Anxiety Disorders

Andres M. Kanner

Alan B. Ettinger

Introduction

Anxiety disorders are common in people with chronic medical disorders, including people with epilepsy (PWE). While population-based studies have suggested prevalence rates of 25%, equivalent to almost twice that of the general population, the actual incidence and prevalence rates of anxiety disorders in PWE is yet to be established.⁵⁴^,⁹⁶ The lack of such data stems from several methodologic problems including a paucity of population-based studies, the use of screening instruments that identify “anxiety symptoms” and not “anxiety disorders” (see section on epidemiology), and, to a large degree, an underrecognition of anxiety disorders by patients and families alike. Indeed, patients often misinterpret symptoms of anxiety as “a normal reaction to a life with epilepsy” or an “expected” response to the stresses associated with the multiple obstacles that PWE have to face, above all when their seizures fail to remit.

Deciding when anxiety symptoms are an appropriate response to stressful experiences or an expression of a pathologic disorder has been the source of debate, with some investigators suggesting a “continuum” between these two extremes. According to Hans Selye, stress is “a nonspecific response of the body to any demand.”¹⁵⁶ He added that stressful situations in daily life are not harmful and, in fact, may help individuals to adapt to new life circumstances. In support of these observations, Levine¹⁰⁶ found that young mice exposed to mild stress from time to time consisting of handling or weak electric shocks were better able to handle stressful events and became stronger and larger as adults than the mice that were not subjected to such stressors.

At what point does a “normal” response to stress become pathologic and symptomatic of an anxiety disorder? Selye postulated the existence of a “general adaptation syndrome” that includes three phases:¹⁵⁶ (a) alarm, (b) resistance, and (c) exhaustion. The alarm phase triggers a response of the sympathetic nervous system with activation of corticotrophin-releasing hormone (CRH), which in turn causes secretion of adrenocorticotropic hormone (ACTH), leading to a release of cortisol and norepinephrine (NE) from the adrenal glands. The resistance stage is considered to be aimed at overcoming the stress-producing event, by preparing the animal for fight or flight; during this phase, there is a significant increment of vesicles containing corticosteroids in adrenal glands available for release. According to Selye’s theory, if resistance is not successful, the body reaches a state of “exhaustion,” during which no further corticosteroid vesicles can be identified, resulting in the animals’ death. The corollary of these changes in humans is expressed in the development of mental illness in the form of depression, anxiety, and psychosomatic disorders. Some of these observations may be applicable to the development of anxiety in PWE. For example, Hermann et al. found that psychopathology was associated with poor adjustment to epilepsy, elevated number of stressful life events during the past year, financial stress, vocational problems, external locus of control with increased perceived stigma, and an earlier onset of epilepsy.⁷¹ Multiple regression analyses identified three independent predictors of psychopathology: An increased number of stressful life events in the past year, poor adjustment to epilepsy, and financial stress.

The unpredictability of seizure occurrence can very well play an important role in the generation of anxiety symptoms or full-blown anxiety disorders facilitated by a perception of “loss” of the locus of control. Experimentally, this phenomenon can be studied in the animal model of fear conditioning.⁷⁴ This model is based on a classical conditioning paradigm consisting of 20-second conditioning stimulus trials in the animal (using a sound as a conditioning stimulus) that are terminated by onset of an aversive unconditioned stimulus consisting of a footshock of 0.5 second’s duration. The resulting conditioned response is expressed by behavioral immobility (freezing) during the 20-second sound-conditioning stimulus. On the first trial, when the sound comes on the animal moves around freely. Within a few trials the animal freezes when the sound comes on, and remains still for most of its duration. The conditioned response—freezing—is used as a measure of fear. The manifestations of the inferred fear state in this animal model closely parallel the clinical criteria of generalized anxiety, as evidenced by increased heart rate and stroke volume, dry mouth/decreased salivation, stomach ulcers/upset stomach, altered respiration, scanning and vigilance, increased urination and defecation, grooming/fidgeting, and freezing/apprehension. Fear conditioning is a strikingly dramatic and reproducible phenomenon and can be elicited among many different animal species.

In addition to the above, it is important to consider the potential pathogenic role of neurophysiologic and neurochemical changes associated with the seizure disorder per se, particularly in temporal lobe epilepsy (TLE). Indeed, mesial temporal structures play a primordial role in the generation of symptoms of anxiety, as exemplified in the animal models of fear sensitization and kindling. Kindling refers to the gradual development and intensification of elicited motor seizures resulting from the repetitive administration of initially subconvulsive stimulations to particular brain regions.⁶¹^,⁸⁷ Kindling of limbic structures has also been shown to effect lasting changes in affect in rodents and cats. For example, kindling of rodents’ amygdala facilitates the development of behaviors suggestive of “symptoms of anxiety,” and partial kindling of amygdala and ventral hippocampus in cats leads to less predatory behavior. The question is then raised whether fear sensitization may result from hyperexcitation of fear circuits perhaps via long-term potentiation of excitatory amygdala efferents and whether kindling could be comparable to repetitive seizures, thereby inducing interictal anxiety.¹^,² In this chapter we review the available epidemiologic data, clinical manifestations, and treatment of the four most frequent anxiety disorders in PWE: Generalized anxiety disorder (GAD), panic disorder (PD), phobias, and obsessive-compulsive disorder (OCD). We devote a section to the discussion of the most relevant pathogenic mechanisms operant in the development of anxiety disorders in PWE, with special attention to the pathogenic mechanisms that may be shared by anxiety disorders and epilepsy.

Epidemiology

Together with mood disorders, anxiety disorders are the more frequent psychiatric comorbidity in PWE. The Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) lists 11 different types of anxiety disorders: GAD, PD (with and without agoraphobia), OCD, posttraumatic stress disorder (PTSD), acute stress disorder, specific phobias (i.e., to animals, injections, etc.), social phobia, anxiety disorders due to medical conditions, substance-induced anxiety disorder, and anxiety disorders not otherwise specified,⁶ which include all those clusters of anxiety symptoms that fail to meet any of the above-cited categories (i.e., subsyndromic types).

As stated in our introduction, the real prevalence of each one of these anxiety disorders in PWE is yet to be established for the following reasons: (a) underrecognition by clinicians and underreporting by patients; (b) paucity of population-based studies; (c) use of diverse methodologies to identify psychiatric semiology, with some of the studies having relied essentially on the use of screening instruments that identify “symptoms,” while only a few studies having used structured interviews designed to establish current and past psychiatric syndromes (Axis I diagnoses) according to the DSM criteria; and (d) the use of relatively small case series, often derived from tertiary epilepsy centers, which attract patients with more severe forms of epilepsy and comorbid disorders. To make sense of published prevalence and incidence rates data, it is necessary to review separately those studies that screened for symptoms of anxiety from those that identified anxiety disorders with structured psychiatric interviews.

Prevalence of Anxiety Symptoms

In a review of the literature, Torta and Keller found anxiety symptoms in up to 66% of patients with epilepsy.¹⁷⁴ Using the Hospital Anxiety and Depression Scale in a study of 201 PWE, Cramer et al. found that 48% reported symptoms of anxiety; in 25% of these patients they were rated as mild, moderate in 16%, and severe in 7%.³⁶ In this study, anxiety symptoms were more prevalent than depressive symptoms, which were reported in 38% of subjects. Similar findings were reported in studies done in other cultures. For example, Nubukpo et al. investigated the presence of symptoms of depression and anxiety in 281 adults with epilepsy in West Africa using Goldberg’s Anxiety and Depression Scale.¹²⁰ Compared to a control group, PWE had significantly higher depression and anxiety scores, which correlated with higher seizure frequency and lack of treatment.

Symptoms of OCD have been found to be more frequent among PWE than healthy controls in small case series. For example, Monaco et al.¹¹⁴ investigated the presence of OCD symptoms among 62 patients with TLE, 20 patients with idiopathic generalized epilepsy, and 82 matched healthy controls. Symptoms of OCD were reported by nine of the TLE patients, none of the idiopathic generalized patients, and one control. In another small study, Isaacs et al. investigated the presence of OCD symptoms in 30 patients with TLE using the Obsessive-Compulsive Inventory (OCI).⁷⁵ As a group, patients with TLE had a higher prevalence of obsessive and compulsive symptoms than the nonpatient normative sample. In addition, TLE patients exhibited elevated scores on all but 3 of the 16 OCI scales and subscales.

Symptoms of anxiety disorders have also been found to be relatively frequent in children with epilepsy. For example, in a study of children whose age ranged from 7 to 18 years old, Ettinger et al. found elevated scores on the Revised Child Manifest Anxiety Scale in 16%,⁵⁰ while Williams et al. found this to be the case in 23%.¹⁸³ Alwash et al. found anxiety symptoms in almost 50% of Jordanian children or adolescents with epilepsy.⁵

Anxiety Disorders

Various studies have estimated the prevalence of anxiety disorders to range from 10% and 25%, with the higher prevalence rates found among patients with intractable epilepsy. In one of the few population-based studies, Gaitatzis et al. found a prevalence of anxiety disorders of 11% among 5,834 PWE compared with 5.6% among 831,163 people without epilepsy.⁵³ The psychiatric diagnoses were obtained from primary care records. In a study of 174 consecutive PWE from five epilepsy centers, current anxiety disorders were identified in 53 patients and comprised 52.3% of all Axis I diagnoses established with the Mini International Neuropsychiatric Interview (MINI).⁸³ Agoraphobia (15.5%), GAD (13.2%), and social phobia (10.9%) were the most common diagnoses among the anxiety disorders. Among these 53 patients, 27 (50.9%) exhibited symptomatology that met criteria for two or more anxiety disorders.

Several studies have been carried out in refractory patients being evaluated for epilepsy surgery. For example, Wrench et al. found a prevalence of 23% among 43 patients being evaluated for an anterotemporal lobectomy and 18% among 17 patients with an extratemporal seizure focus (mostly frontal).¹⁸⁴ In the largest case series of patients who underwent an anterotemporal lobectomy (N = 322), Devinsky et al. found an anxiety disorder diagnosed before surgery with a structured interview in 18%.⁴⁸ In a study of 300 patients with refractory epilepsy (231 patients with a temporal lobe focus, 43 with a nontemporal lobe focus, and 26 with a generalized and multifocal seizure onset), Manchanda et al. found that 88 (29.3%) met criteria for a psychiatric syndrome and 54 (18.0%) for a personality disorder, with anxiety disorders being the most common psychiatric diagnosis (10.7%).¹⁰⁹

Panic disorder is significantly more frequent among PWE than the general population. In a review of the literature, Beyenburg et al. estimated that PWE were six times more likely to suffer from PD than the general population, with point prevalence rates ranging between 5% and 30%,¹⁵ compared with 3.5% in the general population.⁹⁶

Karno et al. have analyzed the prevalence data of obsessive-compulsive disorder measured in five U. S. communities among more than 18,500 persons in residential settings as part of the National Institute of Mental Health–sponsored Epidemiologic Catchment Area program. Lifetime prevalence rates ranged from 1.9% to 3.3% across the five Epidemiologic Catchment Area sites for obsessive-compulsive disorder diagnosed without DSM-III exclusions and 1.2% to 2.4% with such exclusions.⁹⁵ On the other hand, the actual prevalence of OCD in PWE is yet to be established as there are no population-based studies in this group of patients and most of the available data are based on small studies carried out in tertiary care centers.

Several studies have evaluated anxiety in children with epilepsy. In one study of 100 children aged 5 to 16 years with complex partial seizures and similarly sized groups of both children with childhood absence epilepsy and normal children, those with complex partial seizures and childhood absence epilepsy were five times as likely to have an affective or anxiety disorder as normal controls; these disorders were identified in 33% of the epilepsy group.²⁶^,²⁷ Of note, anxiety disorder was the most frequent diagnosis among children with suicidal ideation. Within the epilepsy group, children with absence epilepsy were more likely to have an anxiety disorder alone than the children with complex partial seizures, who were more likely to have comorbid depression with anxiety and depression alone. One additional study confirmed the increased rate
of anxiety disorders in children, as an anxiety disorder was present in 31% of 102 adolescents with epilepsy.⁴

Clinical Manifestations

People with epilepsy can present the same clinical manifestations of the anxiety disorders included in the DSM-IV-TR classification,⁶ though anxiety episodes/disorders with atypical semiology is not unusual. Such is the case when anxiety episodes are restricted to peri-ictal periods (see below). Thus, it is essential to establish the temporal relationship between the occurrence of psychiatric symptomatology and the seizures, as the duration, course, and response to treatment varies depending on whether an anxiety episode is ictal, postictal, or interictal.⁹⁰

Comorbid mood disorders can be identified in a significant percentage of patients with primary anxiety disorders, and this is also the case in PWE. Thus, any investigation of anxiety symptoms/disorders must always be coupled with a search for mood disorders. This important point is discussed in greater detail below. For example, in a study of 199 PWE from five epilepsy centers, Kanner et al. found that 73% of patients with a history of depression met also DSM-IV criteria for an anxiety disorder.⁹¹

Interictal Anxiety Disorders

Generalized Anxiety Disorder

To meet diagnostic criteria of GAD, patients have to have experienced the following symptoms for a period of at least 6 months, occurring more days than not: (a) excessive worry and anxiety about a number of events or activities; (b) difficulty in controlling the worry; (c) the focus of the anxiety is not related to another psychiatric disorder (i.e., panic disorder, social phobia, etc.); (d) three or more of the following symptoms: restlessness or feeling on edge, being easily fatigued, difficulty concentrating, irritability, muscle tension, sleep disturbance manifested by either difficulty falling asleep and/or staying asleep and/or restless unsatisfying sleep; (e) symptoms cause clinically significant distress or impairment in the patients’ social, occupational, or other areas of functioning; and (f) symptoms do not result from the use of medication or substances of abuse (including alcohol) or a general medical condition (i.e., hyperthyroidism) and do not occur exclusively during a mood or psychotic disorder.

Panic Disorder

PD consists of recurrent panic attacks with a frequency of at least one attack per week for a period of at least 1 month.⁶ These attacks are characterized by a subjective sense of dread (feeling of impending doom), associated with a variety of autonomic symptoms including palpitations, sweating, subjective dyspnea, paresthesias, dizziness, nausea, feeling faint, and a sense of abdominal or central chest discomfort. Each attack may last between 5 and 30 minutes and may not have a clear precipitant. Anticipatory anxiety is the second feature of PD, so that the patients fear a recurrence of attacks and may enter a state of chronic lower-grade anxiety. Finally, the patients may show phobic avoidance of situations that they feel may provoke an attack, which may reach total avoidance of leaving the home or fear of being left alone (in which case patients are diagnosed with PD with agoraphobia). Comorbid depression is found in up to 70%, as is the development of secondary psychosocial problems, agoraphobia, and social phobias.¹¹² It is important to keep in mind that ictal fear can be often confused and misdiagnosed as panic attacks (see below).

Phobias

According to the DSM-IV-TR criteria, specific phobias are described as “marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation (i.e., flying, heights, animals, etc.).” Exposure to the phobic stimulus can trigger an anxiety reaction that may reach proportions of a panic attack.⁶ In PWE, agoraphobia or social phobias are among the more frequent types, resulting from fear of injury or social embarrassment should a seizure occur in public. For example, in a study of postictal psychiatric symptoms carried out in 100 consecutive patients with pharmacoresistant partial epilepsy, Kanner et al. found postictal symptoms of agoraphobia in 29 patients; 18 of these patients (62%) attributed these symptoms to the fear of seizure recurrence, but none of these patients experienced seizures in clusters to explain the agoraphobic symptoms.⁹⁰ Nonetheless, none of these patients developed full-blown interictal agoraphobia.

Obsessive Compulsive Disorder

OCD consists of the presence of obsessions and/or compulsions causing marked distress, being time-consuming (occurring for at least 1 hour per day) and significantly interfering with the individual’s normal routine, occupational functions, or social activities or relationships.⁶ The DSM-IV-TR classification defines obsessions as recurrent and persistent thoughts, impulses, or images that are experienced at some time during the disturbance as intrusive and inappropriate and cause marked anxiety or distress. It defines compulsions as repetitive behaviors or mental acts that the person feels driven to perform in response to an obsession or according to rules that must be applied rigidly. These criteria call for the individual to recognize that the obsessions and compulsions are excessive or unreasonable.⁶

There have been several case reports of complete remission of OCD or marked improvement following epilepsy surgery that have spurned hypotheses suggesting common pathogenic mechanisms between OCD and epilepsy. For example, Barbieri et al. reported a patient who had developed obsessive-compulsive symptoms shortly after the onset of temporal lobe epilepsy and who exhibited almost complete symptom remission after being rendered seizure free after a temporal lobectomy.¹¹ Kanner et al. reported the case of a woman with OCD consisting primarily of obsessions that had been intractable to various pharmacologic and psychotherapeutic interventions prior to surgery and that remitted in toto after a right temporal lobectomy.⁸⁸ Remission of OCD has been restricted to TLE surgery. Guarnieri et al. reported two male patients with medically intractable frontal lobe epilepsy and OCD symptoms who experienced remission of obsessive-compulsive symptoms after anterior cingulate cortex ablation.⁶⁶

Peri-ictal Symptoms of Anxiety

Few studies have investigated in a systematic manner the prevalence of peri-ictal anxiety symptoms or episodes, and those available have been limited to selected populations in tertiary centers. The lack of these data is not accidental as clinicians in general fail to inquire about such symptoms in their evaluations of PWE.

Pre-ictal Symptoms

Pre-ictal symptoms of anxiety can precede a seizure by several hours to several days. For example, Blanchet and Frommer identified symptoms of anxiety intermixed with symptoms of depression and irritability in a study of 27 patients who were asked to rate their mood on a daily bases for 1 month.¹⁹ Thirteen patients experienced a variety of dysphoric symptoms,
including symptoms of anxiety 3 days prior to the seizure occurrence that increased in severity as the time of the seizure got closer.

Ictal Symptoms of Anxiety

Ictal fear or ictal panic is the most frequent psychiatric symptom presenting as an expression of a simple partial seizure (or aura). It was identified in 60% of patients with auras consisting of psychiatric symptoms.⁴⁴^,¹⁸⁰ As stated above, ictal panic has been confused and misdiagnosed as a panic disorder. For example, in a series of 112 consecutive PWE, Sazgar et al. identified five patients with ictal fear as part of a partial seizure disorder of right mesial temporal origin who had been misdiagnosed with PD.¹⁵⁰ The difficulty in distinguishing the two disorders stems from the following: (a) an inaccurate and/or incomplete clinical history. (b) The absence of epileptiform activity in scalp interictal recordings in patients whose seizures originate from amygdala, a structure that generates epileptiform discharges with very narrow electric fields. In such patients, the use of video-electroencephalographic (V-EEG) monitoring studies may be necessary to record the actual seizure. Often, sphenoidal electrodes inserted under fluoroscopic guidance may be necessary to identify the electrographic ictal pattern of the aura.⁸⁹ (c) Ictal fear occurs often in the setting of a partial seizure disorder originating in the nondominant hemisphere. In such cases, patients may continue to respond during the ictus (including during a complex partial seizure) and neither witnesses to the seizure nor the patients may be able to identify a period of confusion or loss of awareness of their surroundings, lest a careful testing of the patient is conducted.

A detailed history can help distinguish a panic attack from ictal panic.¹⁶³ Indeed, ictal panic is typically brief (<30 seconds in duration), is stereotypical, occurs out of context to concurrent events, and may be followed by other ictal phenomena such as periods of confusion of variable duration and subtle or overt automatisms when and if the seizure evolves to a complex partial seizure. The intensity of the sensation of fear is mild to moderate and rarely reaches the intensity of a panic attack. On the other hand, panic attacks consist of episodes of 5 to 20 minutes’ duration, which at times may persist for several hours, during which the feeling of fear or panic is very intense, often described as a feeling of impending doom and associated with a variety of autonomic symptoms, including tachycardia, diffuse diaphoresis, and shortness of breath. During a panic attack, patients may become completely absorbed by the panic experience to the point where they may not be able to report what is going on around them; nonetheless, there is no real confusion or loss of consciousness as in complex partial seizures. Finally, patients with panic attacks are more likely to develop agoraphobia, while this is rare among patients with ictal panic unless they suffer from interictal panic disorder as well.

Given the relatively high comorbidity of interictal panic disorder in PWE, the concurrent occurrence of ictal fear and interictal PD has to be investigated in all patients. For example, in a small study of 12 patients with temporal lobe epilepsy, Mintzer and Lopez found ictal fear and interictal panic disorder in four of these patients.¹¹³ Two other patients had other forms of interictal anxiety disorder and eight patients had depressive disorder.

Finally, the presence of ictal fear can herald the development of postsurgical mood disorders. Thus, Kohler et al. studied the association of ictal fear with mood and anxiety disorders before and 1 year after temporal lobectomy.⁹⁹ They compared 22 patients with ictal fear with matched groups of patients with other types of auras and no auras at all. Mood and anxiety disorders declined in the control groups, but not in the ictal fear group after surgery.

Postictal Symptoms of Anxiety

Postictal symptoms of anxiety are relatively frequent among patients with refractory partial epilepsy. In a study of 100 consecutive patients with pharmacoresistant partial epilepsy cited above, Kanner et al. investigated in a systematic manner the occurrence of postictal psychiatric symptoms during a 3-month period.⁹⁰ The postictal period was defined as the 72 hours that followed a seizure. Only symptoms that occurred after more than 50% of seizures were recorded. A median of two postictal symptoms of anxiety (range: 1 to 5) were identified in 45 patients with a median duration of 24 hours (range: 0.5 to 148 hours). In 30 patients, at least 1 postictal symptom lasted 24 hours or longer (15 patients [33%] reported a cluster of 4 symptoms of at least 24 hours); 10 patients reported at least 1 symptom of 1 to 23 hours’ duration; and 5 patients had anxiety symptoms lasting <1 hour. Thirty-two patients reported symptoms of generalized anxiety and/or panic; an additional ten patients also reported symptoms of compulsions and 29 patients experienced postictal symptoms of agoraphobia. In 37 of these 45 patients, postictal symptoms of depression were also identified. A prior history of anxiety disorder was identified in 15 patients (33%). There was an association between a history of anxiety disorder and the occurrence of two postictal symptoms of anxiety: Constant worrying and panicky feelings. In addition, there was a significant association between a history of anxiety and depressive disorders and a greater number of postictal anxiety symptoms.

Comorbid Occurrence of Anxiety and Depression Disorders

In patients with anxiety disorders with or without epilepsy, investigation of symptoms of anxiety is not complete without also screening for symptoms of depression or carrying out structured interviews looking for mood disorders (and vice versa). Thus, in a meta-analysis of studies that investigated comorbidity between primary depression and anxiety disorders, Dobson and Cheung concluded that among patients with a depressive disorder, a mean of 67% (range: 42% to 100%) also experienced anxiety disorders concurrently or in their lifetime.⁴⁹ Conversely, in patients with anxiety disorders, a mean of 40% (range: 17% to 65%) also suffered from depression. By the same token, comorbid occurrence of primary social phobia and both major depression and dysthymia of up to 70% have been reported,¹¹² while higher comorbidity is also identified in first-degree relatives.¹³⁵ Furthermore, improvement in one condition can be expected to have a positive impact on the other. For example, in a study carried out in a general medical clinic setting, 880 patients were screened for depression by using the Diagnostic Interview Schedule version of the DSM-III and the Zung Self-Rating Depression Scale, as well as the Zung Self-Rating Anxiety Scale¹⁹²; 112 patients (13%) were found to have a depressive disorder. Comorbid symptoms of anxiety of moderate severity were identified in 67% of depressed patients. After a follow-up period of 1 year, during which symptoms of depression and anxiety were monitored at five time points, depressed patients who improved showed a significant decrease in severity of comorbid symptoms of anxiety, while depressed patients who worsened showed a significant increase in their anxiety index; the decrease in the anxiety index of patients in the no-change group was not statistically significant.

In PWE, the occurrence of comorbid anxiety and depressive disorders is also common. In a study of 199 patients with epilepsy from five epilepsy centers cited above, 73% of patients with a history of depression met also DSM-IV criteria for an anxiety disorder.⁹¹ In that study the DSM-IV-TR diagnosis of a mood and/or anxiety disorder was established with
the MINI and Structured Clinical Interview for Axis I Diagnosis (SCID). These patients completed a 46-item self-rating instrument, “The Mood and Anxiety Symptoms in Epilepsy” (MASE), that includes symptoms from eight domains (depression, anxiety, irritability, self-consciousness, physical symptoms, disturbances in socialization, suicidal ideation, and increased energy) on two occasions, 2 weeks apart. Sixty-seven patients met criteria for a DSM-IV Axis I diagnosis: Each of the 37 patients that met criteria for major depression reported symptoms of anxiety. Furthermore, several investigators dating back to Kraepelin, Bleuler, Gastaut, and more recently Blumer and Kanner have made a point of emphasizing the pleomorphic nature of the symptomatology of depressive disorders in PWE, in which symptoms of anxiety play a prominent role.²⁰^,²²^,⁵⁵^,⁹³^,¹⁰⁰

Comorbid anxiety symptoms can also occur in subclinical or subsyndromic forms of depression. In the study of 199 consecutive PWE cited above,⁹¹ 132 patients (64%) failed to meet any DSM-IV Axis I diagnosis according to the SCID and MINI; yet, using the self-rating instruments Beck Depression Inventory-II (BDI-II) or the Center for Epidemiologic Studies-Depression (CES-D), 32 patients (16% of the entire cohort) were also found to have been experiencing symptoms of depression of mild to moderate severity. Symptoms of anxiety were identified in 31 of these 32 patients with the MASE.

Screening of Anxiety Symptoms in the Clinic

Anxiety disorders in epilepsy are not homogeneous conditions, and often they occur in association with more than one type of anxiety and/or mood disorders. Thus, how can a neurologist identify an anxiety disorder in PWE? The use of self-rating screening instruments can be an initial step, but by themselves do not establish a diagnosis. Several instruments are available, but none has yet been validated in PWE. Self-rating screening instruments are obviously preferable to questionnaires that have to be administered by a health professional. In addition, instruments that also screen for symptoms of depression should be included for the reasons cited above. Among the multiple screening instruments available, the following can be considered:

Hospital Anxiety and Depression Scale¹⁹¹: This scale is specifically developed for use in patients with medical comorbidity, and consists of seven-item self-rated subscales for both depression and anxiety.
Beck Anxiety Inventory (BAI)¹³: The BAI is a 21-item self-report measure of anxiety severity. The scale consists of 21 items, each describing a common symptom of anxiety over the past week on a 4-point scale ranging from 0 (Not at all) to 3 (Severely—I could barely stand it). The items are summed to obtain a total score that can range from 0 to 63.
Goldberg’s Depression and Anxiety Scales⁶²: The instrument consists of nine questions assessing mood and anxiety over the previous month, and the full set of nine questions needs to be administered only if there are positive answers to the first four. The scales are devised specifically to be used by nonpsychiatrists in clinical investigations. Scores are from 0 to 9.
Hamilton Anxiety Rating Scale (HAM-A or HARS)⁶⁸: This scale is a 14-item clinical interview scale (not self-reported) measuring somatic and psychic anxiety symptoms. The responses include five degrees of severity ranging from 0 (None) to 4 (Frequent and severe symptomatology). This instrument should be used with caution in PWE, given the large number of somatic symptoms included in this scale, which, in patients with epilepsy, can result from adverse effects of antiepileptic drugs (AEDs), potentially yielding false-positive suggestions of more severe anxiety symptomatology.

The Use of Screening Instruments in Research: A Cautionary Note!

One of the most frequent methodologic errors in research studies on psychiatric disorders and epilepsy is the sole reliance on screening instruments to establish a diagnosis. The argument for exclusively using screening instruments is that they have been “validated” to identify the condition at hand with acceptable levels of sensitivity and specificity and the severity of the depressive episodes. Yet, as stated above, patients may often experience more than one type of anxiety disorder at a given point in time and more often than not suffer from comorbid mood disorders. Accordingly, structured psychiatric evaluations are “a must,” aimed at identifying the complexity of current and past psychiatric disorders. Short of that, the conclusions that can be derived from studies that assess any treatment modality or the course of symptomatology are limited.

For example, the course and response to treatment of GAD or PD in a patient with a comorbid history of bipolar disorder is different from that of a patient with major depressive disorder or without a comorbid mood disorder. In short, screening instruments identify “symptoms”; structured interviews establish the presence of a psychiatric disorder, according to classifications like the DSM-IV-TR. Thus, if the aim of a study is to identify the presence of an anxiety disorder, a psychiatric structured interview is necessary. Only once the presence of psychiatric disorders have been established in this manner should screening instruments be used to follow changes of symptom severity over time.

Impact of Anxiety Disorders on Quality of Life

Primary mood and anxiety disorders have a negative impact on the quality of life in the general population. In PWE, research on the effect of psychiatric disorders on health-related quality of life (HRQOL) has been focused on mood disorders (see also Chapter 205) and five studies carried out in patients with pharmacoresistant epilepsy have consistently demonstrated depression to be the most powerful predictor for each domain of health-related quality of life, even after controlling for seizure frequency, severity, and other psychosocial variables.⁵⁸^,⁵⁹^,¹⁰²^,¹⁰⁵^,¹²⁸ Cramer et al. also found that depression was significantly associated with poor quality of life scores on the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) independently of the type of seizures; these investigators found, however, that seizure freedom for the last 3 months increased (i.e., improved) the quality-of-life ratings.³⁵

Few studies have investigated the impact of anxiety symptoms and/or disorders on HRQOL of PWE. In a study of 87 patients with TLE, Johnson et al. found that symptoms of depression and anxiety were the strongest predictors of poor HRQOL.⁸² These investigators found an independent effect of each class of symptoms on HRQOL, however. Furthermore, the psychiatric comorbidity explained more variance in HRQOL than did combined groups of clinical seizure or demographic variables. Furthermore, in a study of 154 outpatient adults with epilepsy carried out in South Korea, Choi-Kwon et al. found that the presence of anxiety symptoms was the most important variable mediating lower quality of life in patients with epilepsy.³²

In the study of 199 patients described above, Kanner et al.⁹¹ found that the scores of the QOLIE-89 were significantly
lower (i.e., worse quality of life) among patients with anxiety disorders than those of asymptomatic patients. Furthermore, patients with comorbid anxiety and major depressive disorders had significantly lower scores in the QOLIE-89 than those with only major depressive episodes.

Impact of Anxiety on Suicidality

Suicidal ideation and attempts are significantly more frequent among PWE than in the general population.⁸⁴ Several studies have already established that anxiety disorders are risk factors for suicidal ideation and suicide attempts. For example, in a large population-based longitudinal study carried out in the Netherlands, Sareen et al. found that the presence of any anxiety disorder at the initial evaluation was significantly associated with suicidal ideation and suicide attempts in both the cross-sectional analysis (adjusted odds ratio [OR] for suicidal ideation, 2.29; 95% confidence interval [CI], 1.85 to 2.82; adjusted OR for suicidal attempts, 2.48; 95% CI, 1.70 to 3.62) and longitudinal analysis (adjusted OR for suicidal ideation, 2.32; 95% CI, 1.31 to 4.11; adjusted OR for suicide attempts, 3.64; 95% CI, 1.70 to 7.83).¹⁴⁹ Furthermore, the presence of any anxiety disorder in combination with a mood disorder was associated with a higher likelihood of suicide attempts in comparison with a mood disorder alone. Pilowsky et al. surveyed 2,043 patients attending a primary care clinic using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, a screening instrument that yields provisional diagnoses of selected psychiatric disorders.¹³¹ A provisional diagnosis of current panic disorder was identified in 127 patients (6.2%). After adjusting for potential confounders (age, gender, major depressive disorder, generalized anxiety disorder, and substance use disorders), patients with panic disorder were about twice as likely to present with current suicidal ideation, as compared to those without panic disorder (adjusted OR, 1.84; 95% CI, 1.06 to 3.18). After adjusting for panic disorder and the above-mentioned potential confounders, patients with major depressive disorder had a sevenfold increase in the odds of suicidal ideation, as compared to those without major depressive disorder (adjusted OR, 7.00; 95% CI, 4.42 to 11.08). Other studies have found that anxiety disorders may increase a suicidal risk only in the presence of comorbid mood disorders.⁷

The impact of anxiety disorders on suicidal ideation and suicide attempts has also been identified in children and adolescents but may not be as clear as in adults. For example, Strauss et al. carried out a study of 1,979 patients aged 5 to 19 years using the Schedule for Affective Disorders and Schizophrenia for School Aged Children–Present Episode at an outpatient mood and anxiety disorders clinic.¹⁶⁸ Subjects were stratified by age and categorized into mutually exclusive groups as being nonsuicidal (N = 817), having suicidal ideation (N = 768), or having attempted suicide (N = 394) in the current episode. After stratifying by age, the investigators found no differences among the ideators, attempters, and nonsuicidal youth in rates of an anxiety disorder in general or in specific rates of PD, agoraphobia, social phobia, simple phobia, and OCD. In older children (age >15 years), GAD was more prevalent in ideators (OR = 1.65; 95% CI, 1.03 to 2.66; p = 0.03) than in nonsuicidal patients. Whether similar findings would be identified in population-based studies is yet to be established.

The impact of anxiety disorders in suicidality of PWE has not been studied extensively. In one study by Jones et al. of 139 PWE, 17 met criteria for current suicidal ideation (12.2%), while a lifetime prevalence of suicidal attempts was found in 29 patients (20.8%).⁸⁴ Anxiety disorders were significantly more common among patients with current suicidal ideation (58.8%), while 41.2% of patients had comorbid anxiety and current major depressive disorders. On the other hand, lifetime major depressive disorder was the most frequent psychiatric disorder identified among patients with lifetime suicide attempt (51.7%).

Pathogenic Mechanisms

There are several operant pathogenic mechanisms of anxiety in PWE, which can be classified into three groups: (a) psychosocial; (b) endogenous, which include neurochemical, neurophysiologic, neuroanatomic, and functional changes related to the seizure disorder per se; and (c) iatrogenic, including adverse effects of AEDs and complications of epilepsy surgery.

Psychosocial Factors

Patients with epilepsy face multiple psychosocial obstacles that can facilitate the development of symptoms of anxiety and/or (in patients with a predisposition) full-blown anxiety disorder. Stigma, to name one of such obstacles, accounts for the development of symptoms of anxiety. For example, in a study of more than 5,000 patients living in 15 countries in Europe, Baker et al. found that 51% reported feeling stigmatized, with 18% reporting feeling highly stigmatized.⁹ High scores were correlated with worry, negative feelings about life, long-term health problems, injuries, and reported side effects of AEDs. Unfortunately, PWE’s perception of being stigmatized is not only a function of their “insecurity” resulting from the epilepsy, but is also a real phenomenon illustrated in a study by Harden et al.⁶⁹ These investigators developed a survey consisting of three vignettes briefly describing a coworker with depression, multiple sclerosis, or epilepsy. Of note, the epilepsy vignette did not describe a seizure. Each vignette was followed by eight identical questions addressing the level of comfort during interactions with the vignette subject. The surveys were hand-distributed in two companies in New York City and returned anonymously by mail. Seventy-four of 200 distributed questionnaires were returned. Respondents reported more discomfort at the thought of interacting with a coworker with epilepsy than with depression or multiple sclerosis, but this difference did not reach significance. However, worry about sudden, unpredictable behavior for the coworker with epilepsy was significantly greater than that with multiple sclerosis. Responders had a significantly lower level of comfort providing first aid for the coworker with epilepsy than for the coworkers with depression and multiple sclerosis. Lower job level and lower income level correlated with more social discomfort for all three illnesses.

People with epilepsy have also been found to suffer from more frequent comorbid physical disorders, some of which are closely associated with stress and anxiety. For example, Téllez-Zenteno et al. analyzed epilepsy-specific and general population health data obtained through two previously validated, independently performed, door-to-door Canadian health surveys, the National Population Health Survey (N = 49,000) and the Community Health Survey (N = 130,882), which represent 98% of the Canadian population.¹⁷² PWE were found to have higher comorbid stomach and intestinal ulcers, bowel disorders, migraine, and chronic fatigue. Likewise, Strine et al. analyzed data obtained from 30,445 adults aged 18 years or older who participated in the 2002 National Health Interview Survey in the United States.¹⁶⁹ They identified an estimated 1.4% subjects who were told by a health care professional that they had seizures; these subjects were significantly more likely than those without seizures to report lower levels of education, higher levels of unemployment, pain, hypersomnia and insomnia, and psychological distress (e. g., feelings of sadness,
nervousness, hopelessness, and worthlessness). In addition, they were significantly more likely to report insufficient leisure time physical activity as well as physical comorbidities such as cancer, arthritis, heart disease, stroke, asthma, severe headaches, lower back pain, and neck pain. It is likely that the comorbid medical disorders play a significant role in the generation of symptoms of anxiety in PWE.

The Role of Seizure Frequency and Seizure Severity

As part of a large community-based study, Jacoby et al. investigated the variables associated with the clinical course of epilepsy and the development of anxiety and depression symptoms in an unselected population of people who had a recent history of seizures or were receiving AEDs.⁷⁶ Epilepsy data were collected from the medical records of the treating primary physicians and information about psychosocial functioning was obtained with questionnaires mailed to identified subjects, 71% of whom returned the questionnaire. Fifty-seven percent of the sample had had at least 2-year seizure-free periods and 46% were in a remission of at least 2 years’ duration. There was a clear relationship between current seizure frequency and levels of anxiety and depression.

Smith et al. reported a study of 100 patients with medically refractory partial seizures who completed a quality-of-life questionnaire including measures of physical (seizure severity and frequency), social, and psychological well-being (anxiety, depression, self-esteem, locus of control, and happiness).¹⁶⁰ Multivariate analysis demonstrated that individual psychological variables were best predicted by other psychological variables. However, when these were removed from analysis, seizure severity, but not seizure frequency, was the most significant predictor of anxiety and self-esteem.

Similar findings have been reported in children with epilepsy, though data have been obtained from tertiary centers and not from population-based studies. For example, in a study of 35 children and adolescents aged 9 to 18 years and 35 healthy controls, Oguz et al. investigated the relationship between epilepsy-related factors and the development of symptoms of anxiety and depression.¹²³ Both study and control groups were divided into two age groups (9 to 11 and 12 to 18 years) to exclude the effect of puberty on anxiety and depression scores. Children and adolescents with epilepsy displayed higher scores on the measures of depression symptoms and suicidal ideation, and the mean trait anxiety score was significantly higher in the 9- to 11-year age group of epileptic patients than the corresponding control group, while the mean state, trait anxiety, and depression scores were significantly higher in the 12- to 18-year age group of epileptic children than in the control group. Duration of the epilepsy, seizure frequency, and polytherapy were the epilepsy-related factors associated with the development of anxiety and depression symptoms. Furthermore, in a study carried out in 102 adolescents aged between 12 and 18 from Nigeria, Abiodoun et al. identified an anxiety disorder in 32 (31.37%) of the adolescents with the Diagnostic Interview Schedule for Children Version IV (DISC-IV) and a depressive disorder in 29 (28.4%).³ As in the above-cited studies, uncontrolled seizures, polytherapy, and felt stigma were identified as predictors of anxiety and depressive disorders by regression analysis. Family factors such as parents’ psychopathology and family stress also played a moderately significant role. On the other hand, Williams et al. did not find a pathogenic role of seizure frequency in the development of anxiety symptoms. In a study of 101 children and adolescents between the ages of 6 and 16 years, mild to moderate symptoms of anxiety were reported by 23% of the patients.¹⁸³ The presence of comorbid learning or behavioral difficulties, ethnicity, and polytherapy were identified as the variables associated with increased anxiety scores.

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