth, when associated with cortical foci, namely temporal (Arroyo et al., 1993). A second type of gelastic seizure represents a pure motor act, without an emotional component.

2.2. Treatment of ictal psychiatric disturbances Adequate seizure control with antiepileptic medications or surgical procedures is the obvious focus of therapy for ictal psychiatric disturbances. However, since the psychiatric symptoms may not be recognized as related to seizures, the importance of a thorough evaluation is underscored. This should include careful review and verification of the epilepsy diagnosis, its features and potential etiologies, and its past and current medication therapies. Since patients may not spontaneously provide their psychiatric history, there should be direct questioning about the features and treatment of past and current psychiatric conditions, including behavioral disturbances during childhood. As with the epilepsy history, other informants may be necessary to obtain accurate information. In addition to antiepileptic medications, nonpharmacological treatments are a cornerstone of effective care when the disturbance is occurring. Close observation is important, with safety during ictal and postictal states a primary concern. To avoid resistive aggression, patients should not be restrained as mere physical presence or gentle touching may be adequate to redirect a confused individual, restrict them to a confined area, and maintain their safety. To accomplish this outside of hospital situations, patients and their families require education about seizure manifestations. The potential for psychiatric symptoms to present

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as ictal events should be specifically reinforced, least others misinterpret the patient’s behavior as a personal affront or sign of an interictal psychiatric syndrome. Patients should be encouraged to recognize signs of an impending seizure, so that they can ask for assistance or move to a safe place. Psychotropic medications should not be used for cases of ictal psychosis or confusion, although benzodiazepines are sometimes used for ictal anxiety (McConnell and Duncan, 1998). Nonconvulsive status epilepticus with psychiatric features should be treated in the same way as other forms of status epilepticus; benzodiazepines are typically used initially. Supportive and behavioral psychotherapies are beneficial for patients with anxious reactions to their seizures or inordinate anxiety about seizure recurrence. Behavioral therapies, including biofeedback and behavioral modification strategies, can effectively reduce seizure frequency in patients with medication-refractory seizures (Dahl, 1990; Dahl et al., 1992). Stress management, coping and relaxation therapies, and psychotherapy may be integral treatments when seizure onset and emotional states are closely linked (Fenwick, 1995).

ment, therefore, requires knowledge of the patient’s typical postictal features, noting that patients may not spontaneously reveal their experiences because of confusion, disorientation, lethargy, sleepiness, impaired comprehension, or fear of stigma. Seizure clusters, convulsions, and status epilepticus can increase the likelihood of postictal psychiatric disturbances. Ambient environmental stimuli, such as crowds or restraints, also provoke behavioral responses. Postictal psychiatric disturbances occur either in the context of a delirium or in clear consciousness. The latter tend to resemble acute interictal psychiatric syndromes, but with a shorter duration, and sometimes a delayed onset following a lucid interval, especially in cases of postictal psychosis. Postictal syndromes tend to remit spontaneously, although psychoactive medications may be necessary to control symptoms. After recovering from the postictal event, some patients become extremely distressed and worried that the psychiatric symptoms will persist. Indeed, in one series patients with well-defined postictal psychiatric events were more likely to experience interictal psychiatric difficulties and some postictal events persisted as interictal disturbances (Kanner et al., 1996).

3. Periictal psychiatric disturbances

3.1.1.1. Postictal delirium. Confusion, impaired awareness and consciousness, and diffuse EEG slowing without ictal discharges characterize postictal delirium. Confusional states are common after complex partial or generalized tonic–clonic seizures, and memory for the event is often impaired. The duration is usually brief, and gradual return to a normal interictal state coincides with resolution of the behavioral, perceptual, or emotional changes. Repetitive or prolonged complex partial or convulsive seizures may prolong the confusional state. Psychosis and phenomena such as tearfulness, agitation, or calling out/screaming behavior can be a feature of the delirium and thus aggravate anxious, fearful, or violent tendencies, or contribute to misinterpretations of ambient stimuli. During the period of impaired consciousness, behavior is relatively undirected and resistive violence occurs fairly often. Postictal automatisms can also occur, with increasingly complex and

Perictal psychiatric disturbances may be either (a) postictal or (b) preictal.

3.1. Postictal psychiatric disturbances 3.1.1. Clinical features The prevalence of postictal psychiatric disturbances is unclear. A 7.8% annual incidence was reported from one epilepsy monitoring unit (Kanner et al., 1996). Psychotic events were most commonly reported, though postictal phenomena include diverse motor, somatosensory, autonomic, and cognitive deficits and vary in their duration. Some patients return to baseline immediately or within seconds to minutes, even after severe generalized or partial seizures. Others experience significant disability, and may not recover for several hours, days, or even weeks. Psychiatric assess-

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directed behavior as normal consciousness returns (Fenwick, 1991b). Mood and behavioral changes can also accompany twilight states, in which there are features of delirium with intermittent epileptiform activity (but not seizures) during the postictal state.

3.1.1.2. Postictal psychosis. Postictal psychosis occurs in up to 10% of patients (Lancman, 1999) and tends to develop several hours to a few days after a seizure or cluster of seizures (with or without secondary generalization) (Betts, 1981; Logsdail and Toone, 1988; Engel, 1989). The psychosis emerges either from a state of postictal confusion or lucidity (Howland, 1993) and includes delusions, hallucinations, thought disorder, or manic or depressive mood changes with mood congruent delusions or hallucinations (Benjamin et al., 1995). Recognition is critical since threatening delusions or hallucinations can motivate aggressive or self-destructive behaviors. Relative to interictal psychosis or postictal confusion, there is greater potential for well-directed violent behavior or suicidality (Nickell, 1994; Kanemoto et al., 1999). By definition, postictal psychoses are transient, but may last up to several weeks and have a tendency to recur (Lancman et al., 1994). After recurrent or even a single postictal psychotic episode, chronic interictal psychotic syndromes with affective or schizophrenia-like features can develop (Logsdail and Toone, 1988; Engel, 1989). The known risk factors for postictal psychosis include bilateral interictal epileptiform discharges, an aura of ictal fear, a long duration of epilepsy before the onset of postictal psychosis, and the presence of gross structural lesions (Engel, 1989; Umbricht et al., 1995; Benjamin et al., 1995; Kanemoto et al., 1996). Family and personal psychiatric history are not consistent antecedents. The physiological basis for postictal psychoses is unclear, though some implicate prolonged seizure symptomatology with psychotic manifestations, neuronal exhaustion after hyperexcitation-as in a Todd’s paralysis, secondary epileptogenesis, or postictal dopaminergic hypersensitivity or GABAmediated mechanisms (Umbricht et al., 1995; Benjamin et al., 1995; Brodie et al., 1997).

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3.1.1.3. Postictal depression and anxiety. Postictal mood changes are common, frequently accompany psychotic phenomena, and can be a component of postictal delirium. Postictal depressions tend to last longer than other postictal psychiatric events, persisting hours to weeks after the seizure (Williams, 1956; Robertson, 1998). The intensity of depressive symptoms ranges from mild to severe. Suicide attempts can occur, and psychosis increases the risk (Kanemoto et al., 1999). In a small series, flattened affect was more common than actual sadness after complex partial seizures from either hemisphere, though rightsided foci predominated (Devinsky et al., 1994). By contrast, a case report identified postictal depression after left temporal discharges, and mania after right temporal discharges (Hurwitz et al., 1985), and others suggest an association with unilateral temporal or frontal foci (Kanner and Nieto, 1999). Acute anxiety also occurs, but is less common that depressive states (Kanner et al., 1996). In either case, there is no evidence that postictal affective changes are emotional reactions to the recent seizure, though families and patients may invoke this interpretation. 3.1.1.4. Postictal mania. A few case reports describe short-lived (less than 3-weeks) hypomanic syndromes following a series of complex partial seizures or a single or series of convulsions (Humphries and Dickinson, 1988; Barczak et al., 1988; Morphew, 1988). While the specifics differ, the described episodes followed a postictal period of confusion, were characterized by irritability, overactivity, euphoria, and disorganized or disinhibited behavior, and EEG findings were negative for seizures or showed diffuse slowing. Psychotic symptoms, including paranoia and mood-congruent delusions can also be present. Since manic and hypomanic episodes tend to be fleeting, an issue is whether the episodes are specifically confined and related to the postictal state, or if they represent an independent bipolar syndrome that is provoked by seizures. In the latter situation, therapy for primary bipolar disorder might improve prognosis (Lyketsos et al., 1993).

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3.1.1.5. Postictal 6iolence. Violent behaviors in epilepsy patients are most frequent during the postictal period. The presentation may involve confusion, an abnormal mood such as depression, psychotic phenomena such as paranoid delusions or visual and/or auditory hallucinations, or a postictal delirium with fluctuating consciousness and orientation. Postictal violence will last longer than an episode of ictal violence, but the behaviors remain out of character and there is usually amnesia for the event. In cases of extreme violence, postictal behaviors tend to be recurrent, relatively stereotyped for a given patient, and may be more likely to occur after a cluster of seizures and in males (Gerard et al., 1998). 3.2. Preictal disturbances 3.2.1. Clinical features Preictal (or prodromal) disturbances are characterized by increased irritability, apprehension, mood lability (mood swings), depression, psychosis, or even directed aggression lasting for several minutes, several hours, or days before a seizure (Blanchet and Frommer, 1986; Hughes et al., 1993). Prodromal behavioral changes may be isolated to the pre-ictal period, or they may represent an exacerbation of interictal behaviors. They should be distinguished from reactive mood changes, such as a low mood, anxiety, or other forms of emotional distress, that precipitate seizure activity or may be a symptom of the seizure itself. Sometimes, there is extreme agitation, mood instability, and impulsivity that causes psychosocial difficulties and is distressing to the patient. The preictal symptoms can wax and wane, but generally escalate up to the time of the seizure, which relieves the prodromal symptoms (Fenwick, 1991b). 3.2.2. Treatment of periictal psychiatric disturbances Immediate management, as with ictal disturbances, is focused on maintaining patient safety, especially when there is agitated or destructive behavior. Environmental support and behavioral redirection, described above, are often adequate. Agitation and postictal psychosis, with or without

accompanying delirium, can require acute treatment with neuroleptics or sedatives, including intramuscular preparations. Continued oral neuroleptic treatment is indicated when symptoms are severe or persistent. The neuroleptic can be tapered with close monitoring for symptom relapse and extrapyramidal signs. Benzodiazepines sedate and calm some patients in the postictal state, but can disinhibit, especially in those with delirium, mental retardation, impulse control disorders, or widespread brain damage. There is no indication for antidepressant medications in postictal affective syndromes, but chronic therapy for bipolar disorder should be considered for postictal mania. Diuretics have been helpful in some patients with prodromal psychiatric symptoms, perhaps because of periictal changes in gonadal hormones and fluid balance (Fenwick, 1991a). Finally, patients should be evaluated for preictal confusion related to medications or other causes, as this may reduce the likelihood or severity of postictal delirium. Improved seizure control is the other obvious treatment goal for periictal disturbances. However, recurrent periictal confusion and other psychiatric disturbances contribute to medication noncompliance because of inadvertent neglect or suspiciousness. Family members or other caregivers must be given clear directions regarding the prescribed regimen, and should monitor compliance. Such supervision can be perceived as an intrusion upon patient autonomy, and specific strategies for maintaining compliance will need to be discussed. Chronic neuroleptic treatment may be necessary to prevent disruptive postictal episodes. For prodromal symptoms, some patients will self-induce seizures, so as to ‘clear the air’. This might be accomplished by skipping a dose of seizure medication, or by willfully thinking a specific thought or feeling known to precipitate a seizure (Fenwick, 1991a). Patients with reactive distress to postictal psychiatric events will require reassurance and education. They should also be monitored for nascent interictal psychiatric disturbances, and educated about incipient signs of psychiatric illness, since they may be more likely to develop interictal psychiatric disturbances (Kanner et al., 1996).

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4. Interictal psychiatric disorders

4.1. Clinical features Interictal psychiatric disorders are common and serious complications of epilepsy. However, many aspects of interictal psychiatric conditions have been controversial for several decades. A central issue is whether there is an increased prevalence of psychiatric illness in epilepsy patients, especially patients with temporal lobe epilepsy (TLE). While differences in reported prevalence rates of interictal psychiatric conditions are related to sampling issues (institutionalized versus community populations) and progressive refinement and consistency in how psychiatric and epilepsy diagnoses are established, most studies indicate an overall higher rate of psychiatric disorders in epilepsy patients as compared with the general population. However, this rate is comparable to other central neurological conditions (McNamara, 1991). For clinicians, the main considerations should be that (1) interictal psychiatric disorders can occur in any epilepsy syndrome, although there has been an emphasis on psychopathology in patients with TLE and (2) the relationship between epilepsy and interictal psychopathology involves many potential factors. These include the epilepsy type and severity, associated non-epileptic brain dysfunction, structural brain abnormalities, cognitive vulnerabilities, medication effects, social stigmatization related to epilepsy, and specific neurotransmitter alterations, as well as all the usual considerations relevant to nonepileptic patients with psychiatric problems (Schwartz and Marsh, 2000).

4.1.1. Interictal mood disorders Interictal mood disorders involve qualitative differences in mood and are among the most common and serious psychiatric complications associated with epilepsy. They range from transient episodes of low or elevated mood to persistent mood disturbances associated with neurovegetative signs and symptoms such as changes in sleep, appetite, weight, energy, and/or concentration. As with the different epilepsy syndromes, appropriate management is predicated on proper recognition of the specific mood syndrome.

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Table 2 Risk factors for the development of depression in people with epilepsy Biologic

Psychosocial

Iatrogenic

Age onset of epilepsy Duration of epilepsy Seizure type Lateralization of focus Number of seizure types Generalized seizures Cognitive dysfunction

Perceived stigma Fear of seizure Learned helplessness Pessimistic attributional style Decreased social supports Unemployment

Polytherapy with AEDs Secondary AED effects Serum level of AEDS Epilepsy surgery

4.1.1.1. Major depression. Prevalence rates for major depression in the interictal phase range from 22 to 77% (Mendez, 1996), with variation attributed to methodological differences. As shown in Table 2, the etiology is multifactorial and probably represents an interaction of biologic, psychosocial and iatrogenic factors (Lambert and Robertson, 1999; Kanner and Nieto, 1999). Numerous studies that correlate depression with demographic and epilepsy-related variables have been inconclusive. In a study of 76 patients with complex partial seizures attending a tertiary epilepsy center, over 50% had either current or past episodes of depression (Wiegartz et al., 1999) that was associated with a history of depression in first-degree relatives and stressful adverse life events. However, demographic factors such as age and education, and IQ and seizure-related characteristics (e.g. age at epilepsy onset, duration of epilepsy, family history of epilepsy, laterality of interictal EEG focus) were not significantly related. Others implicate a positive correlation between TLE, male gender and left sided foci (Altshuler et al., 1990; Strauss and Moll, 1992). Neuropsychological and functional neuroimaging data suggest an elevated risk for depression with left temporal lobe seizures and concomitant frontal lobe dysregulation (Hermann et al., 1991; Bromfield et al., 1992; Schmitz et al., 1997).

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Several studies also suggest an association between depression and surgery for epilepsy. Postoperative depression tends to be more common in the first two months after surgery and is often transient (Chovaz et al., 1994). Among 49 patients evaluated about 10 years after temporal lobectomy for intractable complex partial seizures, 77% had a prior history of depression and 53% continued to have depressive episodes after their surgery (Altshuler et al., 1999), suggesting that presurgical presence of depression is a significant risk factor for the development of postoperative depression. By contrast, about 10% of the sample developed a de novo depressive illness within 1 year after surgery. Preoperative psychosocial adjustment and neurological deficits, older age, generalized seizures, and a family history of psychiatric illness and/or seizures are also associated with chronic postoperative depressive symptoms (Derry et al., 2000). Proposed causes of post-operative depression invoke limbic system dysfunction (Altshuler et al., 1999), seizure-suppressing inhibitory mechanisms (Blumer et al., 1998) and poor life-style adjustment after the surgery (Bladin, 1992). Development of depression is also influenced by psychosocial factors, including the quality of social supports, low self esteem, stigma related to epilepsy, a perceived lack of control over ones life because of the random occurrence of seizures, and the need to make adjustments in response to epilepsy, such as changing jobs or giving up a driving license (DeVellis et al., 1980; Hermann and Whitman, 1989). Given these issues, the learned helplessness theory of depression has been applied to patients with epilepsy and provides a useful perspective for therapy in some patients. Learned helplessness refers to a pattern of emotional, cognitive and behavioral deficits that is based on observations of dogs exposed to uncontrollable and unpredictable electric shocks from which no escape was possible (Maier et al., 1969; Seligman, 1975). Eventually, the dogs ‘gave up’ and made no attempt to escape the shocks, and this behavior generalized to other situations so that the animals appeared helpless and apathetic. For some patients, the unpredictable and uncontrollable nature of seizures may contribute to a tendency to ‘give up’ and become depressed, helpless and poorly motivated.

Personality features are another important factor in the development of interictal mood disorders. Self-esteem can be adversely affected and contribute to automatic feelings of defeat, incapability, and depression, especially in patients who are prone to a pessimistic outlook. Colligan et al. (1994) described this as a pessimistic explanatory or attributional style in that pessimistic explanations were often given to both bad and good events. A separate study of 143 patients with medically intractable unilateral TLE showed that an association between depression and a pessimistic attributional attitude (Hermann et al. 1996). Diagnosis of depression requires a high degree of clinical suspicion. Major depression should be considered when a patient describes (or others report) a persistently low mood, a reduced level of interest in life or activities, or the inability to enjoy usually pleasurable activities. The importance of diagnosing and treating major depression is underscored by the fact that suicide is four times more common in epilepsy patients and 25 times more common in TLE patients than in the general population (Harris and Barraclough, 1997). Risk factors for suicidality in epilepsy are associated with a prior history of attempts, and a family or personal history of psychiatric disorders such as depression, alcohol and drug abuse and psychosis and stressful life situations (Robertson, 1997). A meta-analysis revealed the highest suicide rates in surgically treated epilepsy patients (Harris and Barraclough, 1997).

4.1.1.2. Dysthymic disorder and atypical depressi6e syndromes. The prevalence of dysthymia in the general population is about 3%, with a subgroup of cases occurring in the context of neurological disorders, including epilepsy (Akiskal et al., 1996). Also referred to as minor depressive or atypical depressive syndromes, dysthymia is characterized by periods of lowered mood that are relatively mild and predominant features in the cognitiveemotional domain compared with major depression. A prevailing sense of anhedonia (inability to experience pleasure) is especially common. Other symptoms include insomnia, low energy or fatigue, low self-esteem, reduced interest, and feel-

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ings of hopelessness. Anxiety, inappropriate guilt, and suicide attempts are not typical of dysthymia. In addition, impairment and disability are subtle compared with major depression, but the symptoms tend to be chronic and patients suffer considerably when the condition remains untreated. Current nosologic criteria require persistent symptoms for at least 2 years in the diagnosis of dysthymic disorder. However, relevance of this stipulation to chronic neurological disorders has been challenged, since it may increase the likelihood that dysthymic conditions are neglected and untreated (Akiskal et al., 1996). Indeed, several investigations of interictal psychiatric illnesses report intermittent recurrent affective syndromes that resemble dysthymia and last for several hours up to several weeks (Hermann et al., 1991; Mendez et al., 1993; Blumer et al., 1995; Kanner and Nieto, 1999). The term interictal dysphoric disorder has been proposed for chronic intermittent dysthymia with bouts of extreme irritability, insomnia, anxiety, distress, and impulsivity, including self-injurious behaviors and proposed (Blumer, 1997; Kanner and Nieto, 1999). Some women with epilepsy also report mood swings, irritability, anxiety, bloating sensation and changes in sleep, appetite and weight during the premenstrual phase. The relationship of these transient interictal mood and behavioral changes to seizure activity is unclear. Several factors suggest a need for early antidepressant treatment in epilepsy patients with dysthymia., although earlier conceptualizations focused on the role of personality vulnerabilities, adverse life experiences, and psychological maldevelopment. Many patients with dysthymia have comorbid psychiatric conditions, such as major depression, anxiety syndromes, alcohol use, and dependent and avoidant personality traits (Akiskal and Weise, 1992). Furthermore, controlled antidepressant trials show a favorable response in nonepileptic patients with dysthymia. Additional brain abnormalities in epilepsy patients with psychiatric illness was suggested by amygdalar enlargement using in quantitative magnetic resonance imaging methods in TLE patients with dysthymia (Tebartz van Elst et al., 1999).

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4.1.1.3. Bipolar disorder. Bipolar disorder, a condition characterized by periods of depressed mood similar to major depression as well as episodes of mania or hypomania. Some patients cycle between depressive and manic states, whereas others have primarily depressive or manic episodes. Only a few case reports describe interictal mania, and many note the predominance of right-sided hemispheric foci or lesions (Robertson, 1998). Several case series note the presence of mania- or hypomania-like conditions in epilepsy, namely in patients with partial seizures (Dongier, 1960; Flor-Henry, 1969; Perez and Trimble, 1980; Toone et al., 1982). However, prevalence rates remain relatively low, e.g. B 5% (Gibbs et al., 1948). The central feature of a hypomanic or manic syndrome is an elevated, euphoric, or irritable mood. Patients are often overactive with increased energy, an inflated sense of self, a decreased need for sleep, disinhibition, rapid pressured speech, racing thoughts, poor concentration, and distractibility. While some patients are productive when hypomanic because of increased energy and activities, mania is associated with significant disorganization and impaired functioning. Patients often engage impulsively in activities with potentially disastrous consequences, such as overspending or promiscuity. Psychotic symptoms, if present in mania, are usually mood congruent and include hallucinations and delusions. Interictal hypergraphia may be a feature of mania or hypomania, as well as other affective disturbances (Sanders and Mathews, 1994). In general, manic episodes are relatively sustained, lasting for at least 1 week, although hypomanic and manic episodes can be brief, sometimes heralding the onset of a depressive episode. 4.1.1.4. Adjustment disorders with depressed mood. Patients with epilepsy experience a multitude of stressors, including recurrent unpredictable seizures, social stigma, employment and scholastic difficulties, financial constraints, social isolation, increased dependency on others, and adverse medication side effects such as weight gain and cognitive impairment. These factors can predispose patients to adjustment disorders, but cumu-

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lative effects of chronic stressors can contribute to pervasive major depressive syndromes. The diagnosis of adjustment disorder is made when there are inordinate and impairing emotional and behavioral changes in response to an identifiable stressor(s). However, as the stressor terminates, mood and function are expected to improve. The clinical features include low mood, tearfulness, hopelessness, suicidal feelings and/or changes in sleep, appetite energy and concentration. Clinical manifestations may also include assaultive behavior, reckless driving, excessive drinking, or defaulting on responsibilities. Compared with major depression, adjustment disorders are associated with less intense mood and behavior changes, as well as an obviously reactive mood (i.e. experiencing pleasure or feeling good in response to positive events) and a positive self-attitude (i.e. the inherent belief that one is a worthy person). Serial examinations may be necessary to differentiate the two conditions. Adjustment disorders should be distinguished from demoralization, which is a normal response to adversity (Slavney, 1999). Demoralization may have symptoms in common with major depressive and adjustment disorders, but, like a grief reaction, is a nonpathological response to stress and not a psychiatric disorder. Demoralized patients can attribute their depressive symptoms to a particular stressor and social or occupational functioning is unaffected. Unlike major depression, patients almost never believe that he/she deserves to suffer. It is important to consider demoralization in the differential diagnosis of depressed mood as treatment includes education, support, reassurance and more engagement from the treating physician. It is also important for the treating doctor to explain to the patient that his/her response is a natural reaction to a difficult situation and not a psychiatric illness. Of all the stressors mentioned above, real or perceived stigma is a significant psychosocial risk factor for depressed mood in epilepsy patients (Scambler and Hopkins, 1986). Real or ‘enacted’ stigma refers to discrimination that occurs because a person has the diagnosis of epilepsy, such as difficulty in obtaining insurance policies or being treated unfairly by employer. Perceived or

‘felt’ stigma refers to the shame and embarrassment of being an ‘epileptic’ and the fear of being discriminated (Jacoby, 1994). Perceived stigma is more common than enacted stigma and often associated with dysphoria, anxiety, low self-esteem, helplessness, and somatic symptoms (Arnston, 1986).

4.1.2. Anxiety disorders Like depression, anxiety is a normal emotion that clinicians need to distinguish from pathological anxiety. Anxiety disorders refer to pathological states in which the intensity and duration of anxiety exceeds what is typically expected for a given situation. In addition, there is impairment in social, occupational and other areas of functioning. Interictal anxiety symptoms occur at a higher rate in epilepsy patients relative to the general population (Mittan and Locke, 1982), and can be a feature of specific syndromes, such as panic disorder, generalized anxiety, agoraphobia, social phobia, specific phobias, or obsessive-compulive disorder. Similarities between partial seizures and the episodic features of some anxiety syndromes suggest that the two conditions have common physiologic underpinnings, perhaps involving limbic dysfunction (Torta and Keller, 1999). Some studies report high levels of interictal anxiety with severe depressive syndromes and TLE, especially left-TLE (Perini and Mendius, 1984; Robertson et al., 1987), whereas others have not shown significant anxiety with less severe mood syndromes (Altshuler et al., 1990). Anxiety syndromes also occur with primary generalized epilepsies (Devinsky and Vazquez, 1993). Other medical causes of anxiety symptoms, such as thyroid and other endocrine conditions, mitral valve prolapse, medication effects, respiratory or cardiac disease, and alcohol or sedative/anxiolytic drug withdrawal should also be considered in patients with interictal anxiety. Unpredictable seizures, psychosocial difficulties, and social stigma also contribute to anxiety symptoms. 4.1.2.1. Generalized anxiety disorder. The essential feature of generalized anxiety disorder is excessive and persistent worrying about a number of rela-

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tively minor matters along with impaired functioning. Affected patients find it difficult to control their worrying, and may be described as a ‘worry wart’ by friends and family members. The anxiety or apprehension is associated with a number of vegetative signs and symptoms such as irritability, fatigue, insomnia, restlessness, impaired concentration and muscle tension.

4.1.2.2. Phobias. Phobias are irrational fears with consequent avoidance of the feared object, situation or activities. Phobias are the most common mental disorders in the United States affecting 5–10% of the population. Many patients are fearful of having seizures, but true seizure phobias are rare (Newsom Davis et al., 1998). In such cases, the patient can become housebound. The related anxiety, especially with accompanying hyperventilation, can increase the rate of seizures, and reinforce the fears (Betts, 1981). 4.1.2.3. Panic disorder. Panic disorder affects about 1% of the US general population and about 21% of epilepsy patients (Pariente et al., 1991). Whereas epileptic seizures with panicky sensations are generally brief (B 2 min), panic disorder involves recurrent attacks with longer periods (e.g. 5– 30 min) of anxiety or extreme apprehension accompanied by physical and emotional symptoms such as palpitations, dyspnea, sweating, tremors, nausea, chest pain or pressure, choking sensations, nausea, lightheadedness, and fears that one is losing control or is going to die. Panic attacks are sometimes associated with agoraphobia, the fear of being in places from which escape may be difficult. As noted in the Section 2.1.1, distinguishing between panic attacks and epileptic seizures requires careful assessment (Genton et al., 1995). 4.1.2.4. Obsessi6e compulsi6e disorder. OCD is relatively uncommon in patients with epilepsy, although cases are reported (Kanner et al., 1993). Obsessions are recurrent and persistent thoughts, images or impulses that cause marked anxiety and distress, as they are intrusive and inappropriate. Epileptic seizures may involve

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‘forced thoughts’, which are similar to obsessions in that they are intrusive and unpleasant. Compulsions are repetitive and ritualistic behaviors that the person feels driven to carry out. These should be distinguished from the stereotypic ictal and postictal automatisms. Obsessivecompulsive disorder (OCD), in which there is significant dysfunction associated with the abnormal thoughts and behaviors, occurs in about 2% of the population. Attempts to resist intrusive thoughts usually exacerbate anxious feelings, whereas performing the repetitive behavior reduces anxiety.

4.1.3. Psychotic disorders About 7% of epilepsy patients have chronic interictal psychotic syndromes, though prevalence rates vary according to the diagnostic criteria and population studied (general practice surveys versus psychiatric institutions) (McKenna et al., 1985; Victoroff 1994; Umbricht et al., 1995). There has been considerable controversy over the clinical features of interictal psychoses and their underlying relationship to epilepsy. Many reports refer to persistent schizophrenia-like syndromes and emphasize the role of TLE, but psychotic symptoms occur in interictal depressive or bipolar affective disorder and in patients with other epilepsy syndromes, mental retardation or other cognitive disturbances, extensive brain damage, or after resective surgery (Neppe and Tucker, 1988; Stevens, 1991). Reported risks include bilateral temporal foci, seizure clustering, a relative absence of past febrile convulsions (Umbricht et al., 1995), temporal and extratemporal neuropathological (Bruton et al., 1994) and structural imaging abnormalities (Marsh et al., 2001), and dopaminergic abnormalities (Reith et al., 1994). Persistent interictal psychoses typically involve delusions, usually paranoid or religious in nature, visual and auditory hallucinations, and occasionally Schneidarian First Rank symptoms (e.g. third person auditory hallucinations commenting on the patient, audible thoughts, thought insertion, withdrawal, or broadcasting and ‘made’ thoughts and actions). Some reports suggest that the schizophrenia-like psychoses

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lack the negative symptoms (e.g. amotivation, asociality, apathy, flattened affect), disorganized behavior, and thought disorder seen in primary schizophrenia, but most studies fail to substantiate this claim (Mace, 1993). In clinical practice, there is extensive overlap in the phenomenology of nonepileptic schizophrenic syndromes and the chronic interictal psychoses, such that the syndromes can be indistinguishable (Marsh et al., 1999). Therefore, as with schizophrenic patients, epileptic patients with chronic psychoses should also be evaluated for cognitive, social, and behavioral deficits that affect daily function, in addition to psychotic symptoms.

4.1.4. Medication-induced psychiatric disorders Antiepileptic drugs (AEDs) have positive and negative psychotropic effects, but associated psychiatric disturbances are multifactorial in origin, including polytherapy, dosing levels, reduced serum folate and tryptophan levels, and a personal history of psychiatric illness (Schmitz, 1999). Behavioral problems and depression are most common; psychosis is relatively rare. In general, the AEDs can be divided into those with sedating versus activating effects (Ketter et al., 1999). Sedating AEDs, such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin potentiate effects of g-amino-butyric acid (GABA), an inhibitory neurotransmitter, and cause depression, fatigue, mental slowing and weight gain. They also have anxiolytic and antimanic effects. A second group of AEDs attenuates glutamate, an excitatory neurotransmitter, and has antidepressant and anxiogenic effects. Examples are lamotrigine and felbamate. Drugs such as topiramate have a dual action and may exhibit mixed profiles. Vagal nerve stimulation for treatment-resistant partial seizures has been shown to have beneficial effects on cognition and mood (Handforth et al., 1998), prompting trials in nonepileptic patients with treatment-resistant depression (Rush et al., 2000). Patients at risk for psychiatric complications of AEDs require close monitoring and education. Several studies show that phenobarbital can cause depression, behavioral changes and cognitive dulling (O8 zdirim et al., 1978; Smith and Collins,

1987) and that a history of psychiatric illness increases the risk for adverse psychiatric side effects (Dale, 1966). Phenytoin can cause dose-related psychotropic side effects such as irritability, somnolence, psychmotor slowing and cognitive difficulties (Idestro¨ m et al., 1972; Reynolds and Travers, 1974). Withdrawal of either phenobarbital or phenytoin can cause depression, anxiety, hypomania or psychosis (Ketter et al., 1994). AED withdrawal-related psychopathology typically occurs in the final week of tapering and resolves within 2 weeks of restarting the original drug. Again, the causes are multifactorial and probably involve the combined effects of seizures, demographic factors, past psychiatric history and pharmacodynamic drug effects (Ketter et al., 1999). Carbamazepine (CBZ) and valproate have anxiolytic, antimanic, and antidepressant effects and can cause modest cognitive side effects. The positive psychotropic effects of CBZ may be related to its tricyclic structure, its reduced effects on serum folate levels, and related increases in tryptophan and serotonin levels (Trimble, 1996). Vigabatrin (VGB), a GABAergic drug, is associated with depression in about 10% of patients. It occurs within a few weeks after starting the drug or increasing the dosage (Ring et al., 1993; Sander and Duncan, 1996). Tiagabine, another GABAergic drug, may also contribute to depressive symptoms and there should be additional monitoring when it is prescribed for patients with a psychiatric history. The activating properties of felbamate can be helpful to some patients, but detrimental to those with preexisting psychopathology, including anxiety disorders or insomnia (Ketter et al., 1994). Lamotrigine, gabapentin and topiramate are not significantly associated with depression, but are sometimes used as mood stabilizers or antidepressants in nonepileptic patients (Schmitz, 1999). Delirium and dementia syndromes have been attributed to chronic AED therapy, including valproate and phenytoin (Schmitz, 1999). Psychosis is an infrequent complication of almost all AEDs, including vigabatrin, primidone, benzodiazepines, phenobarbital, carbamazepine, ethosuccimide, phenytoin, and carbamazepine (Lancman, 1999).

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There may not be other signs of AED toxicity, as in psychoses that occur with high serum levels of phenytoin in the absence of typical cerebellar side effects. Carbamazepine-induced hyponatremia is also associated with the development of psychosis. Improved seizure control is occasionally associated with treatment-emergent psychopathology, though the concept of physiological antagonism between seizures and psychopathology has been controversial (Lancman, 1999). ‘Forced normalization’, a term introduced by Landolt, refers to the development of psychosis when there is relative normalization of the EEG, i.e. a reduction or disappearance of epileptiform abnormalities, as compared with previous and subsequent EEGs. ‘Alternative psychosis’, the corresponding clinical term, emphasizes the emergence of psychopathology when seizures are controlled (Tellenbach, 1965). Most cases involve psychosis, but there can be other behavior and mood disorders, which should be distinguished from preexisting interictal psychiatric conditions or medication-induced delirious states. Landolt’s original cases were largely associated with ethosuximide, but most AEDs are implicated with vigabatrin most closely studied (Thomas et al., 1996). The phenomenon occurs with both focal and generalized epilepsy syndromes and the risk may be greater with polytherapy and when patients become seizure-free abruptly, especially when there is a prior psychiatric history. Therefore, new AEDs should be started at low doses and increased slowly. Since insomnia, irritability, mood lability can precede overt psychiatric symptoms, patients should be educated about potential symptoms and monitored closely. Antidepressant or antipsychotic treatment may be added, but it may be necessary to reduce the AED and allow the return of seizures. Hypothesized mechanisms for treatment emergent psychopathology include secondary dopaminergic and GABAergic changes in association with a raised seizure threshold, kindling phenomena, a role for the reticular activating system, and epileptic status in the limbic system (Krishnamoorthy and Trimble, 1999).

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4.2. Treatment of interictal psychiatric disturbances A detailed and critical review on use of psychiatric medications in epilepsy patients is available (McConnell and Duncan, 1998). Except for a single study using antidepressants (Robertson and Trimble, 1985), there are no controlled trials examining efficacy and safety of treatments for interictal psychiatric conditions. For patients without epilepsy, most successful treatments include a combination of pharmacotherapy and psychotherapy, though either may be used alone in milder disturbances. Early recognition and treatment is important because it alleviates suffering and reduces risk of relapse. Therefore, a central treatment focus is patient and family education about epilepsy and its psychiatric complications, medication effects, and the clinical features they should monitor as signs of improving or relapsing psychiatric illness. Support groups for people with epilepsy or with psychiatric disorders can also be helpful.

4.2.1. Treatment of interictal depressi6e & bipolar disorders Although, medications may be the cornerstone of treatment for mood disorders, comprehensive treatment in the patient with epilepsy (or any patient) also requires attention to temperamental and cognitive attributes, behavioral issues, and the meaning of life experiences (Schwartz and Marsh, 2000). Specialized psychiatric care is often warranted for complex medication and psychotherapeutic management, especially since mood disturbances cause significant morbidity, including fatal consequences when there are suicides. Table 3 lists currently available antidepressants, their dosages and common side effects. Since all antidepressants are equally effective (although specific data pertaining to epilepsy patients is lacking), antidepressant selection is based on maintaining a favorable side effect profile. For example, sedating or activating side effects, respectively, are desired in patients with insomnia or anergia. Other considerations include the patient’s history of using the medica-

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tion, concomitant medical problems, medication cost, and a family history of response to specific antidepressants. The relative risks of lowering the seizure threshold with a given antidepressant are discussed in the next section. Since all antidepressants take about 4– 6 weeks to be effective, it is important that patients take a therapeutic dose for at least 4 weeks before discontinuation on the basis of inefficacy. However, determining the therapeutic dose in a patient with epilepsy is not always straightforward. The clinical adage ‘‘Start low and go slow’’ is often applied to epilepsy patients, since higher doses or a rapid dose increase may not be toler-

ated, and lower doses may be effective compared with healthy adults of the same age. Going too slowly, however, could prolong suffering needlessly. When a patient fails to respond to one medication, a second antidepressant agent that acts on a different class of neurotransmitters should be used to supplant or augment the initial agent. Individual patient characteristics should also guide treatment. Compliance is increased by simple regimens, e.g. once or twice daily dosing regimens, especially in patients with cognitive limitations or personality features that predispose to poor compliance, such as executive dysfunction,

Table 3 Commonly used antidepressants and their side effects Names

Usual adult dose (mg)

Tricyclic antidepressants (TCAs) Amitriptyline 100–300 Nortriptyline 50–200 Selecti6e serotonin Citalopram Fluoxetine Paroxetine Sertraline Fluvoxamine

Common side effects

Comments

Sedation, orthostasis, sexual dysfunction, GI distress, and arrythymias

Overdose can be fatal. Night time dosage best. Blood levels should be monitored regularly

reuptake inhibitors (SSRIs) 20–60 Sexual dysfunction, nausea, vomiting, 10–80 diarrhea 10–60 50–200 100–300

Monoamine oxidase inhibitors (MAOIs) Isocarboxazid 10–60 Sedation, orthostasis, GI distress, sexual Phenelzine 45–90 dysfunction Tranylcypromine 10–60 Norepinephrine–dopamine reuptake inihibitors (NDRIs) Bupropion 150–450 Nausea, vomiting diarrhea, insomnia

Serotonin–norepinephrine reuptake inhibitors (SNRIs) Venlafaxine 75–375 GI distress, sedation

Serotonin antagonist and reuptake inihibitors (SARIs) Nefazodone 100–600 Sedation, orthostasis, GI side effects Trazodone 50–400 Norepinephrine antagonist and serotonin antagonist (NASAs) Mirtazapine 15–60 Sedation, orthostasis

SSRIs have variable effects on the hepatic P450 system. Hence caution must be exercised and given with other medications

Require strict dietary restrictions Avoid tyramine rich foods and sympathomimetics

Slow release formulation available. Contraindicated with seizures and anorexia/bulimia. Seizures in 0.4% at 300–450 mg per day Extended release available. Increase in diastolic blood pressure in a small percentage of patients Priapism —rare side effect of trazodone. Nefazodone is a potent inihibitor of P450 3A4 system. Caution when used with drugs metabolized through P450 3A4 Sedation common in lower doses

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low intelligence, or impulsivity. Large supplies of medications, especially tricyclic antidepressants, are avoided in patients at risk for self-injurious or suicidal behavior. Special precautions are necessary when medications are dispersed for several months at a time through local or mail-order pharmacies. Stigma associated with taking a psychiatric medication also complicates medication management. Electroconvulsive therapy (ECT) should be considered for antidepressant-resistant major depression. Relative to medications, the ECT response is much quicker, often apparent after the first treatment, and can be life-saving, especially when there are psychotic features. ECT may also help seizure control (Kalinowsky and Kennedy, 1943; Keller and Bernstein, 1993). Among 98 epilepsy patients who received ECT, only two developed status epilepticus and one had an increase in seizure frequency (Hsiao et al., 1987). ECT is reportedly safe in patients who have undergone temporal lobectomy (Krahn et al., 1996). Mood stabilizers are used to treat mood instability, irritability, impulsivity and bipolar disorder. Lithium is a first-line agent, but tremor, renal effects, and cognitive side effects can limit its use. Valproate, carbamazepine, lamotrogine, and gabapentin are among the AEDs used to treat seizures and mood lability (Trimble, 1996). Antidepressants may be added during depressive episodes and neuroleptic medications are often necessary for psychosis or to reduce agitated behavior during severely depressed or manic states.

4.2.2. Treatment of interictal anxiety Anxiety disorders respond well to a combination of pharmacotherapy and psychotherapies aimed at anxiety reduction. Pharmacotherapy includes antidepressants, benzodiazepines, and non-benzodiazepine anxiolytics such as propanolol or antihistamines. Benzodiazepines are indicated for short-term treatment only, given their addictive potential and the potential for associated memory problems, falls and paradoxical disinhibition. Slow gradual tapering of

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benzodiazepines can limit withdrawal-related seizures or psychiatric symptoms. Buspirone, an anxiolytic drug that acts as an agonist or partial agonist on the serotonin-1A receptor and lowers the seizure threshold in animals, is contraindicated in epilepsy patients in British formularies (McConnell and Duncan, 1998).

4.2.3. Treatment of interictal psychoses Treatment of interictal psychotic disorders should first address the role of AEDs and whether symptoms are a feature of an affective syndrome. Otherwise, long-term antipsychotic agents (neuroleptics), patient and family education, and psychosocial support are the focus of treatment. Rehabilitation and psychosocial day programs provide structured settings that enhance independence and general functioning, especially when there are associated cognitive limitations and psychotic or negative symptoms that interfere with daily functioning. Antipsychotic side effects vary according to the receptor activity profile of each agent. Conventional or ‘typical’ antipsychotics exert effects via dopamine type 2 (D2) receptor antagonism, whereas atypical antipsychotics more effectively block serotonin type-2 than D2 receptors. Typical antipsychotics are divided into three classes. High potency neuroleptics have a high affinity for D2 receptors, are clinically used in low dosages, and produce less anti-cholinergic side effects but more extrapyramidal symptoms (EPS; e.g. parkinsonism, dystonia, akathisia). Examples are haloperidol (Haldol) and fluphenazine (Prolixin). Low potency drugs, such as chlorpromazine (Thorazine) and thioridazine (Mellaril) have a low affinity for D2 receptors and a lower risk of EPS, but require higher dosages clinically and are associated with greater anticholinergic side effects and epileptogenicity. Intermediate potency neuroleptics, e.g. molidone (Moban) have features of both high and low potency agents. ‘Atypical’ antipsychotics differ from typical neuroleptics in that they are more effective for negative symptoms, cause fewer EPS, raise prolactin levels only minimally, and may be less likely to produce tardive dyskinesia. Personal experience suggests that

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epilepsy patients, compared with patients with idiopathic psychoses are highly susceptible to EPS with high potency as well as atypical neuroleptics, even at low doses.

4.2.4. Psychotherapy in the treatment of interictal psychiatric disturbances Psychotherapy is used to address life experiences, including stigma, confront demoralization or other interpersonal issues, and enhance coping and overall well-being. It may be used alone for mild depression, adjustment disorders and some anxiety disorders, but is best used as an adjunct in the treatment of more severe mood disorders, anxiety disorders and psychosis. A number of individual, group, and family psychotherapeutic methods can be useful for epilepsy patients. Individual psychotherapy may involve supportive, cognitive, behavioral, interpersonal or insight-oriented approaches (O’Brien et al., 1995). Supportive therapy includes education, counseling, guidance, and reassurance and should be offered to all patients. Cognitive-behavioral therapies are often used for mood and anxiety disorders, as therapy aims to identify negative and distorted thoughts and replace them with more positive constructs. In behavior therapy, the goal is to replace negative behaviors that exacerbate depression or anxiety with positive and functionally adaptive ones. Biofeedback, stress management or relaxation techniques can also be helpful for anxiety syndromes. Interpersonal therapy attempts to improve social and interpersonal functioning by increasing the ability to cope with stressors, deal with the physical, personal and social consequences of epilepsy and other life issues, and restore morale. Psychoanalysis, a specialized form of insight-oriented therapy in which unconscious feelings and conflicts of the past are explored and related to the present, is not specifically relevant as a therapy for interictal psychiatric disorders, but other insight-oriented approaches may relieve symptoms. Family therapy provides a means to address the consequences of epilepsy on the family, as well as the effects of family dynamics on the patient’s epilepsy and overall well-being. Group therapies help patients learn from each other, realize that

others share their problems, vent frustrations, and foster self-acceptance. Support groups provide a similar informal mechanism and are a launching point for patient education.

5. Interactions between treatments for epilepsy and for psychiatric disorders Management of ictal, peri-ictal, and interictal psychiatric disturbances includes thorough identification of symptoms, proper diagnosis, elimination or minimization of risk factors, and active intervention. To limit adverse drug interactions, increase compliance, and facilitate clinical improvement, many patients will benefit from specialized psychiatric assessment and treatment recommendations. For some, especially those with chronic or recurrent interictal psychiatric syndromes, psychiatric stability requires ongoing comanagement between their neurologist, psychiatrist, and primary medical doctor. In such cases, communication between physicians is vital to avoid adverse drug interactions or inappropriate prescriptions of new medications.

5.1. Effects of psychotropic agents on the seizure threshold Studies on the epileptogenicity of psychotropic agents reveal contradictory results. Risks for psychotropic-induced seizures vary according to each drug’s pharmacological class and potential for lowering the seizure threshold, the drug dosage and plasma concentration, pharmacokinetic drug interactions, and patient-related factors. Increased seizure risk is associated with antidepressant or antipsychotic overdoses, and with high therapeutic doses of select medications (Alldredge, 1999). Among antidepressants, the highest relative risk for seizures occurs with high therapeutic doses of buproprion, clomipramine, and maprotoline and the lowest relative risk occurs with the SSRIs, MAOIs, SARIs, and the NaSAs. Clinically, the occurrence of psychotropic related seizures is not a consistent problem. For example, in a large prospective series, seizure frequency was unchanged or improved and psychiatric status im-

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proved in the majority of epilepsy patients taking psychotropic agents (Ojemann et al., 1987). Antipsychotic agents are associated with a 1% risk for seizures (Lancman, 1999). Among typical neuroleptics, high potency agents carry a lower risk than low potency drugs. Clozapine, an atypical antipsychotic agent, causes epileptiform EEG abnormalities and is associated with a dose-related higher risk for seizures. Use of carbamazepine with clozapine is not recommended because both have potential adverse hematologic effects. Valproate is commonly used to treat clozaril-induced seizures in nonepileptic schizophrenic patients. Newer atypical agents, such as risperidone, olanzapine, quetiapine, and ziprasidone are less likely to reduce the seizure threshold.

5.2. Drug interactions between AEDs and psychotropic agents Two recent articles provide detailed reviews on drug interactions between AED and psychotropic agents (McConnell and Duncan, 1998; Monaco and Cicolin, 1999). Hospital pharmacies that maintain updated information on drug– drug interactions are an additional resource. A main point is that pharmacokinetic effects and interactions of AEDs and psychotropics are complex because of individual variation in cytochrome p450 (CYP2D6), a key isoenzyme involved in metabolism of several tricyclic antidepressants, fluoxetine, paroxetine and venlafaxine. About 4– 10% of Caucasians lack CYP2D6 and are called ‘slow metabolizers’. To prevent toxic or subtherapeutic dosing, clinical effects and plasma levels of both AEDs and psychotropics should be carefully monitored in patients taking both classes of agents (Ereshefky et al., 1996). Carbamazepine, phenobarbitol, primidone, and phenytoin also stimulate the catabolic degradation of TCAs, antipsychotics, and benzodiazepines. The SSRIs and TCAs increase plasma levels of AEDs by inhibiting degradation through CYP2D6, but antipsychotics do not significantly alter AED plasma levels. Serious drug interactions between antidepressants and AED can occur. Monoamine oxidase inhibitors (MAOIs) administered with carba-

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mazepine carry the risk of hypertensive crises, even though some studies showed no adverse interactions phenelzine or tranylcypromine were coadministered (Ketter et al., 1995; ABPI, 1996). Similarly, fluoxetine and carbamazepine can cause a serotonin syndrome characterized by autonomic instability, agitation, confusion, incoordination and hyperreflexia (Dursun et al., 1993). AEDs that are potent liver enzyme inducers, e.g. carbamazepine, phenytoin, and barbiturates, reduce plasma levels of antidepressants metabolized by the same pathway. Conversely, SSRIs such as paroxetine, when given with tricyclic agents, inhibit TCA degradation, increase TCA levels and can cause cardiac side effects. The risk of adverse interactions between epilepsy and psychiatric medications underscores the importance of coordination and communication between treating clinicians for provision of optimal care.

6. Summary Psychiatric disturbances develop in epilepsy patients under a variety of circumstances. At times, psychiatric conditions are directly related to abnormal brain activity associated with the seizure, as the ictus itself or during postictal mental state changes. Interictal psychiatric disturbances are related to multiple factors, including medication effects, psychosocial difficulties, and underlying brain dysfunction that may or may not be directly related to the epileptic condition. At times, the epileptic and psychiatric illnesses will be so closely intertwined that it may not be possible to separate etiologies for one versus another. Nonetheless, it is important for clinicians to recognize psychiatric conditions as syndromes warranting specific management, since definitive treatment helps to alleviate suffering, potentially reduces the intensity and frequency of seizures, and improves overall quality of life for the patient.

Acknowledgements Support provided by NIH (R29-MH53485 and T32-MH15330).

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