Psychiatric Disorders Associated With Epilepsy

Updated: Feb 04, 2016
  • Author: Fahad Salih Algreeshah, MD; Chief Editor: Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS, FAES  more...
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Overview

Overview

The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) define epilepsy as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the biologic, cognitive, psychological, and social consequences of this condition. This association may reflect the anatomical and neurobiological source of both epileptic seizures and the behavioral manifestations.

Antiepileptic drugs (AEDs) can play a role in the genesis of psychiatric symptoms; on the other hand, some psychotropic medications can lower the seizure threshold and provoke epileptic seizures.

Indeed, there is a 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.

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 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

Multiple interacting biologic and psychosocial factors determine the risk for the development of either schizophreniform psychoses or major depression in patients with epilepsy, and behavioral disorders in epilepsy have multiple risk factors and multifactorial etiologies. [1]

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. Recognizing psychiatric manifestations is an area that needs improvement. Once symptoms are identified, the following questions arise [2] :

  • Are the symptoms related to the occurrence of seizures (preictal, ictal, postictal)?
  • Are the symptoms related to 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." [3]

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. [4]

Frequency of psychiatric disorders in patients with epilepsy

It is estimated that 20-30% of patients with epilepsy have psychiatric disturbances. [5]

Of patients with intractable complex partial seizures, 70% may have 1 or more diagnoses consistent with the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R); 58% of these patients have a history of depressive episodes, 32% have agoraphobia without panic or other anxiety disorder, and 13% have psychoses. [6]

The risk of psychosis in 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%. [7]

Differences in the rates may result from differences in the populations studied, time periods investigated, and diagnostic criteria.

The most common psychiatric conditions in epilepsy are depression, anxiety, and psychoses. [8, 9, 10, 11, 12, 13] (See the Table below.)

Table. Prevalence Rates of Psychiatric Disorders in Patients With Epilepsy and the General Population (2007 data) [8] (Open Table in a new window)

Psychiatric Disorder Controls Patients With Epilepsy
Major depressive disorder 10.7% 17.4%
Anxiety disorder 11.2% 22.8%
Mood/anxiety disorder 19.6% 34.2%
Suicidal Ideation 13.3% 25.0%
Others 20.7% 35.5%

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
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Psychotic Disorders

Psychotic disorders are severe mental disorders that cause abnormal thinking and perception. Psychotic individuals lose relation with reality. Symptoms generally described as either positive, such as hallucinations, delusions, and disorganized behaviors, or negative, such as diminished range of emotion, reduced speech, and inability to initiate and sustain goal-directed activities.

Vuilleumier and Jallon found that 2-9% of patients with epilepsy have psychotic disorders. [14]

Perez and Trimble reported that about half of epileptic patients with psychosis could be diagnosed with schizophrenia. [15]

The etiology and pathogenesis of psychosis in epilepsy are poorly understood; however, neuroanatomical changes have been observed in patients with psychosis and include the following:

  • Asymmetry of amygdala and anterior segment of the hippocampus [16]
  • Rule of hippocampal-amygdala complex in pathogenesis of schizophrenia [17]
  • Smaller gray matter volume in the left and middle temporal gyri and left posterior superior temporal gyrus [18]
  • Rule of bilateral middle frontal gyrus (prefrontal cortex) in overt psychosis occurring with schizophrenia [19]
  • Superior temporal cortex and dysfunction of corollary discharges in auditory hallucination [20]

Patients with temporal lobe epilepsy and psychosis of epilepsy have significantly smaller brain volume than people with temporal lobe epilepsy alone, and psychosis of epilepsy is a distinct nosologic entity differing from schizophrenia. [21]

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 (eg, interictal psychosis), and iatrogenic psychotic processes related to antiepileptic drugs. [22]

Ictal events

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

Postictal events

So and colleagues distinguished between postictal psychosis, which is characterized by well-systematized delusions and hallucinations in a setting of preserved orientation and alertness, as well as postictal confusion. They also distinguished between self-limited postictal psychosis and the unremitting chronic interictal psychosis seen in long-standing epilepsy. [23]

Criteria proposed by Stagno for postictal psychosis include the following [24] :

  • 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 may be 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. [25]

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. [26, 27, 28]

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. [29, 30, 31, 32]

Tarulli et al documented cases of patients who had multiple episodes of postictal psychosis before developing interictal psychosis. [33] 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 the 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 [34, 35, 36, 37, 38]
  • Type of seizure - The existence of complex partial seizure (mostly temporal lobe epilepsy) may be strongly associated with interictal psychoses [39, 40]
  • Intelligence - Patients with borderline intellectual functioning tend to develop psychotic symptoms relatively frequently [34, 35]

The risk factors for developing psychosis in epilepsy found in some studies also include the following [41] :

  • 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
  • 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. [41]

Schizophrenia

In a review study of patients with epilepsy who developed psychosis, Tandon and DeQuardo found that the patients’ psychoses were usually a form of schizophrenia, most commonly paranoid schizophrenia. [42]

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 [43] :

  • 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. [44] Interictal psychosis is treated with antipsychotic drugs. Medications that lower the 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.

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Bipolar Affective Disorders

Bipolar affective disorder is chronic psychiatric disease with severe changes in mood with a wide spectrum of clinical manifestations. A number of studies have demonstrated that affective disorders in epilepsy represent a common psychiatric comorbidity; however, most of the neuropsychiatric literature focuses on depression, which is actually prominent. [45]

The incidence of developing bipolar affective disorder in epilepsy is 1.69 cases per 1000 persons-year, compared with 0.07 in the general population. [46]

Bipolar symptoms were 1.6-2.2 times more common in subjects with epilepsy than with migraine, asthma, or diabetes mellitus and are 6.6 times more likely to occur than in healthy subjects. A total of 49.7% of patients with epilepsy who screened positive for bipolar symptoms were diagnosed with bipolar disorder by a physician, nearly twice the rate seen in other disorders. [47]

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. [48]

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. [49]

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. [50]

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. [51]

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 [52] :

  • 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 [53]
  • 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. [54] 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.

Therefore, parallel changes of serotonin, norepinephrine, dopamine, and 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. [55]

Flor-Henry speculated that depression might be related to right (nondominant) foci, a finding confirmed by a few other investigators. [56]

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. [57]

Other authors report no laterality differences in depression rates.

Other factors associated with depression in epilepsy

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. [58, 59, 60, 61, 62]

Increased financial stress, life stressors, and poor adjustment to seizures are predictive of increased depression. [63]

The lack of control over the illness may be an additional risk factor for depression. [64, 65]

Depression in epilepsy may also result from iatrogenic causes (pharmacologic and surgical).

The AEDs most frequently associated with iatrogenic depressive symptoms include the following [66] :

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%. [67]

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. [68] 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. [68]

Blumer has defined an interictal dysphoric disorder in patients with epilepsy in which symptoms tend to be intermittent. [69]

On average, the patients tend to have 5 of the following symptoms (range 3-8):

  • Depressed mood
  • Anergia
  • Pain
  • Insomnia
  • Fear
  • Anxiety
  • Paroxysmal irritability
  • 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. [70]

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.”

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 [71] :

  • 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 (ADHD) 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. [72]

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. [73]

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. [74]

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. [75]

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. [76, 77, 78]

In 1986, Mendez et al used the term atypical depression in epilepsy patients using the DSM-III-R criteria.

Treatment

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

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 epilepsy-associated mood disorders.

There is evidence that some anticonvulsant therapies, including vagus nerve stimulation, 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. [79]

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. [80]

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 (owing 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 the 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, treatment-resistant, or psychotic 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. [81]

Mania

In a carefully selected series of patients with epilepsy, Williams found that only 165 of 2000 patients had complex, including emotional, ictal experiences. [82]

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.

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Suicidal Behaviors

Suicidality (completed suicide, suicide attempt, and suicidal ideation) is significantly more frequent among people with epilepsy than in the general population. [81, 83, 84, 85, 86, 87]

The risk of suicide in the general population averages about 1.4%. Depression is one of the psychiatric disorders that increases 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. [88]

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. [89, 90, 91, 92]

The incidence of suicidal phenomena linked to specific AEDs has not been systematically well studied. These 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.

Frequent risks associated with suicidality include the following [81] :

  • 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, 1.8-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 of 1,000 patients treated with AEDs in the active arm, compared with 2.2 of 1,000 patients in the comparison arm. The results of this meta-analysis must be considered with great caution, and more research is necessary. [81, 93, 94]

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. [95]

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Anxiety Disorders

Anxiety is an experience of fear or apprehension in response to anticipated internal or external danger, accompanied by muscle tension, restlessness, sympathetic hyperactivity, and/or 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. Evidence suggests that the abnormal functioning of GABA receptors could be of great importance in the pathophysiology of epilepsy and anxiety disorders. [82, 81]

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, 83, 84] According to Goldstein and Harden, epileptic events can produce symptoms indistinguishable from those of primary anxiety disorder. [85]

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. [85]

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, 86]

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, 83, 86, 87]

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. [88]

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.

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Personality Disorders

Personality disorders in epileptic patients can cause abnormal behavior that can have a direct impact on seizure control and quality of life. The question of the relationship has a long history and remains controversial. In 1975, Woxman and Geschwind described a syndrome consisting of circumstantiality (excessive verbal output, stickiness, and hypergraphia), altered sexuality, and intensified mental life in a patient with temporal lobe epilepsy. It was called Geschwind syndrome. [89]

Bensan and Herman reported that data are insufficient to state with certainty that a consistent pattern of behavioral changes occur in patient with temporal lobe epilepsy. The 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. [90]

The link of personality disorders to epilepsy was not only seen in temporal lobe epilepsy. Trinka et al found that personality disorders were present in 23% of patients with juvenile myoclonic epilepsy. [91]

Trimble has summarized the data and concluded that the personality profile of a patient with epilepsy can be explained by a complex combination of the effect of (1) dealing with a chronic illnesses, (2) AED effects, (3) and temporal lobe pathology. He supported that certain personality disturbances in epilepsies should be viewed as associated with cerebral abnormalities that also lead to seizures. [92]

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Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is another psychiatric comorbidity in patients with epilepsy and is more common in children. The co-occurrence may result from altered neurobiological mechanisms involved in early brain development.

The incidence of ADHD is about 7.76 cases per 1000 person-years in patients with epilepsy and 3.22 in patients without epilepsy. The incidence of epilepsy is 3.24 cases per 1000 person-year in patient with ADHD and 0.78 in those without ADHD. [93]

A neuropsychiatrist may find difficulty in differentiating impaired attention secondary to absence of seizure and attention deficit as a phenotypical representation of ADHD.

Many AEDs can cause symptoms that mimic ADHD, and the most commonly implicated are the GABAergic drugs such as barbiturates, benzodiazepines, and vigabatrin. Behavioral changes should be monitored when levetiracetam is administered to patients with concomitant autism or ADHD. [96]

Methylphenidate can cause aggravate seizures in patients with ADHD, although generally it is considered safe in those who are seizure free. [94]

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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.

Lacosamide has no effect on depression or anxiety symptoms in epileptic patients. [97]

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. [95]

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Psychiatric Disorders and Epilepsy Surgery

Generally, psychiatric outcomes improve or no changes are noted with epilepsy surgery. A history of psychiatric disorders before epilepsy surgery is associated with poorer chance of postsurgical seizure remission. After resective surgery, only patients with good or excellent seizure control had sustained long-term improvement in mood.

Postsurgical patients had higher suicidal mortality rate compared with the general population, and people who continue to have seizures after surgery had a higher suicidal mortality rate, in contrast to those who were seizure free after surgery (4-5 times). [98] In a series of 26 patients, gamma knife radiosurgery for mesial temporal lobe epilepsy showed no significant psychiatric changes from preoperative baseline for up to 24 months. [99]

About one third of patients present with depression after surgery (25% of whom have no history of preexisting mood disorders). Depression de novo is the highest risk factor and is found in 75% of patients. Psychosocial factors (maladaptive personality and adjustment, financial difficulties, and poor postoperative family dynamics) may play a role in postoperative depression even in those with excellent seizure control. [100]

Disturbed behavior may interfere with the preoperative evaluation, and the patient may not be able to provide informed consent for investigation and surgery.

Vagus nerve stimulation showed better responses in patients with chronic major depressive disorders over 12 months of study. [101, 102] In small studies, Elger et al and Harden et al showed that treatment with vagal nerve stimulation improves depression in epileptics independent of effects on seizure frequency. Vagal nerve stimulation is a useful therapeutic tool in treatment-resistant depression. [103]

Cranially implanted responsive neurostimulators (RNS) are a new option for treating refractory epilepsy, and available data showed no effect on mood. [104]

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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:

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Conclusion

Psychiatric comorbidities in patients with epilepsy are relatively frequent. Despite the high prevalence rates, few data are available. Because of this, the data used are 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. Considering AED side effects and their impact on preexisting psychiatric symptoms can help to avoid worsening of patient symptoms and help in tretmant compliance.

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