Psychiatric Disorders Associated With Epilepsy

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Psychiatric Disorders Associated With Epilepsy
Author: Pedro E Hernandez-Frau, MD; Chief Editor: Jose E Cavazos, MD, PhD, FAAN more... Updated: Jun 8, 2011

Overview
Epilepsy is a chronic disorder characterized by seizures, or a paroxysmal brain dysfunction due to excessive neuronal discharge. Psychiatric and cognitive disturbances are relatively common in epilepsy, especially in refractory epilepsy.[1, 2, 3] Indeed, there is now general agreement that the incidence of neurobehavioral disorders is higher in patients with epilepsy than in the general population (although some authors argue that this apparent overrepresentation is due to sampling errors or inadequate control groups). Many, but not all, authors also accept the proposition that the link between neurobehavioral disorders and temporal lobe or complex partial epilepsy is particularly strong. Edeh and Toone asserted that the difference is between focal epilepsies, both temporal lobe and nontemporal lobe, and primary generalized epilepsy.[4] In studying the relationship between epilepsy and psychiatric disorders, care must be taken to differentiate between the following: Psychiatric disorders caused by the seizures of the epilepsy - Ictal disorders, postictal disorders, and interictal disorders Epileptic and psychiatric disorders caused by common brain pathology Epileptic and psychiatric disorders that happen to coexist in the same patient but are not causally related Go to Epilepsy and Seizures for an overview of this topic. Additionally, go to Psychogenic Nonepileptic Seizures for complete information on this topic.

Factors in the relationship between epilepsy and behavioral disorders
Mechanisms for a relationship between epilepsy and behavioral disorders include the following: Common neuropathology Genetic predisposition Developmental disturbance Ictal or subictal neurophysiologic effects Inhibition or hypometabolism surrounding the epileptic focus Secondary epileptogenesis Alteration of receptor sensitivity Secondary endocrinologic alterations Primary, independent psychiatric illness Consequence of medical or surgical treatment Consequence of psychosocial burden of epilepsy Schmitz et al found that multiple interacting biologic and psychosocial factors determine the risk for development of either schizophreniform psychoses or major depression in patients with epilepsy and concluded that behavioral disorders in epilepsy had multiple risk factors and multifactorial etiology.[5]

Role of the neurologist in the psychiatric management of patients with epilepsy
As neurologists, we tend to focus on seizure control, and psychiatric comorbidities are often underestimated.

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Recognizing psychiatric manifestations is an area that needs improvement. Once symptoms are identified, the following questions arise[6] : Are the symptoms related to the occurrence of seizures (preictal, ictal, postictal)? Are the symptoms related to antiepileptic drugs (AEDs)? Is the onset of symptoms associated with the remission of seizures in patients who had previously failed to respond to AEDs? Because of the phenomenology of epilepsy, the close association between epilepsy and psychiatry has a long history. The traditional approach to epilepsy care has been to focus on the seizures and their treatment. Concentrating only on the treatment of the seizures, which occupy only a small proportion of the patient's life, does not seem to address many of the issues that have an adverse impact on the quality of life of the patient with epilepsy. Sackellares and Berent stated that comprehensive care of the epileptic patient requires "attention to the psychological and social consequences of epilepsy as well as to the control of seizures."[7] Although undoubtedly important in the care of the patient with epilepsy, advances in neurologic diagnosis and treatment tended to obscure the behavioral manifestations of epilepsy until Gibbs drew attention to the high incidence of behavioral disorders in patients with temporal lobe epilepsy.[8]

Frequency of psychiatric disorders in patients with epilepsy
Vuilleumier and Jallon estimated that 20-30% of patients with epilepsy have psychiatric disturbances.[9] Tucker reported that 70% of patients with intractable complex partial seizures had 1 or more diagnoses consistent with Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R); 58% of these patients had a history of depressive episodes, 32% had agoraphobia without panic or other anxiety disorder, and 13% had psychoses.[10] Torta and Keller reported that the risk of psychosis in populations of patients with epilepsy may be 6-12 times that of the general population, with a prevalence of about 7-8% (in patients with treatment-refractory temporal lobe epilepsy, the prevalence has been reported to range from 0-16%).[11] Differences in the rates may result from differences in populations studied, time periods investigated, and diagnostic criteria. The most common psychiatric conditions in epilepsy are depression, anxiety, and psychoses.[12, 13, 14, 15, 16, 17] (See the Table below.) Table. Prevalence Rates of Psychiatric Disorders in Patients With Epilepsy and the General Population (2007 data)[12] (Open Table in a new window) Psychiatric Disorder Anxiety disorder Mood/anxiety disorder Suicidal Ideation Others Controls Patients With Epilepsy 17.4% 22.8% 34.2% 25.0% 35.5% 11.2% 19.6% 13.3% 20.7%

Major depressive disorder 10.7%

The psychiatric symptoms characteristic of the neurobehavioral syndrome of epilepsy (ie, Morel syndrome) tend to be distinguished in the following ways: Atypical for the psychiatric disorder Episodic Pleomorphic

Case study
A 27-year-old man with history of primary generalized epilepsy not controlled with medical therapy presented to a third neurologist for evaluation. His generalized tonic-clonic seizures began 7 years ago. The patient had a complete

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Psychiatric Disorders Associated With Epilepsy

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neurologic workup, with some of the tests repeated a few times. Everything was unremarkable except for interictal generalized sharp and wave complexes on electroencephalography. The patient has tried multiple antiepileptic medications (AEDs) without improvement. He has at least 1-2 seizures per week. Since the diagnosis, the patient has not been very motivated. He did not complete graduate school; has worked only at a bookstore, part time; still lives at home; and is uninterested in a relationship or in marriage. His parents fear that he will not be able to support himself independently in the future. Lately, he is staying at home most of the time because he is afraid he will have a seizure.

History and Mental Status Examination
The history and Mental Status Examination (MSE) are the most important diagnostic tools a psychiatrist has to obtain information to make an accurate diagnosis. When patients enter the office, pay close attention to their personal grooming. Other behaviors to note may include patients talking to themselves in the waiting area or perhaps pacing outside the office door. Record all observations. The next step for the interviewer is to establish adequate rapport with the patient by introducing himself or herself. Speak directly to the patient during this introduction, and pay attention to whether the patient is maintaining eye contact. As the interview progresses, more specific or close-ended questions can be asked to obtain specific information needed to complete the interview. At some point during the initial interview, a detailed patient history should be taken. Every component of the patient history is crucial to the treatment and care of the patient it identifies. The patient history should begin with identifying patient data and the patient's chief complaint or reason for coming to the clinic. This also is where all history of illness is recorded, including psychiatric history, medical history, surgical history, family psychiatric and medical history, medications, and allergies. Following completion of the patient's history, perform the MSE to test specific areas of the patient's spheres of consciousness. Next, the interviewer's task is to define the patient's affect, which will range from expansive (fully animated) to flat (no variation). The patient's speech is then evaluated. Thought process and content are evaluated next, including any hallucinations or delusions, obsessions or compulsions, phobias, and suicidal or homicidal ideation or intent. Then, the patient's sensorium and cognition are examined, most commonly using the Mini-Mental State Examination. A compilation of all information gathered throughout the interview and MSE leads to the differential diagnosis of the patient. Once this diagnosis is established, a treatment plan is formulated.

Psychosis
Psychosis is a mental and behavioral disorder causing gross distortion or disorganization of a person’s mental capacity, affective response, and capacity to recognize reality, communicate, and relate to others to the degree of interfering with that person’s capacity to cope with the ordinary demands of everyday life. Vuilleumier and Jallon found that 2-9% of patients with epilepsy have psychotic disorders.[9] Perez and Trimble reported that about half of epileptic patients with psychosis could be diagnosed with schizophrenia.[18] Kanner states that various classifications have been proposed for the psychoses associated with epilepsy. He asserts that for the neurologist, the most useful might be that which distinguishes among psychoses closely linked to seizures (ictal or postictal psychosis), those linked to seizure remission (alternative psychosis), psychoses with a more stable and chronic course (such as interictal psychosis), and iatrogenic psychotic processes related to antiepileptic drugs.[19]

Ictal events
Status epilepticus (ie, complex partial status epilepticus and absence status epilepticus) can mimic psychiatric disorders, including psychosis.

Postictal events

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So and colleagues distinguished between postictal psychosis, which is characterized by well-systematized delusions and hallucinations in a setting of preserved orientation and alertness, and postictal confusion. They also distinguished between self-limited postictal psychosis and the unremitting chronic interictal psychosis seen in long-standing epilepsy.[20] Criteria proposed by Stagno for postictal psychosis include the following[21] : Psychotic or other psychiatric symptoms occur after a seizure or, more frequently, a series of seizures, after a lucid interval, or within 7 days of the seizure(s) The event may be psychosis, depression or elation, or an anxiety-related symptom The event is time-limited, lasting days or, rarely, weeks; no significant clouding of consciousness occurs. Logsdail and Toone believe that clouding of consciousness, disorientation, or delirium may be noted, and, if consciousness is unimpaired, delusions and hallucinations are present; a mixture of both also may be noted.[22] Clouding should not be attributed to other medical or psychiatric causes (eg, drug intoxication, complex partial status epilepticus, metabolic disturbance).

Interictal events
Interictal psychotic phenomena, particularly hallucinations and delusions, are common in patients with epilepsy.[23,
24, 25]

Although many etiologies of psychosis in epilepsy have been proposed, the significance of such factors as the

type of seizure, epilepsy classification, lateralization of foci, and age at onset of epilepsy remains uncertain.[26, 27, 28,
29]

Tarulli et documented cases of patients who had multiple episodes of postictal psychosis before developing interictal psychosis.[30] They concluded that a progression from postictal to interictal psychosis may be at play and that increased awareness and prompt treatment of postictal psychosis may inhibit or prevent development of some instances of interictal psychosis.

Factors in the development of psychosis
The following variables are believed to have particularly strong links to the development of psychotic phenomena in patients with epilepsy: Family history of psychosis - Patients who had a positive family history of psychosis were extremely susceptible to psychosis, so a genetic factor appears to be involved Age at onset of epilepsy - Patients with interictal psychosis showed a significantly earlier onset of epilepsy[31,
32, 33, 34, 35]

Type of seizure - The existence of complex partial seizure (mostly temporal lobe epilepsy) may be strongly associated with interictal psychoses[36, 37] Intelligence - Patients with borderline intellectual functioning tend to develop psychotic symptoms relatively frequently[31, 32] The risk factors for developing psychosis in epilepsy found in some studies also include the following[38] : Partial complex seizures, especially with temporal lobe foci The presence of "alien tissue" (eg, small tumors, hamartomas) Mesial temporal lobe gangliogliomas Left-handedness, especially in women With regard to the first item above, some authors have noted a predominance of left-sided foci. Frontal lobe epilepsy is also common. Schmitz et al studied risk factors and classified them by the following system: Biologic factors Earlier onset of epilepsy More severe epilepsy Psychosocial factors Disturbed family background

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Lack of interpersonal relationships Social dependency Professional failure More frequent temporal lobe and unclassifiable epilepsies and less frequent generalized epilepsies With regard to the last item above, no significant differences in types of epilepsies between patients with epilepsy and psychosis and patients with epilepsy without psychiatric disease have been found. Trimble and Schmitz believe that the conclusions presented in the literature on risk factors are highly controversial.[38]

Schizophrenia
In a review study of patients with epilepsy who developed psychosis, Tandon and DeQuardo found that the patients’ psychosis was usually a form of schizophrenia, most commonly paranoid schizophrenia.[39] Stagno reported that persistent interictal psychoses of epilepsy and the schizophrenialike psychoses of epilepsy are distinguishable from schizophrenia in the traditional psychiatric sense by the following[21] : Lack of negative symptoms of schizophrenia, particularly flattening of affect and personality deterioration Better premorbid personality Paranoid delusions Delusions of reference More benign and variable course

Treatment
Status epilepticus and ictal abnormalities are treated in the same way as nonpsychiatric epileptic events. Postictal events are treated by improving seizure control. So et al believe that postictal psychosis remits spontaneously even without treatment but that the use of effective neuroleptics may shorten the duration.[20] Interictal psychosis is treated with antipsychotic drugs. Medications that lower seizure threshold should be avoided. Some studies indicate that risperidone, molindone, and fluphenazine may have better profiles than older antipsychotic medications; clozapine has been reported to confer a particularly high risk of seizures.

Forced normalization
Treatment of any of the psychoses of epilepsy should take into consideration the phenomenon termed forced normalization, which is a concept described by Landolt in the 1950s. When the electroencephalogram (EEG) in psychotic patients is normalized, often with anticonvulsant medicines, the psychiatric problem worsens. Alternative psychosis, or antagonism between seizures and behavioral abnormalities (ie, worsening of behavior with improvement in seizure control) is a similar phenomenon that has been known for a longer time. Forced normalization frequently is described in patients treated with ethosuximide; anecdotally, however, forced normalization effects have been produced by treatment with most antiepileptic agents, including the newer agents. The mechanism underlying these interesting phenomena is not yet understood. Many authors consider the idea of forced normalization to be somewhat controversial.

Depression
Depression is a mental state or chronic mental disorder characterized by feelings of sadness, loneliness, despair, low self-esteem, and self-reproach. Accompanying signs include psychomotor retardation (or, less frequently, agitation), withdrawal from social contact, and vegetative states, such as loss of appetite and insomnia. Depression is the most frequent psychiatric comorbidity seen in patients with epilepsy. It is more likely to occur in patients with partial seizure disorders of temporal and frontal lobe origin. It is also more frequent in patients with poorly controlled seizures.[40]

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Two possibilities exist: (1) depression is a reaction to the epilepsy, or (2) depression is a part of the epilepsy. Mendez et al compared patients with epilepsy to matched controls without epilepsy but with a similar degree of disability from other chronic medical diseases and found that, while 55% of the patients with epilepsy reported depression, only 30% of the matched controls reported depression.[41] Mendez et al concluded that depression is related to a specific epileptic psychosyndrome. On the other hand, Robertson concluded that, with few exceptions, the phenomenology of the depression to a large degree is not attributed to neuroepilepsy variables; however, not all studies have found this difference.[42] In patients with refractory epilepsy, the presence of depression is one of the most important variables to have an impact on their quality of life, even more than the frequency and severity of the seizures. Several studies have documented that the quality of life improves significantly in patients with epilepsy who are made seizure free. If those patients are excluded, Boylan et al have found that the quality of life is related to depression but not to degree of seizure control.[43] Despite its high prevalence in patients with epilepsy, depression very often remains unrecognized and untreated. The reasons for clinicians’ failure to recognize depressive disorders in patients with epilepsy include the following[40] : Patients tend to minimize their psychiatric symptoms for fear of being further stigmatized The clinical manifestations of certain types of depressive disorders in epilepsy differ from depressive disorders in patients without epilepsy and therefore are not recognized by physicians Clinicians usually fail to inquire about psychiatric symptoms Patients and clinicians tend to minimize the significance of symptoms of depression because they consider them to be a reflection of a normal adaptation process to this chronic disease.[44] The concern that antidepressant drugs may lower the seizure threshold has generated among clinicians a certain reluctance to use psychotropic drugs in patients with epilepsy. Risk factors for the development of depression in patients with epilepsy include the following: Temporal lobe (but not frontal lobe) partial complex seizures Vegetative auras Family history of psychiatric illness, particularly depression Laterality effects, which are controversial

Physiologic factors associated with epilepsy and depression
Decreased serotonergic, noradrenergic, and GABAergic functions have been identified as pivotal etiologic mechanisms in depression and have been the basis for antidepressant pharmacologic treatments.[45] Decreased activity of these same neurotransmitters has been shown to facilitate the kindling process of seizure foci, to exacerbate seizure severity, and to intensify seizure predisposition in some animal models of epilepsy.[16] Therefore, parallel changes of serotonin (5HT), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA) may be operant in the pathophysiology of depressive disorders and epilepsy. Jobe et al have presented evidence that some types of depression and some types of epilepsy may be associated with decreased noradrenergic and serotonergic transmission in the brain.[16] Flor-Henry speculated that depression might be related to right (nondominant) foci, a finding confirmed by a few other investigators.[46] Some authors have suggested that elation is associated with right-sided lesions and depression or sadness with left-sided lesions. Most studies that find a relationship between laterality and depression have found depression to be more common with left-sided foci. Lopez-Rodriguez et al found that major depressive episodes were statistically more frequent in patients with left temporal lobe seizures than in patients with right temporal lobe seizures.[47] Other authors report no laterality differences in depression rates.

Other factors associated with depression in epilepsy

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One of the variables linking depression and epilepsy is a family history of depression. A greater frequency of depression has been found in patients with seizures originating in limbic structures; also, a frontal lobe dysfunction has been associated with depression. The quality of life is often suboptimal for patients with epilepsy, and this may adversely affect mood.[40, 48, 49, 50, 51] Increased financial stress, life stressors, and poor adjustment to seizures are predictive of increased depression.[52] The lack of control over the illness may be an additional risk factor for depression.[48, 53] Depression in epilepsy may also result from iatrogenic causes (pharmacologic and surgical). The AEDs most frequently associated with iatrogenic depressive symptoms include the following[54] : Phenobarbital Primidone Vigabatrin Levetiracetam Felbamate Topiramate Depressive disorder can also occur following the discontinuation of AEDs with positive psychotropic properties, such as carbamazepine, oxcarbazepine, valproic acid, and lamotrigine.

Frequency of depression in epilepsy
In patients with epilepsy, the reported rates of depression range from 8-48% (mean 29%, median 32%); the prevalence of depression in the general population ranges, in different epidemiologic studies, from 6-17%.[55] In a study of patients with epilepsy who were admitted to a psychiatric hospital, Betts found that depression was the most common psychiatric diagnosis. Williams studied 2000 patients with epilepsy and found that depressed mood was part of the attack in 21. According to Williams, depressed mood was the second most common emotion constituting part of the attack, with fear being the most common.[56] Others have found similar results.

Characteristics of depression in patients with epilepsy
Characteristics of patients with epilepsy who also have depression include the following: Fewer neurotic traits More psychotic traits Higher trait and state anxiety scores More abnormal affect and chronic dysthymic disorder High hostility scores, especially for self-criticism and guilt Sudden onset and brief duration of symptoms Perhaps 10-20% of persons with epilepsy have a peri-ictal prodrome consisting of depressed-irritable mood, sometimes with anxiety or tension and headaches. Although Williams noted in his patients that the mood disturbance would persist for 1 hour to 3 days after the ictus, postictal affective syndromes have received little attention in the literature.[56] Blumer has defined an interictal dysphoric disorder (IDD) in patients with epilepsy in which symptoms tend to be intermittent.[57] On average, the patients tend to have 5 of the following symptoms (range 3-8): Depressed mood Anergia Pain Insomnia Fear Anxiety Paroxysmal irritability

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Euphoric moods Kanner has noted that the symptoms of depression in patients with epilepsy are different from those in patients without epilepsy. He believes that patients with epilepsy who are felt to warrant antidepressant therapy often do not meet formal DSM criteria for a mood disorder and concludes that the problem of depression in epilepsy may be underestimated by using screening instruments designed for use in psychiatric patients.[58] Kanner continued with this research using the DSM-IV criteria. Most symptoms presented with a waxing and waning course, with symptom-free periods. He referred to this form of depression as dysthymic-like disorder of epilepsy (DLDE). Caplan et al believe that depression in children and adolescents with epilepsy tends to have a different presentation from that seen in adults with epilepsy, although some adolescents with depression may present with a syndrome similar to that seen in adults. They reported that children with depression often do not appear sad and that the depression may be manifested by the following[59] : Irritability Oppositionality Aggression Anger For this reason, special instruments are used to assess depression in children. Thome-Souza et al reported that depression in children with epilepsy may be underdiagnosed and untreated for longer periods than in adults. They found that 70.5% of children and adolescents in the study had psychiatric disorders and that the most frequent psychiatric disorder in children was attention-deficit hyperactivity disorder and the most frequent psychiatric disorder in adolescents was depression. They found that family history was also an important determinant in mood disorders in children and adolescents.[60]

Preictal symptoms of depression
Categorizing depression in patients with epilepsy as depression occurring peri-ictally (preictally, ictally, or postictally) and interictally may be useful. Preictal symptoms of depression are believed to present as symptoms of irritability, poor frustration tolerance, motor hyperactivity, and aggressive behavior in children with epilepsy. However, very few studies have been performed in the literature.[6, 61]

Ictal symptoms of depression
Ictal symptoms are the clinical expression of a simple partial seizure. Psychiatric symptoms occur in approximately 25% of auras. The most frequent symptoms include feelings of anhedonia, guilt, and suicidal ideation.[6, 62]

Postictal symptoms of depression
Postictal symptoms of depression have been recognized for a long time, but they have been poorly studied in a systematic manner.[6, 63]

Interictal symptoms of depression
For patients with epilepsy to experience depressive episodes that fail to meet any of the DSM-IV-TR criteria is not unusual. Kraepelin and Bleuler were the first to describe affective symptoms of prominent irritability, intermixed with euphoric mood, fear, and symptoms of anxiety, as well as anergia, pain and insomnia.[6, 64, 65] In 1986, Mendez et al used the term atypical depression in epilepsy patients using the DSM-III-R criteria.[41]

Treatment
The treatment of mood disorders in patients with epilepsy includes reevaluation of the anticonvulsant regimen, cautious but aggressive use of antidepressants, and psychotherapy.

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First and foremost, treatment involves seizure control with appropriate anticonvulsant therapies. A phenomenon analogous to alternative psychosis, worsening of behavior with better seizure control, has been reported in epilepsyassociated mood disorders. There is evidence that some anticonvulsant therapies, including VNS, valproate, gabapentin, carbamazepine, and lamotrigine, also have antidepressant effects and may prove effective in treating depression in patients with epilepsy. Phenobarbital is known to produce depression. According to Schmitz, vigabatrin has been linked to psychoses and to major depression, and phenytoin has been associated with toxic encephalopathies.[66] McConnell and Duncan cite some patients in whom phenytoin had been linked to depression and mania. A case has been made that the GABAergic drugs may be associated with an increased incidence of psychiatric problems.[67] However, antidepressants may be necessary to effectively treat depression in these patients. When an antidepressant is prescribed, the epileptogenic potential, adverse effects, and drug interactions must be evaluated. Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (due to its lack of drug interactions) and multireceptor-active compounds such as nefazodone or venlafaxine are suggested as first-line treatments. Bupropion, maprotiline, and clomipramine should be avoided. Virtually all non-monoamine oxidase inhibitor (MAOI) antidepressants have been reported to lower seizure threshold. In the treatment of epilepsy-related depression, priority should be given to optimizing seizure control, since improved psychosocial functioning tends to accompany seizure remission. Antidepressants may manifest convulsant and anticonvulsant effects. Maprotiline and amoxapine have the greatest seizure risk; doxepin, trazodone, and fluvoxamine appear to have the lowest risk. Electroconvulsive therapy is not contraindicated and may prove effective for epilepsy patients with severe, treatmentresistant, or psychotic depression. In small studies, Elger et al[68] and Harden et al[69] showed that treatment with vagal nerve stimulation improves depression in epileptics independent of effect on seizure frequency. Vagal nerve stimulation is a useful therapeutic tool in treatment-resistant depression. It is imperative that depression be recognized and treated in patients with epilepsy. Further prospective studies of new treatment options for depression in this patient population are needed.[70]

Suicide
Suicidality (completed suicide, suicide attempt, and suicidal ideation) is significantly more frequent among people with epilepsy than in the general population.[71, 72, 73, 74, 75, 76] The risk of suicide in the general population averages about 1.4%. Depression is one of the psychiatric disorders that increase the risk of suicide. The risk of suicide in depressed patients is believed to be around 15%. On average, the risk of suicide in patients with epilepsy is about 13% (prevalence rate ranges from 5-10 times that of the general population). Although some authors question its methodological and patient selection techniques, most authors cite Barraclough's meta-analysis, which revealed that the risk of suicide in patients with temporal lobe epilepsy is increased to as much as 25-fold that of the general population.[77] Even so, depression remains underrecognized and untreated. The relationship between epilepsy and suicidality is complex and multifactorial. Psychiatric adverse events, including symptoms of depression and anxiety, have been reported with the use of several AEDs, particularly barbiturates (phenobarbital and primidone), topiramate, tiagabine, zonisamide, vigabatrin, and levetiracetam.[64, 78, 79, 80, 81] The incidence of suicidal phenomena linked to specific AEDs has not been systematically well studied. This data may either reflect the natural course of an underlying, recurrent psychiatric illness with no real effect from AEDs or could suggest that AEDs lower the threshold for manifesting psychiatric symptoms in individuals who are vulnerable because of a genetic or historical predisposition to psychiatric disorders.

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Frequent risks associated with suicidality include the following[71] : Current or past history of mood and anxiety disorders Family psychiatric history of mood disorders, particularly of suicidal behavior Past suicidal attempts In January 2008, the US Food and Drug Administration (FDA) issued an alert regarding the association between suicidality and AEDs, having concluded that there was a statistically significant, 1.80-fold increased risk of suicidality with exposure to AEDs. This conclusion was based on the results of a meta-analysis that included data from 199 randomized clinical trials of 11 AEDs: carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. The meta-analysis encompassed 43,892 patients treated for epilepsy, psychiatric disorders, and other disorders, predominantly pain. In the study, suicidality occurred in 4.3 per 1,000 patients treated with AEDs in the active arm, compared with 2.2 per 1,000 patients in the comparison arm. The results of this meta-analysis must be considered with great caution, and more research is necessary.[71, 82, 83] The FDA has decided to insert suicide warnings in the package inserts of all AEDs; thus, physicians need to identify patients with increased risk of suicide.[71]

Mania
In a carefully selected series of patients with epilepsy, Williams found that only 165 of 2000 patients had complex, including emotional, ictal experiences.[56] Of those 165 patients, only 3 described elation. Mania and hypomania are rare in association with epilepsy. Manic-depressive illness is also rare; of 66 patients with epilepsy and major depression, only 2 had bipolar disorder. This rarity is probably, to some degree, secondary to the antimanic effect of drugs such as carbamazepine and valproate. However, mania was uncommonly associated with epilepsy even before the use of modern antiepileptic drugs. Valproic acid, lamotrigine, and carbamazepine are well-known mood stabilizers. One AED can treat both seizures and bipolar disorder, if chosen wisely. Patient quality of life and compliance both improve.

Anxiety Disorders
Anxiety is an experience of fear or apprehension in response to anticipated internal or external danger, accompanied by some or all of the following signs: muscle tension, restlessness, sympathetic hyperactivity, and cognitive signs and symptoms (hypervigilance, confusion, decreased concentration, or fear of losing control). Anxiety is common in patients with epilepsy; of 49 patients with epilepsy attending a tertiary epilepsy care center, 57% had high-level anxiety. Anxiety in patients with epilepsy can be ictal, postictal, or interictal. GABA is the most important inhibitory transmitter in the central nervous system (CNS). Evidence suggests that the abnormal functioning of GABA receptors could be of great importance in the pathophysiology of epilepsy and anxiety disorders.[84, 85] Differentiating between spontaneous fear and reactive fear (ie, reaction to the knowledge that a seizure may occur) can be difficult. Panic disorder can produce paroxysmal symptoms, which can be confused with epileptic events and may go unrecognized in patients with epilepsy. Anxiety also may be related to nonepileptic attack disorder.

Symptoms of anxiety in epilepsy
Symptoms of anxiety in epilepsy may result or be exacerbated by psychological reactions, including responses to the unpredictability of seizures and restrictions of normal activities. This results in low self-esteem, stigmatization, and social rejection.[1, 86, 87] (According to Goldstein and Harden, epileptic events can produce symptoms indistinguishable from those of primary anxiety disorder.[88] )

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Fear and anxiety are often associated with simple partial seizures. Torta and Keller estimated that fear occurs as an aura in as many as 15% of patients,[11] and Goldstein and Harden concluded from several studies that fear is one of the most common ictal emotions.[88] Ictal anxiety symptoms manifest as fear or panic, sometimes with other characteristics of temporal discharges, such as depersonalization and déjà vu, as well as other psychological and autonomous phenomena.[1, 89]

Anxiety in association with type of epilepsy and frequency of seizures
The highest rates of psychiatric comorbidities, including anxiety, are reported in patients with chronic, refractory seizure disorders.[1, 86, 89, 90] Interestingly, however, Goldstein et al found that patients with epilepsy with high seizure frequency had lower anxiety scores than did patients with lower seizure frequency.[91] The risk of anxiety is higher in focal (more frequent in temporal lobe) epilepsy than in generalized epilepsy. In patients with temporal lobe epilepsy, Trimble et al reported that 19% of the patients were diagnosed with anxiety and 11% were diagnosed with depression. Edeh and Toone found that patients with temporal lobe epilepsy scored higher for anxiety than did those with focal, nontemporal lobe epilepsy.[4] Anxiety can also be seen in frontal lobe epilepsy.

Ictal and interictal anxiety
Anxiety in epileptic patients may occur as an ictal phenomenon, as normal interictal emotion or as part of an accompanying anxiety disorder, as part of an accompanying depressive disorder, or in association with nonepileptic, seizurelike events as part of an underlying primary anxiety disorder. Interictal anxiety has a great influence on the quality of life of patients, since most of them have a permanent fear of new discharges. Torta and Keller have estimated that as many as 66% of patients with epilepsy report interictal anxiety. Goldstein and Harden proposed 2 major psychological mechanisms for this, as follows: Fear of seizure recurrence (seizure phobia) Issues surrounding locus of control They concluded that documented cases of actual seizure phobia are rare but that a sense of dispersed locus of control can cause profound problems in patients with epilepsy.

Treatment
Several studies have shown that pregabalin, used as an adjunct for partial seizures, has been an effective, rapidly active, and safe treatment for generalized anxiety disorder.

Research
Although, as shown above, studies looking into the association between anxiety and epilepsy have been performed, because of the difficulty in separating the anxiety that accompanies a chronic disease from pathologic anxiety, studies investigating anxiety in epilepsy have nonetheless been relatively few.

Personality Disorders
The question of personality disorders associated with epilepsy has a long history and remains controversial. Trimble has summarized the data and concluded that the personality profiles of patients with epilepsy can be explained by a complex combination of the effects of (1) dealing with a chronic illness (being epileptic), (2) AEDs, and (3) temporal lobe pathology. Waxman and Geschwind have defined a collection of behavioral abnormalities (now called Geschwind syndrome)

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that they associated with temporal lobe epilepsy.[92] Characteristics of the syndrome include viscosity, circumstantiality, hypergraphia, and, less frequently, hyperreligiosity. Benson and Hermann reported that data are insufficient to state with certainty that a consistent pattern of behavioral changes occurs in patients with temporal lobe epilepsy.[93] Complex partial epilepsy should not be diagnosed on the basis of the presence of Geschwind syndrome without any paroxysmal episodes that can be proven to be epileptic.

Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) is another common psychiatric comorbidity in patients with epilepsy. ADHD, predominantly the inattentive type, is more common in children.[6, 94, 95] Many AEDs can cause symptoms of ADHD. The more common AEDs implicated are the GABAergic drugs, such as barbiturates, benzodiazepines, and vigabatrin.[6, 80, 96, 97, 98, 99, 100, 101]

Psychotropic Effects of Antiepileptic Drugs
Knowledge about the psychotropic effects of AEDs is crucial and yet very limited in the epilepsy population. Evidence suggests that lamotrigine and the vagal nerve stimulator may have antidepressant properties that could be of use in light of common comorbid depression. Carbamazepine, valproate, lamotrigine, and possibly oxcarbazepine may have mood stabilizing properties. Gabapentin, pregabalin, and tiagabine may have anxiolytic benefits. There is a risk of depression related to barbiturates and topiramate, and possibly to phenytoin. Underlying depression and anxiety symptoms may be exacerbated by levetiracetam, while psychotic symptoms, albeit rare, have been reported with topiramate, levetiracetam, and zonisamide.[102]

Patient and Family Education
For patient education information, see Epilepsy, Depression, Schizophrenia, Bipolar Disorder, and Anxiety. The following Web sites are useful patient and family education tools: American Epilepsy Society Centers for Disease Control and Prevention, Epilepsy Epilepsy.com Epilepsy Foundation Epilepsy Foundation, Communities MayoClinic.com, Epilepsy Medline Plus, Epilepsy National Institute of Neurological Disorders and Stroke, NINDS Epilepsy Information Page

Conclusion
As discussed, psychiatric comorbidities in patients with epilepsy are relatively frequent. Despite the high prevalence rates, few data are available. Because of this, we are using the data from primary psychiatric disorders, assuming it can be applicable to patients with epilepsy. Early recognition and management of psychiatric disorders in patients with epilepsy is extremely important, because it improves the quality of life, decreases suicidality, and aids in better seizure control.

Contributor Information and Disclosures
Author Pedro E Hernandez-Frau, MD Clinical Neurophysiology Fellow, Department of Neurology, Tampa General Hospital, University of South Florida College of Medicine

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Pedro E Hernandez-Frau, MD is a member of the following medical societies: American Academy of Neurology Disclosure: Nothing to disclose. Coauthor(s) Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting Specialty Editor Board Andrew S Blum, MD, PhD Director, Adult Epilepsy and EEG Laboratory, Comprehensive Epilepsy Program, Rhode Island Hospital; Associate Professor of Neurology, The Warren Alpert Medical School of Brown University Andrew S Blum, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Massachusetts Medical Society Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Chief Editor Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director of the San Antonio Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association Disclosure: GXC Global, Inc. Intellectual property rights Medical Director - company is to develop a seizure detecting device. No conflict with any of the eMedicine articles that I wrote or edited.

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