Dr. Passaro is director of the Bayfront Medical Center Comprehensive Epilepsy Program in St. Petersburg, Florida.
Disclosure: Dr. Passaro is a consultant for and on the speaker’s bureau of Ortho-McNeil.
Please direct all correspondence to: Erasmo A. Passaro, MD, Bayfront Medical Center Comprehensive Epilepsy Program, 601 7th St South, St. Petersburg, FL 33701; Tel: 727-824-7149; Fax: 727-824-7133; E-mail: email@example.com; Web site:
• Psychiatric comorbidity in epilepsy is underrecognized and contributes to reduced quality of life in epilepsy patients.
• Comorbid psychiatric symptoms most commonly occur in the inter-ictal state of epilepsy, but can also occur in the ictal and post-ictal states.
• Inter-ictal depression is 17-fold greater in patients with temporal lobe epilepsy, and the risk for suicide is 5-fold greater than in the general population.
• The most common ictal psychiatric symptom is fear and anxiety that typically lasts several seconds and can be accompanied by autonomic symptoms.
• The inter-ictal psychosis of epilepsy differs from schizophrenia.
• In epilepsy patients, pathology within the hippocampus and the amygdala may increase the risk for psychiatric comorbidity.
A relationship between psychiatric disorders and epilepsy has been recognized for several centuries. This psychiatric comorbidity manifests as psychoses, mood disorders, anxiety disorders, and personality disorders. Psychiatric disorders are classified in three categories with regard to their relationship to seizures: inter-ictal—the state during which the patient is not having seizures; ictal—psychiatric symptoms during the seizure; and3 post-ictal—psychiatric symptoms that are followed by a seizure. The most common inter-ictal psychiatric disorders in epilepsy patients are depression and inter-ictal anxiety. Ictal psychiatric symptoms, such as ictal psychosis and ictal depression, are rare. Ictal fear and anxiety, on the other hand, are common. Post-ictal psychosis has been well described, while post-ictal depression and anxiety have not been well characterized. Although psychiatric disorders in epilepsy have been known for centuries, they are often underrecognized and undertreated. This psychiatric comorbidity contributes to the stigma associated with epilepsy.
The relationship between epilepsy and psychiatric disorders has been recognized for several centuries (Table 1).1-6 Throughout the 20th century, investigators looked for an association between behavioral disturbances, psychiatric syndromes, or personality disorders in patients with temporal lobe epilepsy (TLE).6-8 This relationship continued to be misunderstood; in fact, through part of the 20th century, epilepsy was classified as a major functional psychosis.9
Psychiatric comorbidity manifests as psychoses, mood disorders, anxiety disorders, and personality disorders. These psychiatric disorders are classified with regard to their relationship to the seizures: (1) inter-ictal—psychiatric disorder occurs during a time when the patient is not having seizures; (2) ictal—psychiatric symptoms occur during the seizure; and (3) post-ictal—psychiatric symptoms are followed by a seizure.
Comorbidity in epilepsy is often unrecognized and untreated, contributing to impaired quality of life10 and to the stigma associated with epilepsy.11 In fact, >50% of epilepsy patients report stigma as one of their major concerns.11 The relationship between psychiatric disorders and epilepsy is further illustrated by the psychotropic effect of antiepileptic drugs (AEDs). For example, many AEDs have mood-stabilizing properties. Infrequently, AEDs can produce psychiatric adverse effects, such as psychosis or mood disorders. This article reviews the clinical features of the psychiatric comorbidity of epilepsy.
Psychoses in Epilepsy
The prevalence of psychosis in patients with epilepsy is greater than in the general population.12 Psychosis in epilepsy most often occurs in the inter-ictal or post-ictal state, and rarely in the ictal state. In the 1950s, Bartlett13 reported that 1.1% of a patient group suffered from both epilepsy and psychosis, but others have reported different prevalence findings, such as 6%,14 9.4%,8 and 25%.15 The variability in these early findings can be explained by the heterogeneity of the inclusion criteria for psychosis, and the lack of a refined classification system, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR).16
Inter-ictal psychosis is defined as a chronic psychosis that is not temporally related to the occurrence of seizures or medication side effect. While epilepsy patients can have comorbid schizophrenia, the inter-ictal psychosis of epilepsy can fulfill DSM-IV-TR criteria for schizophrenia or a delusional disorder, the characteristics of which and prognoses can be very different.
Inter-ictal psychosis accounts for 10% to 30% of cases of psychosis in epilepsy.17 In one study,18 the prevalence of schizophrenia, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R),19 was found to be nine times greater in an epilepsy clinic than in a migraine clinic. Another study found a standardized incidence ratio of 1:48 for all epilepsy patients and 2:35 for TLE patients.20
The inter-ictal psychosis of epilepsy usually presents with paranoid delusions, suspiciousness, and hypervigilance toward the environment; delusions are usually less circumscribed and have a religious or a persecutory content.21 Taylor22 found that mesial temporal sclerosis is an important risk factor for psychosis in epilepsy patients. A more recent study by Kanemoto and colleagues23found similar results.
Ictal psychosis, defined as psychotic symptoms during a simple partial seizure, is very rare. In one series, it was observed in 4 of 29 cases of simple partial (focal) status epilepticus.24 Sometimes a visual or an auditory aura can be misinterpreted as a psychosis. In one case report, a patient had complex visual hallucinations for 2 weeks associated with an ictal discharge.25 However, unlike patients with psychosis, patients with prolonged visual or auditory simple partial seizures recognize that the phenomena they are experiencing are not real. Some patients in nonconvulsive status epilepticus are mistakenly diagnosed as psychotic because they are intermittently responsive, with inappropriate nonpurposeful behavior and waxy flexibility.26 Although ictal psychosis is rare, it is probably often misdiagnosed since simple partial seizures (focal seizures without loss of awareness) only show an electroencephalogram (EEG) correlate approximately 25% of the time.27 In patients with a history of epilepsy and stereotyped episodes of psychosis, ictal psychosis should be excluded. If the index of suspicion is high, and the EEG shows either no change or a nonepileptiform pattern, ictal subtraction single photon emission computerized tomography should be considered for definitive diagnosis.28
Post-ictal psychosis occurs following a single seizure or a cluster of seizures, and accounts for approximately 25% of psychosis in epilepsy.29 It may be preceded by a lucid period with psychotic symptoms that follow within 24–72 hours.29 Since there may be a latency of a few days between the seizures and the onset of the psychosis, the relationship between the seizure(s) and the psychosis is often not initially recognized. This is particularly true in patients with nocturnal seizures or those who live alone, cases where seizures are often unrecognized. Post-ictal psychosis is often accompanied by a prominent alteration in mood that usually lasts for an average of 14 days with spontaneous recovery being the usual course.29 Post-ictal psychosis can be disabling since the patient’s relationships at home and at work are often strained by the unpredictable nature of the psychotic episodes. Post-ictal psychosis is most frequently associated with TLE.
Inter-ictal depression is the most common mood disorder in epilepsy. Bipolar mood disorder is infrequently observed in epilepsy patients. Ictal mood disorders are rare, and post-ictal mood disorders are uncommon and have been infrequently described.
A relationship between epilepsy and depression was first described in 400 B.C. by Hippocrates, who observed a relatively high frequency of “melancholia” among epilepsy patients.30 Among patients with TLE, a history of depression is 17 times more frequent than controls.31 Patients with epilepsy and depression are at higher risk for psychiatric hospitalization than nonepileptic depressed patients.32 Risk factors for depression include male gender, left-sided lesion, and use of polypharmacy to control the seizures.32 The severity of the depression is not related to the duration of epilepsy, the frequency of seizures, or a positive family history of depression.33 Depression in epilepsy patients is rarely of the bipolar type.
An association between ictal depression and the experience of olfactory hallucinations supporting an anteromesial temporal localization has been noted by several authors.34 Gloor and colleagues35 reported on three patients who experienced depression or guilt only when temporolimbic structures were stimulated. While inter-ictal depression and prodromal depressive symptoms are common, ictal depression is rarely observed.36 Rare cases have reported an association between simple partial and absence status epilepticus and prolonged depressive affect.36
Post-Ictal Depression and Mania
One study found that 65% of poorly controlled patients with epilepsy experienced post-ictal depressive symptoms with a mean duration of 37 hours.37 Such symptoms are more common in patients with frontal or temporal lobe seizures without a predominant lateralization.38 Rarely, post-ictal hypomania has been described.39
Although the prevalence of bipolar affective disorder has not been formally assessed, some reports suggest that the prevalence of bipolar affective disorder in patients with epilepsy is between 0.1% and 4.3%.40 The current use of AEDs that are effective in bipolar illness may contribute to the lack of manic episodes in epilepsy patients. However, mania was uncommon even before the use of current AEDs.41 Population-based studies comparing the incidence of bipolar illness in epilepsy patients as compared to the general population have not been done.
Anxiety is a common comorbid condition in epilepsy patients.14,42,43 Anxiety symptoms are most commonly observed in patients with TLE. It occurs in the inter-ictal, ictal, or post-ictal state. Ictal anxiety and fear represent the most common forms of ictal affect in TLE patients.44,45
Anxiety conditions, such as generalized anxiety disorder and panic disorder with or without agoraphobia, are more prevalent in the epilepsy population than in the normal population.46 Currie and colleagues14 found anxiety disorders in 19% of TLE patients. In refractory epilepsy patients considered for epilepsy surgery, anxiety was the most common Axis I DSM-III-R diagnosis present in 10.7% of patients42 and in 32% in another study.43 Seizure severity was found to be a significant predictor of anxiety in 100 patients with medication-resistant epilepsy.47 Anxiety symptoms can develop as anticipation of a seizure sometimes leading to avoidance behaviors.48 AED withdrawal can also precipitate anxiety symptoms.49
Sometimes the autonomic symptoms of simple partial seizures, such as increased heart rate, shortness of breath, and diaphoresis, may simulate panic disorder.50 In the author’s experience, many patients with simple partial seizures with autonomic symptoms are mistakenly diagnosed with anxiety until a secondarily generalized tonic-clonic seizure immediately follows the autonomic symptoms.
Ictal Fear and Anxiety
Anxiety and fear also represent the most common form of ictal affect in patients with epilepsy.45 It can be accompanied by a rising epigastric sensation, palpitations, diaphoresis, mydriasis, and pallor.51 An early study reported ictal fear in up to 35% of patients with temporal lobe epilepsy,45 but a more recent study found an incidence of 10% to 15%.52 Up to 33% of patients with ictal fear have been found to have a comorbid panic disorder.53
The amygdala is important in the regulation of emotion. Stimulation of the amygdala in humans, for example, produces ictal fear.51 Simple partial status has been reported in a patient with depth electrode recording of seizures in the amygdala.54 Cendes and colleagues55 studied 50 patients with TLE and compared volumetric measurements of the amygdala in patients with ictal fear to patients with other types of auras. They found that TLE patients with ictal fear had smaller amygdalar volumes than TLE patients without this aura. The accompanying Figure illustrates the magnetic resonance imaging of a patient with atrophy of the amygdala and ictal fear. It is likely that ictal fear arises from seizures originating or propagating to the amygdala.
Post-ictal anxiety, which lasts for 12–24 hours, has received little attention in the literature.56 In the author’s experience, a prodrome of anxiety that lasts for hours or days and is subsequently relieved after a seizure, is more frequently observed.
The existence and specificity of a characteristic behavioral syndrome in TLE patients is controversial. The behavior pattern of many epilepsy patients differs from that of age, sex, and socioeconomic matched control subjects. Kraepelin5 noted “meticulousness and slowing of mental process” in half of his epilepsy patients. Epilepsy patients have been described as circumstantial and tangential in their thinking.57 Gastaut and colleagues58 found that viscosity and irritability was greater in two thirds of 60 outpatients with TLE, and he emphasized that the behavioral and personality changes observed in TLE patients developed at least 2 years after the onset of clinical seizures. He also noted that the majority of his patients were hyposexual. He compared epilepsy patients to Kluver-Bucy syndrome patients who exhibited heightened emotions, viscosity, and hyposexuality. Later, Geschwind59 reported that TLE patients were overly concerned with ethical and religious issues, were unusually serious, lacked a sense of humor, and wrote excessively. Bear and Fedio60 found that patients with right TLE reported more emotional traits and minimized their behavioral changes (ie, polished their image), whereas left TLE patients had more ideational traits and often tarnished their image.
Devinsky and Najar61 recently challenged the characterization of personality changes in epilepsy patients as a disorder, viewing it rather as a change that is not necessarily maladaptive or negative. They hypothesized that the association between hypergraphia, hyposexuality, viscosity, religious concerns, and deepened emotions is unusual and may strongly suggest a limbic seizure origin. They argue that the characterization of TLE patients into narrowly defined personality traits predisposes to further stigmatization.
A study of 52 medically refractory epilepsy patients showed that 21% met the criteria for an Axis II DSM-III-R disorder.62 The presence of auras correlated with the presence of a personality disorder. Dependent and avoidant personality disorders were the most common diagnoses. Further studies are necessary to determine whether these personality changes are due to the chronic disability of epilepsy, treatment with AEDs, cognitive dysfunction, or the seizures themselves.
Antiepileptic-Related Psychiatric Effects
AEDs infrequently cause psychiatric symptoms in epilepsy patients. While these psychiatric adverse effects are sometimes observed in clinical practice, most of the reports are anecdotal. Many of these studies did not assess the confounding effect of baseline psychiatric diagnoses, concomitant medication, and the seizures.
Primidone, tiagabine, topiramate, vigabatrin, and felbamate are other AEDs known to cause depressive symptoms in some patients (Table 2).63-71 There have been no consistent reports of psychiatric adverse effects associated with lamotrigine, oxcarbazepine, gabapentin, valproate, phenytoin, and carbamazepine.64 In fact, one study comparing valproate to lamotrigine in epilepsy patients found that lamotrigine had a greater beneficial effect on health-related quality of life that correlated with measures of mood on several scales.72
A first episode of psychosis may occur in association with changes in AEDs.71 These symptoms can occur with the introduction of AED add-on therapy, abrupt AED discontinuation, and after AED overdose. Some cases of psychosis are related to AED withdrawal.
Barbiturate and benzodiazepine withdrawal may produce anxiety, irritability, psychosis, and delirium.64 There have been anecdotal reports of psychiatric symptoms with the introduction of phenytoin and carbamazepine, but none have been consistent.64
Psychiatric symptoms also occur with AED withdrawal. For example, Ketter and colleagues73 showed that 40% of epilepsy patients withdrawn from phenytoin, carbamazepine, and valproate, developed moderate to severe psychiatric symptoms. Depression and anxiety were most common, and psychosis occurred less frequently. AED withdrawal-induced psychopathology usually occurs in the final week of the AED taper, and tends to resolve within 2 weeks of restarting the original AED.64
When evaluating patients with possible AED-related psychiatric changes, it is important to inquire about a history of similar psychiatric symptoms and their frequency, and to determine if there is a temporal relationship between the initiation or the discontinuation of the AED. In addition, AEDs should be introduced slowly and withdrawn slowly. Both zonisamide and topiramate reduce appetite and cause weight loss, and therefore should be used with caution in patients with eating disorders. Many of the reports of AED-induced psychiatric changes have occurred with AED polytherapy. In this regard, pharmacodynamic interactions between AEDs may be partly responsible for the AED-induced psychiatric changes. Patients who are at greater risk for AED-induced psychiatric changes, such as those with a past psychiatric history, brain injury, or mental retardation, should be closely monitored.
The mechanism for AED-induced psychiatric changes is largely unknown. Some have speculated that AEDs with predominant g-aminobutyric acid (GABA)ergic activity, such as benzodiazepines, barbiturates, tiagabine, and vigabatrin, produce sedative psychiatric adverse effects (ie, depression).64 AEDs that attenuate antiglutamatergic excitatory activity either presynaptically or postsynaptically, such as lamotrigine and felbamate, are likely to produce activating psychiatric effects. Topiramate, which has both GABA-enhancing and glutamate-attenuating properties, can produce a combination of sedating and activating effects.74 However, there is no empirical data to support these mechanistic hypotheses.
The most common psychiatric disorders associated with epilepsy are inter-ictal depression and anxiety. Inter-ictal psychosis is observed with greater frequency in TLE patients than in the general population, while inter-ictal mania is rarely observed. Ictal fear and anxiety, the most common ictal psychiatric symptoms, are usually brief (lasting seconds to minutes) and stereotyped. They can occur in isolation or as part of an amygdala pathology-associated aura prior to a complex partial seizure. Ictal fear/anxiety can be confused with panic disorder since the two conditions share similar features. Ictal psychosis and ictal depression, on the other hand, are rarely observed. Post-ictal psychiatric changes, such as post-ictal psychosis, post-ictal anxiety, and post-ictal depression, occur less frequently and their association with seizures sometimes go unrecognized.
The existence of an inter-ictal personality disorder of TLE is controversial, and such a characterization further contributes to the stigma associated with epilepsy since these traits have a pejorative connotation. However, avoidant and dependent personality disorders are more commonly observed in TLE patients, particularly, those with auras.
AEDs may also produce psychiatric side effects that should always be considered as a cause of psychiatric symptoms. These include depression, irritability, agitation, and psychosis. AED withdrawal can provoke transient psychiatric symptoms, and therefore AEDs should always be slowly tapered when they are discontinued.
Refractory TLE patients, particularly those with hippocampal sclerosis or amygdalar pathology, are at greatest risk for developing psychiatric comorbidity. Early recognition of psychiatric comorbidity and understanding the psychiatric adverse effects of AEDs, will allow for prompt psychiatric referral and treatment to reduce this comorbidity and improve overall quality of life.75 PP
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