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Seizure phobia: A distinct psychiatric disorder among people with epilepsy

  • Aviva Weiss
    Affiliations
    Psychiatric Hostels affiliated with Kidum Rehabilitation Projects, Jerusalem, Israel

    Alma Center for Treatment of Sexually Abused Patients, Jerusalem, Israel
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  • Laura Canetti
    Affiliations
    Department of Psychiatry, Hadassah Medical Center, Jerusalem, Israel

    Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel
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  • Shiri Ben David
    Affiliations
    Neuropsychiatry Clinic, Hadassah Medical Center, Jerusalem, Israel

    Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel
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  • Inbal Reuveni
    Affiliations
    Department of Psychiatry, Hadassah Medical Center, Jerusalem, Israel

    Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
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  • Dana Ekstein
    Correspondence
    Corresponding author at: Department of Neurology and Agnes Ginges Center for Neurogenetics, Hadassah Medical Center, and the Faculty of Medicine, The Hebrew University of Jerusalem, POB 12000, Jerusalem, 91120, Israel.
    Affiliations
    Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Department of Neurology, Ginges Center for Neurogenetics, Hadassah Medical Center, Jerusalem, Israel
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Published:December 23, 2021DOI:https://doi.org/10.1016/j.seizure.2021.12.009

      Highlights

      • The prevalence of seizure phobia was 27.5% among the participants of the study.
      • Seizure phobia was associated with female gender, anxiety disorders, a past major depressive episode, and psychogenic non-epileptic seizures.
      • Seizure phobia was not associated with the severity or duration of epilepsy.
      • Seizure phobia is a distinct psychiatric disorder worthy of further exploration.

      Abstract

      Objective

      Epilepsy is characterized by unpredictable attacks. Hence, people with epilepsy (PWE) may develop anxious anticipation of upcoming seizures. Seizure phobia is an anxiety disorder wherein seizure anticipatory situations trigger fear, accompanied by avoidance behaviors. Research on seizure phobia among PWE is scarce. Therefore, we aimed to describe the diagnosis of seizure phobia and its association with demographic, psychiatric and neurological variables.

      Methods

      This is a cross-sectional study of adult PWE in a tertiary epilepsy outpatient clinic. Data were collected from semi-structured interviews, demographic questionnaires and medical records. Patients with and without seizure phobia were compared in terms of sociodemographic, psychiatric, and neurological variables. A logistic regression analysis was performed to identify variables that predicted seizure phobia.

      Results

      Among 69 PWE included in the study, 19 (27.5%) were diagnosed with seizure phobia. In comparison with PWE without seizure phobia, PWE with seizure phobia were predominantly female (84.2% vs 44.2%, p = 0.005), and had more comorbid anxiety disorders (84.2% vs 34.9%, p = 0.01), past major depressive episode (MDE) (63.2% vs 20.9%, p = 0.003), and post-traumatic stress disorder (26.3% vs 7%, p = 0.05). There was a significant association between seizure phobia and comorbid psychogenic non-epileptic seizures (36.8% vs 11.6%, p = 0.034). However, no significant association was found with epilepsy-related variables. A multivariate logistic regression model indicated anxiety and a past MDE as predictive factors for seizure phobia (R2 = 0.43).

      Conclusion

      Seizure phobia is a distinct psychiatric entity among PWE. Further research is required to understand its etiology, risk factors, and potential interventions for these patients.

      Keywords

      1. Introduction

      Epilepsy, by definition, is not merely a disease with predisposition for seizures, but is rather comprised of a myriad of accompanying neurobiological, psychological, cognitive, and social consequences [
      • Fisher R.S.
      • Acevedo C.
      • Arzimanoglou A.
      • et al.
      ILAE official report: a practical clinical definition of epilepsy.
      ]. Psychiatric manifestations of epilepsy, such as anxiety and depression, are known to negatively affect the quality of life of people with epilepsy (PWE) [
      • Johnson E.K.
      • Jones J.E.
      • Seidenberg M.
      • Hermann B.P.
      The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy.
      ]. Anxiety symptoms in epilepsy are often classified according to their temporal occurrence to seizures: peri‑ictal and interictal [
      • Beyenburg S.
      • Mitchell A.J.
      • Schmidt D.
      • et al.
      Anxiety in patients with epilepsy: systematic review and suggestions for clinical management.
      ,
      • Hingray C.
      • McGonigal A.
      • Kotwas I.
      • Micoulaud-Franchi J.A.
      The relationship between epilepsy and anxiety disorders.
      ]. Although interictal anxiety is frequent among PWE [
      • Alsaadi T.
      • El Hammasi K.
      • Shahrour T.M.
      • et al.
      Prevalence of depression and anxiety among patients with epilepsy attending the epilepsy clinic at Sheikh Khalifa Medical City, UAE: a cross-sectional study.
      ], it remains underrecognized and understudied [
      • Kanner A.M.
      Anxiety disorders in epilepsy: the forgotten psychiatric comorbidity.
      ].
      The International League Against Epilepsy (ILAE) recognized fear of seizures, social phobia and agoraphobia as distinct interictal anxiety disorders in epilepsy. These disorders were defined as phobias revolving around epilepsy, and the fear of the situation and subsequent avoidance are linked to the fear of having a seizure in that situation, and its possible consequences [7]. Hingray et al. suggested anxiety disorders in the interictal period could be classified as anticipatory anxiety of epileptic seizures (AAS), epileptic social phobia, epileptic panic disorder, and seizure phobia [
      • Hingray C.
      • McGonigal A.
      • Kotwas I.
      • Micoulaud-Franchi J.A.
      The relationship between epilepsy and anxiety disorders.
      ]. The occurrence of AAS, characterized by persistent fear, dread, or excessive worry of having a seizure, was 53% among patients with focal epilepsy [
      • Ertan D.
      • Hubert-Jacquot C.
      • Maillard L.
      • et al.
      Anticipatory anxiety of epileptic seizures: an overlooked dimension linked to trauma history.
      ].
      Fear and anxiety are overlapping concepts. However, fear typically refers to the emotional state when confronting an immediate and overtly dangerous stimulus, whereas anxiety is elicited when there is an actual or imagined impending threat [
      • Merikangas K.R.
      Anxiety disorders: introduction and overview.
      ]. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines specific phobia as a disorder characterized by “marked fear or anxiety about a specific object or situation, which almost always provokes immediate fear or anxiety and is actively avoided or endured with intense fear or anxiety”. The feared object or situation are termed the phobic stimulus and could be actual or anticipated. The level of fear experienced may vary in intensity, ranging from anticipatory anxiety to a full panic attack [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. In the case of seizure phobia, the phobic stimulus refers to situations that their presence evokes immediate fear of having a seizure. Although recognized by the epilepsy and the psychiatric communities, seizure phobia as a distinct anxiety disorder among PWE is insufficiently described in the medical literature. There is one case report of a woman with seizure phobia, characterized by marked anticipatory anxiety of seizures, fear and avoidance of agoraphobic and social situations, and usage of benzodiazepines as a safety behavior, which responded positively to cognitive behavioral therapy (CBT) [
      • Newsom-Davis I.
      • Goldstein L.H.
      • Fitzpatrick D.
      Fear of seizures: an investigation and treatment.
      ].
      The present study aimed to characterize seizure phobia as a distinct anxiety disorder among PWE visiting a tertiary epilepsy outpatient clinic, and to identify psychosocial, psychiatric, and neurological contributors related to this disorder. We hypothesized that seizure phobia will be positively associated with the severity of epilepsy and with psychiatric comorbidity.

      2. Methods

      2.1 Subjects

      We conducted an observational cross-sectional study in the tertiary epilepsy clinic in Hadassah Hebrew University Medical Center in Jerusalem, Israel. Patients visiting the epilepsy clinic of one epileptologist (DE) between January 2017 and July 2018 were approached at dates that coincided with the availability of the psychiatrist (AW) and were offered to participate in the study. Inclusion criteria were: (1) a definite diagnosis of epilepsy (based on clear clinical, electrographic and imaging data), (2) ages 18–60 years, (3) Hebrew speakers, (4) able to give informed consent. Exclusion criteria were: (1) cognitive disability according to medical history, (2) psychosis according to medical history and/ or diagnosed upon the psychiatric interview, (3) suicidality in the past 2 years, and (4) substance use disorder in the past 2 years. Comorbid psychogenic non-epileptic seizures (PNES), diagnosed using concomitant video and EEG recordings during the events, were allowed, but patients with PNES and without a clearcut diagnosis of epilepsy were excluded from the study.
      Data were collected by means of a semi-structured psychiatric interview, demographic questionnaires and from the patients’ electronic medical records. The study was approved by the Ethics Review Board of the Hadassah Hebrew University Medical Center (protocol 0089–17-HMO) and all patients signed an informed consent form.

      2.2 Measures

      2.2.1 Clinical and sociodemographic variables

      Sociodemographic information was obtained via a self-report questionnaire, including age, marital status, number of children, country of birth, religiosity, years of education, employment status, and socioeconomic status. If participants did not hand in a full questionnaire, missing information regarding sociodemographic information was retrieved from their medical files.
      Patients’ clinical information regarding clinical variables of epilepsy, medications, and medical comorbidity was obtained from the patients’ electronic medical records. Seizure severity was assessed based on seizure activity in the past year, seizure types, and drug resistance.

      2.2.2 Seizure phobia diagnostic criteria and psychiatric comorbidity assessment

      Patients underwent a semi-structured clinical interview with the Hebrew version of the Semi-Structured Clinical Interview for DSM-IV (SCID-I/P, version 2.0) [
      • Shalev A.Y.
      • Abramowitz M.Z.
      • Kaplan-DE-Nour A
      Structured clinical interview for axis i dsm-iv -Patient edition (SCID I/P, version 2.0), Hebrew version.
      ], to identify past or present psychiatric disorders. Seizure phobia was diagnosed in accordance with the criteria of specific phobia in the DSM-5 [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ], as described in Table 1 (criteria A to G). All criteria must be met for the diagnosis of seizure phobia.
      Table 1Proposed Seizure Phobia Diagnostic Criteria Corresponding Questions for Clinical Interview
      Criteria are based on the DSM-5 criteria for Specific Phobia.
      .
      Seizure Phobia Diagnostic CriteriaInterview
      A.Marked fear or anxiety about having a seizure1. Screening question: Are you afraid of having a seizure?

      2. Are there situations which evoke this fear that you are especially afraid of? If yes, what are these situations?
      B.Seizure-anticipatory situations almost always provoke immediate fear or anxiety.What usually happens when you are exposed to the above situations? (Refer to the situations mentioned by the patient in criteria A.2.)

      (Screen for symptoms of a panic attack.)
      C.Situations evoking seizure fear are actively avoided or endured with intense fear or anxiety.Do you go out of your way to avoid these situations? (Refer to the situations mentioned by the patient in criteria A.2.)

      Or: Are there things you did not do due to fear of having a seizure, which you would otherwise have done?

      Or: How hard is it for you to confront these situations? (Refer to the situations mentioned by the patient in criteria A.2.)
      D,The fear or anxiety is out of proportion to the actual danger posed by the situation in which the seizure is anticipated and to the sociocultural context.Is the feared situation seizure-evoking or life-threatening? If the situation may evoke seizures - check if the patient's response is proportionate to the level of threat the stimulus imposes.
      E,The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.How long have you had these fears?
      F.The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.If not clear from patient's narrative:

      How much does this fear of seizures interfere with your life?

      Or: How much does the fact that you are afraid of seizures cause you distress?
      G.The fear or anxiety is not better explained by the symptoms of another mental disorder.This is for the clinician to differentiate between cases where the anxiety is related and not related to seizure fear after completing a full interview.
      low asterisk Criteria are based on the DSM-5 criteria for Specific Phobia.

      2.3 Data analysis

      The association between seizure phobia and categorical variables was tested by comparing between patients with and without seizure phobia using Fisher's exact tests for 2 × 2 contingency tables, and χ2 tests for larger tables. Due to the small sample size of the seizure phobia group, we performed Mann Whitney U tests for continuous variables. To create a quantitative model of seizure phobia prediction, a logistic regression was calculated with “PWE with seizure phobia vs. without seizure phobia” as the dependent categorical variable, and “Any anxiety disorder” and “Past MDE” as the independent variables. Reported p values are two-sided. All analyses were performed using IBM SPSS (IBM Corp 2012) statistical software.

      3. Results

      3.1 Seizure phobia prevalence

      A total of 95 PWE were eligible to participate in the study, of which 70 patients agreed to be interviewed. One patient was excluded post consent due to a diagnosis of a concurrent psychotic disorder. All 69 patients in this sample were Jewish, 58 (84%) of them were born in Israel, their average age was 36.8 years old (Sd ±12), 41 (59.4%) were female, and 41 (59.4%) were married.
      Nineteen of the 69 subjects (27.5% - 95%CI (17.4–39.1)) were diagnosed with seizure phobia (see Figure S1 for details of the diagnoses). Seven patients (10.1% - 95%CI (4.3–17.4)) fulfilled all criteria of seizure phobia in the past, but no longer reached the clinical threshold for this diagnosis (see table S1 in supplementary material). As we aimed to define the diagnosis of seizure phobia, we omitted this group from the analyses to ensure an accurate description of the disorder.

      3.2 Seizure phobia characteristics

      Overall, 47 patients (68%) responded affirmatively to the screening question: "Are you afraid of having a seizure?” However, when further questioned in the clinical interview (see table 1), only 19 of them (40.4%) fulfilled all requisite criteria for the diagnosis of seizure phobia.
      The manifestation of seizure phobia varied among participants who fulfilled all criteria for the diagnosis. Thirteen patients (68%) reported a history of panic attacks when anticipating a seizure. Patients with seizure phobia described a wide array of seizure anticipatory situations that evoke fear, as well as various avoidance behaviors (see table 2). Common fear-evoking situations included: agoraphobic situations, such as public transportation, closed spaces, and crowds (N = 11); somatic sensations such as dizziness, tremor, aura, and headaches (N = 10); exposure to stimuli that may trigger seizures including flickering lights, high temperatures, stress, and sleep deprivation (N = 9); being alone (N = 6); social situations such as being around strangers or acquaintances (N = 5). Avoidance behaviors varied and included overt avoidance from phobic stimuli, or when exposure is unavoidable, the use of safety behaviors to reduce anxiety. Most of the patients (N = 13) reported avoiding crowded and closed spaces such as the cinema and public transportation. Moreover, many reported avoiding leaving the house unaccompanied and/or traveling away from home (N = 8). Some patients described measures taken when exposed to fearful situations, such as escaping the situation (N = 2), using benzodiazepines (N = 2), or sitting down (N = 2).
      Table 2Characteristics of participants diagnosed with seizure phobia.
      Patient no.Phobic Situations (seizure anticipatory situations):Avoidance Behaviors (overt avoidance, safety behaviors and escape):
      1.FOS is triggered by onset of nighttime due to nocturnal seizures, especially if forgot to take his medicine.Avoids sleep- may stay awake for hours.
      2.FOS is triggered by the company of people and by closed spaces.Avoids company of people and closed spaces. When frightened- escapes and takes clonazepam.
      3.FOS is triggered by feeling dizzy.Avoids any situations which induce dizziness- such as exercise and alcohol. When dizzy- sits down and prays.
      4.FOS is triggered by being away from home and in crowds, and by somatic sensations including tremor and dizziness.Avoids crowds and public transportation.
      5.FOS is triggered by crowds, being alone, loud noises, and strong lights.Avoids parties and traveling. Escapes fearful situations.
      6.FOS is triggered by crowds, being alone, flickering lights, and experiencing an aura.Avoids crowds, public transportation, going to the movies, and walking around unaccompanied.
      7.FOS is triggered by being alone with baby, baths, crowds and being alone.Avoids crowds, being alone, and tries to avoid holding baby when possible.
      8.FOS is triggered by being alone, new places, feeling dizzy and by headaches.Avoids public transportation, large gatherings, and walking around unaccompanied.
      9.FOS is triggered by being alone, or being alone with kids, and when in company with people who are not close friends or family.Avoids public transportation, crowds, and walking around unaccompanied. When frightened -distances herself from kids.
      10.FOS is triggered by crowds, certain smells, hot temperature, and cold water.Avoids crowds, parties, and public transportation.
      11.FOS is triggered by being alone, crowds, taking a shower and intense heat.Avoids public transportation and shopping.
      12.FOS is triggered by onset of nighttime, a feeling of presyncope, and crowds.Avoids crowds.
      13.FOS is triggered by crowds, heights, and heat.Avoids public transportation. When frightened - opens the windows and sits next to the door.
      14.FOS is triggered by strong flickering lights, being alone with the baby, sharp objects, feeling dizzy and experiencing a headache.Avoids exposure to strong lights. When frightened- closes eyes, holds-on to something and calls for help.
      15.FOS is triggered by sleep deprivation, stressful situation, headaches, dizziness, palpitations.Avoids stressful situations and walking around unaccompanied.
      16.FOS is triggered by heat, working with kids, and experiencing a headache.Avoids exposure to sun, going to the pool, tours.

      Frequently sits next to air conditioner and only eats cold food.
      17.FOS is triggered by being around acquaintances, crowds, and closed spaces, flickering lights.Avoids walking around unaccompanied, crowds, closed spaces, and strong lights. When frightened- takes clonazepam.
      18.FOS is triggered by being away from home, strangers, crowds, experiencing an aura, and nausea.Avoids goings to the movies, travelling, and large gatherings. Frequently stays at home.
      19.FOS is triggered by crowds, strangers, prodromal feeling, tremor, and fatigue.Avoids company of other people when possible. When frightened– cancels meeting and does not go to work.
      Abbreviations: FOS- fear of seizures.

      3.3 Demographic and clinical data

      Patients diagnosed with seizure phobia did not differ from patients without seizure phobia in terms of age, marital status, number of children, years of education, employment, and socioeconomic status. However, among the seizure phobia group there was a greater proportion of women and of native Israelis (Table 3).
      Table 3Demographic characteristics of patients with and without seizure phobia.
      Seizure Phobia (n = 19)No Seizure Phobia (n = 43)Fisher's exact test/ Mann-Whitney Up
      Gender8.59.005
       Male3 (15.8%)24 (55.8%)
       Female16 (84.2%)19 (44.2%)
      Age35.5 (SD=9.7)37.9 (SD=12.9)379.5.658
      Marital status.011.000
       Married12 (63.2%)26 (61.9%)
       Single/Divorced/Widow7 (36.8%)16 (38.1%)
      Number of children1.5 (SD=1.7)2.0 (SD=2.33)372.5.665
      Country of birth4.54.047
       Israel18 (100%)33 (78.6%)
       Other
      Countries of birth: Western Europe-4, Middle east-2, Eastern Europe- 1, Africa-1, South America-1.
      0 (0%)9 (21.4%)
      Religiosityχ2(3)=2.99.393
       Secular6 (33.3%)9 (22.5%)
       Traditional7 (38.9%)11 (27.5%)
       Religious3 (16.7%)8 (20%)
       Ultraorthodox2 (11.2%)12 (30%)
      Educational level (years)14.0 (SD=3.3)13.7 (SD=3.1)290.0.341
      Employment.75.541
       Employed8 (50%)22 (62.9%)
       unemployed8 (50%)13 (37.1%)
      socioeconomic statusχ2(2)=0.06.969
       No financial difficulties3 (18.8%)6 (18.8%)
       Some financial difficulties9 (56.3%)19 (59.4%
       Financial difficulties4 (25%)7 (21.9%)
      SD- standard deviation.
      1 Countries of birth: Western Europe-4, Middle east-2, Eastern Europe- 1, Africa-1, South America-1.
      Table 4 depicts the clinical characteristics of the epilepsy in patients diagnosed with seizure phobia compared to those without seizure phobia. Seizure activity in the past year and drug resistance were not associated with seizure phobia. Epilepsy etiology, seizure types, location of epileptic foci, and level of consciousness during seizures were also not associated with seizure phobia. Medications taken by patients with seizure phobia did not differ from those taken by patients without seizure phobia (see Table S2 in supplemental material). The only significant difference between the groups was the existence of video-EEG verified evidence of comorbid PNES, which were more common among patients with seizure phobia.
      Table 4Epilepsy clinical characteristics of patients diagnosed with seizure phobia and of patients without seizure phobia.
      Seizure Phobia (n = 19)No Seizure Phobia (n = 43)Fisher's exact test/ Mann-Whitney Up
      Age of onset18.5 (SD=10.3)23.1 (SD=15.3)348.5.359
      Years since onset16.9 (SD=12.6)14.8 (SD=13.6)348.0.355
      Etiologyχ2(2)=1.18.553
       structural6 (33.3%)19 (48.7%)
       idiopathic/genetic6 (33.3%)10 (25.6%)
       unknown6 (33.3%)10 (25.6%)
      Epileptic focus location
      Patients may have multiple or bilateral foci.
       Right focus5 (26.3%)14 (32.9%).24.768
       Left focus6 (31.6%)15 (34.9%).061.000
       Temporal lobe6 (31.6%)19 (44.2%).87.410
       Frontal lobe2 (10.5%)10 (23.3%)1.37.313
       Parietal lobe0 (0%)4 (9.3%)1.89.303
       Occipital lobe0 (0%)1 (2.3%).451.000
      Seizure Type
       GTCS18 (94.7%)41 (95.3%).011.000
       myoclonus5 (26.3%)5 (11.9%)1.98.261
       absence4 (21.1%)6 (14.3%).44.710
       focal- impaired awareness10 (52.6%)17 (40.5%).78.415
       focal aware6 (31.6%)22 (52.4%)2.28.170
      Seizure activity in the Past Year
      seizure free7 (38.9%)22 (52.4%).92.405
      GTCS7 (38.9%)10 (23.3%)1.54.229
      impaired consciousness (including GTCS)11 (57.9%)18 (41.9%)1.36.280
      seizures with impaired consciousness without GTCS3 (16.7%)8 (18.6%).031.000
      only seizures with retained consciousness0 (0%)4 (9.5%)1.84.306
      Drug resistant epilepsy6 (31.6%)12 (27.9%).09.770
      Seizures with no electrographic correlation (comorbid PNES)7 (36.8%)5 (11.6%)5.37.034
      SD- standard deviation, GTCS- generalized tonic-clonic seizures, PNES-psychogenic non-epileptic seizures.
      1 Patients may have multiple or bilateral foci.

      3.4 Psychiatric disorders

      Table 5 shows the prevalence of comorbid anxiety and depressive disorders in patients with and without seizure phobia. Anxiety disorders (84.2% vs 34.9%, p = 0.01) and a past major depressive episode (MDE) (63.2% vs 20.9%, p = 0.003) were significantly more frequent among PWE with seizure phobia in comparison with PWE without seizure phobia, as well as posttraumatic stress disorder (PTSD) (26.3% vs 7%, p = 0.05). The specific anxiety disorders shown to be associated with seizure phobia were agoraphobia (52.6% vs 4.7%, p<0.001), panic disorder (26.3% vs 2.3%, p = 0.009) and specific phobia (42.1% vs 11.6%, p = 0.015), yet social anxiety disorder and generalized anxiety disorder were not.
      Table 5Anxiety and depressive disorders among patients diagnosed with seizure phobia and patients without seizure phobia.
      Seizure Phobia (n = 19)No Seizure Phobia (n = 43)Fisher's exact testp
      Depressive disorders
       Past MDE12 (63.2%)9 (20.9%)10.49.003
       Present MDE4 (21.1%)2 (4.7%)4.06.066
       Dysthymia3 (15.8%)3 (7.0%)1.17.359
      Anxiety disorders
      Present anxiety disorder as classified by the DSM-5.
       Panic disorder5 (26.3%)1 (2.3%)8.68.009
       Agoraphobia10 (52.6%)2 (4.7%)19.44<0.001
       Specific phobia
      The types of specific phobias included: flight (n = 3), height (n = 6), blood (n = 4), closed spaces (n = 3), animals/insects (n = 5).
      8 (42.1%)5 (11.6%)7.39.015
       Social anxiety disorder3 (15.8%)6 (14%).0361.000
       GAD3 (15.8%)3 (7%)1.17.359
       Any anxiety disorder16 (84.2%)15 (34.9%)12.83.001
      Anxiety related disorders
      Present anxiety related disorders that are no longer classified as anxiety disorders according to DSM-5.
       OCD1 (5.3%)3 (7%).0641.000
       PTSD5 (26.3%)3 (7%)4.39.050
      History of panic attacks14 (73.7%)6 (14.0%)21.51<0.001
      MDE- major depressive episode, GAD- generalized anxiety disorder, OCD- obsessive compulsive disorder, PTSD- post traumatic stress disorder.
      1 Present anxiety disorder as classified by the DSM-5.
      2 The types of specific phobias included: flight (n = 3), height (n = 6), blood (n = 4), closed spaces (n = 3), animals/insects (n = 5).
      3 Present anxiety related disorders that are no longer classified as anxiety disorders according to DSM-5.
      Panic attacks were reported among 58.3% of patients with a diagnosis of comorbid PNES, whereas only 26% reported panic attacks among patients without PNES (Fisher's exact test=4.63; p = 0.043), and all patients with both comorbid PNES and panic attacks were diagnosed with seizure phobia.
      The quantitative prediction model for seizure phobia included disorders whose prevalence was significantly different between the groups: “past MDE” and “any anxiety disorder” (which relates to all anxiety disorders). PTSD was just on the limit of significance (p = 0.05) and thus did not enter the model. The prediction model is presented in Table 6. According to the model, the odds of having seizure phobia are 10.45 times higher if the patient reported any anxiety disorder, and 6.85 times higher if the patient had a history of MDE. This model correctly predicted having seizure phobia in 57.9% of the cases (sensitivity), not having seizure phobia in 95.3% of the cases (specificity), correctly identifying 83.9% of all cases. The explained variance of this model was R2 = 0.43.
      Table 6Logistic regression model based on anxiety and depression comorbidities that differentiate pwe diagnosed with seizure phobia from pwe without seizure phobia.
      BSEΧ2 (Wald)POR95% CI for OR
      Any anxiety disorder2.35.779.33.00210.452.32 - 47.14
      Past MDE1.93.707.58.0066.851.74 - 26.96
      Constant−3.05.7616.06<0.001
      SE- standard error, CI- confidence interval, OR- odds ratio, PWE- patients with epilepsy, MDE-major depressive episode.

      4. Discussion

      In this first study thoroughly characterizing the phenomenon of seizure phobia, we found its prevalence among our PWE group to be 27.5%. The diagnosis of seizure phobia was significantly associated with being female, comorbid anxiety disorders, a past MDE and comorbid PNES. However, seizure phobia was not associated with any epilepsy variables such as duration, etiology, type of seizures, location of epileptic foci, seizure activity, medications used, and drug resistance.

      4.1 Seizure phobia characteristics

      Participants with seizure phobia reported various situations which can trigger anxiety and avoidance behaviors that accompany these. A similar pattern of phobic fears and avoidance behaviors has been described in the literature among patients with other medical conditions, such as asthma [
      • Deshmukh V.M.
      • Toelle B.G.
      • Usherwood T.
      • et al.
      Anxiety, panic and adult asthma: a cognitive-behavioral perspective.
      ], diabetes mellitus [
      • Green L.
      • Feher M.
      • Catalan J.
      Fears and phobias in people with diabetes.
      ], and stroke [
      • Chun H.Y.
      • Whiteley W.N.
      • Dennis M.S.
      • et al.
      Anxiety After Stroke: the Importance of Subtyping.
      ]. These disorders are also characterized by unpredictable events which can occur in any place and at any time, and thus anxiety of certain situations and avoidance behaviors are to be expected. These differ from other specific phobias (i.e., arachnophobia, acrophobia, caniphobia etc.), wherein the phobic situations and accompanying avoidance behaviors are relatively confined.
      The key feature of specific phobia is that the fear or anxiety is circumscribed to the presence of a particular situation or object meaning that the level of anxiety can change abruptly depending on the level of threat the environment imposes [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. This differs from generalized anxiety disorder, a disorder of worry and apprehensive expectation, which is not object dependent. In seizure phobia, the key component is fear of having seizures, but the level of fear is object- dependent, and changes according to the level of exposure to the feared object. All patients with seizure phobia fear seizures, as this is a core criterion, but the level of baseline apprehensive worry when in a non-threatening environment may vary. This differs from AAS, a disorder of anxious anticipation of future seizures where the anxiety in not circumscribed to any object or situation [
      • Hingray C.
      • McGonigal A.
      • Kotwas I.
      • Micoulaud-Franchi J.A.
      The relationship between epilepsy and anxiety disorders.
      ]. It can be assumed that the more anxious a patient is about having a seizure the more he will be likely to develop a phobic disorder, but this an object for further research.
      Seizure phobia was found to significantly associate with a history of panic attacks. The essential feature of a panic attack is an abrupt surge of intense fear that reaches a peak within minutes, while panic disorder involves two cardinal features: unexpected panic attacks and anxious anticipation of future panic attacks [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. Thus, not all patients with panic attacks develop panic disorder, the lifetime prevalence of panic attacks and panic disorder being reported to be 9% and 2%, respectively [
      • Wittchen H.U.
      • Essau C.A.
      Epidemiology of panic disorder: progress and unresolved issues.
      ]. Since it is now known that panic attacks can occur in the context of any anxiety disorder as well as other mental disorders, a panic attacks specifier was added to the DSM-5 [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. Many patients with seizure phobia in our study revealed a history of panic attacks when anticipating seizures, and some of them developed a phobic fear related to specific bodily sensations such as dizziness. Some of these patients may also suffer from "epileptic panic disorder", a disorder presented by Hingray et al. wherein patients with AAS and seizure phobia interpret anxiety symptoms as the beginning of a seizure and develop an anxious anticipation and fear of panic attacks [
      • Hingray C.
      • McGonigal A.
      • Kotwas I.
      • Micoulaud-Franchi J.A.
      The relationship between epilepsy and anxiety disorders.
      ]. Further research is needed to characterize this disorder.
      Fear of seizures in agoraphobic situations was common in our cohort, and this is a known phenomenon in PWE [
      • Beyenburg S.
      • Mitchell A.J.
      • Schmidt D.
      • et al.
      Anxiety in patients with epilepsy: systematic review and suggestions for clinical management.
      ,
      • Krishnamoorthy E.S.
      • Trimble M.R.
      • Blumer D.
      The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on Psychobiology of Epilepsy.
      ]. The core feature of agoraphobia is that escape might be difficult, or help might not be available in the event they develop panic-like symptoms or other incapacitating or embarrassing symptoms [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. Patients with seizure phobia may fear agoraphobic situations due to fear that in case they experience a seizure it may be difficult to seek help or leave. In this case, both diagnoses- seizure phobia and agoraphobia- may be given.
      Although social phobia was not found to correlate with seizure phobia in our cohort, some patients reported that fear of seizures was evoked by social situations. Hingray et al. coined the term epileptic social phobia for social phobia in PWE defined as "excessive fear of being seen by others specifically during a seizure that interferes with normal life" [4]. The core feature of social phobia as defined by the DSM-5 is fear of situations wherein one could be embarrassed or ridiculed [
      American Psychiatric Association
      Anxiety disorders. In diagnostic and statistical manual of mental disorders, fifth edition.
      ]. However, fear of social situations among PWE can be related to fear of not getting the appropriate help in these social situations, which is more reminiscent of agoraphobia. It has been shown that patients with panic attacks and "secondary social phobia" have more characteristics of panic and agoraphobia rather than "primary social phobia" [
      • Perugi G.
      • Simonini E.
      • Savino M.
      • et al.
      Primary and secondary social phobia: psychopathologic and familial differentiations.
      ]. See also the diagram in Figure S2 for details on the relationship between seizure phobia and other disorders.

      4.2 Anxiety and depression

      The logistic regression model revealed a higher risk of having seizure phobia among patients with any anxiety disorder, as evaluated by the semi-structured interview. This may be due to higher trait or state anxiety among these patients. We suggest that high trait anxiety may interact with environmental triggers, such as traumatic seizure events, eliciting seizure‐related anxiety, in concordance with the diathesis-stress model [
      • Larsson M.R.
      • Bäckström M.
      • Johanson A.
      The interaction between baseline trait anxiety and trauma exposure as predictor of post-trauma symptoms of anxiety and insomnia.
      ]. High state anxiety may result in hypervigilance and an increased alertness to threat; increased alertness to potential seizure-related threats may increase anxiety via a forward feedback loop where hypervigilance and anxiety fuel each other, resulting in increased fear of seizures [
      • Kimble M.
      • Boxwala M.
      • Bean W.
      • et al.
      The impact of hypervigilance: evidence for a forward feedback loop.
      ]. The current study did not measure levels of state or trait anxiety directly, and future studies are needed to establish this relationship.
      We also found a significant relationship between seizure phobia and a history of, but not a current, MDE. Our results suggest that MDE, a known predictor of specific phobia [
      • Jacobson N.C.
      • Newman M.G.
      Anxiety and depression as bidirectional risk factors for one another: a meta-analysis of longitudinal studies.
      ], may predispose the development of seizure phobia, but does not maintain it. A recent systematic review found mood and anxiety disorders are the most common comorbidities in PWE, with a prevalence of a prevalence of 24.2%. of major depressive disorder [
      • Lu E.
      • Pyatka N.
      • Burant C.J.
      • Sajatovic M.
      Systematic literature review of psychiatric comorbidities in adults with epilepsy.
      ]. It is possible that a common vulnerability factor may contribute both to depression and seizure phobia, such as neurotic personality traits [
      • Bienvenu O.J.
      • Samuels J.F.
      • Costa P.T.
      • et al.
      Anxiety and depressive disorders and the five-factor model of personality: a higher- and lower-order personality trait investigation in a community sample.
      ]. However, these psychometric properties were not evaluated in this study and warrant further research.

      4.3 Gender

      We showed a significant association between female gender and seizure phobia, in line with the reported higher prevalence of specific phobia among women [
      • Fredrikson M.
      • Annas P.
      • Fischer H.
      • Wik G.
      Gender and age differences in the prevalence of specific fears and phobias.
      ]. However, on logistic regression analysis, gender was not a significant predictor of seizure phobia. Therefore, gender may be a confounding factor since both anxiety and depression, which strongly predicted seizure phobia in our model, are known to be more prevalent among women [
      • Seedat S.
      • Scott K.M.
      • Angermeyer M.C.
      • et al.
      Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys.
      ].

      4.4 Psychogenic non-epileptic seizures

      We found that seizure phobia was significantly associated with comorbid PNES, that PNES was significantly associated with panic attacks, and that all patients with both panic attacks and comorbid PNES were diagnosed with seizure phobia. Panic attacks are known to be prevalent among patients with PNES [

      Indranada A.M., Mullen S.A., Duncan R., et al. The association of panic and hyperventilation with psychogenic non-epileptic seizures: a systematic review and meta-analysis. Seizure. 2018 Jul;59:108–15.

      ], and patients with PNES were shown to have more ictal panic symptoms [
      • Hendrickson R.
      • Popescu A.
      • Dixit R.
      • Ghearing G.
      Bagic A. Panic attack symptoms differentiate patients with epilepsy from those with psychogenic nonepileptic spells (PNES).
      ]. Additionally, PWE with comorbid PNES were shown to have a greater sensitivity to threat than PWE without PNES [
      • Bakvis P.
      • Spinhoven P.
      • Roelofs K.
      Basal cortisol is positively correlated to threat vigilance in patients with psychogenic nonepileptic seizures.
      ]. Panic attacks and PNES are distinct entities, regarded as a component of anxiety disorders and as a conversion disorder, respectively. However, panic attacks and PNES share some traits, which may characterize patients with seizure phobia as well. Both patients with panic attacks and patients with PNES are characterized by higher attentiveness to bodily symptoms, and by a difficulty to interpret one's bodily states and feelings, or a tendency to interpret them catastrophically [
      • Moore P.M.
      • Baker G.A.
      Non-epileptic attack disorder: a psychological perspective.
      ,
      • Vein A.M.
      • Djukova G.M.
      • Vorobieva O.V.
      Is panic attack a mask of psychogenic seizures? A comparative analysis of phenomenology of psychogenic seizures and panic attacks.
      ]. Catastrophic misinterpretation of seizure-related bodily sensations may play a role in the development of seizure phobia, but this warrants further research. Seizure phobia may also constitute a possible link between panic attacks and PNES whereby panic symptoms triggered by seizure anticipation, such as hyperventilation, may induce a PNES [

      Indranada A.M., Mullen S.A., Duncan R., et al. The association of panic and hyperventilation with psychogenic non-epileptic seizures: a systematic review and meta-analysis. Seizure. 2018 Jul;59:108–15.

      ]. The relationship between seizure phobia and PNES calls for further investigation.

      4.5 Epilepsy variables

      Seizure activity in the past year, types of seizures, and drug resistance were not associated with seizure phobia. This suggests that contrary to our hypothesis, epilepsy severity is not associated with seizure phobia. The relationship between anxiety and epilepsy severity has been reported with conflicting findings [
      • Pham T.
      • Sauro K.M.
      • Patten S.B.
      • et al.
      The prevalence of anxiety and associated factors in persons with epilepsy.
      ,
      • LaGrant B.
      • Marquis B.O.
      • Berg A.T.
      • Grinspan Z.M.
      Depression and anxiety in children with epilepsy and other chronic health conditions: national estimates of prevalence and risk factors.
      ], possibly due to different measurement tools. One of the proposed key mechanisms in the etiology of specific phobia, is the attentional threat bias [
      • Wieser M.J.
      • Keil A.
      Attentional threat biases and their role in anxiety: a neurophysiological perspective.
      ], where patients may catastrophize or misinterpret threat-related stimuli. Based on our results, we suggest that it may not be the severity of the epilepsy that leads to the development of seizure phobia, but rather the exaggerated misinterpretations of seizure-related threats, regardless of how objectively severe they are.
      Psychiatric and behavioral side effects, including anxiety, are known to occur with anti-epileptic medications, especially with levetiracetam [
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • et al.
      Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.
      ], whereas other medications, such as valproic acid [
      • Bach D.R.
      • Korn C.W.
      • Vunder J.
      • Bantel A.
      Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.
      ], have anti-anxiety properties. In our study, there were no statistically significant differences between patients with seizure phobia and patients without seizure phobia with regards to medications taken, however this could be partly due to the small sample size of the study. Further research on a larger group is needed to understand the relative contribution of certain medications to the amplification or the alleviation of seizure phobia symptoms.

      4.6 Suggested etiology and management

      The etiology underlying comorbid epilepsy and anxiety disorders is multifaceted. However, common cognitive mechanisms, known to play a role in anxiety disorders, emerged as major themes in our cohort. Cognitive behavioral therapy (CBT) examines the relationships between thoughts, emotions, and specific events, and it has been proven to be effective for various disorders such as anxiety disorders [
      • Kaczkurkin A.N.
      • Foa E.B.
      Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence.
      ], depression [
      • Gautam M.
      • Tripathi A.
      • Deshmukh D.
      • Gaur M.
      Cognitive Behavioral Therapy for Depression.
      ], and PNES [
      • Kamil S.H.
      • Qureshi M.
      • Patel R.S.
      Cognitive behavioral therapy (CBT) in psychogenic non-epileptic seizures (PNES): a case report and literature review.
      ]. Several CBT techniques, including systematic desensitization and cognitive restructuring, were suggested as adjunctive therapies for epilepsy, with the goal of fostering an increased sense of self-control over seizure occurrence [
      • Leeman-Markowski B.A.
      • Schachter S.C.
      Cognitive and Behavioral Interventions in Epilepsy.
      ]. Systematic desensitization progressively exposes patients to stimuli that evoke fear of seizures, teaches relaxation techniques to counteract negative emotions, and reduces avoidance behaviors, which are key in fear maintenance [
      • Helbig-Lang S.
      • Petermann F
      Tolerate or eliminate? A systematic review on the effects of safety behaviors across anxiety disorders.
      ]. Additionally, through cognitive restructuring, patients may benefit from exploring their distorted cognitions and reframe negative thoughts related to seizure occurrence. Finally, the treatment of seizure phobia may warrant the involvement of family members, friends, and medical staff to reinforce positive modeling regarding attitudes towards the seizures and epilepsy at large.

      4.7 Limitations

      This study has several limitations. First, the diagnosis of seizure phobia was determined through a semi-structured clinical interview, which may be subject to bias by the interviewer. However, as this is a first study characterizing specific phobia, it allowed the collection of qualitative data regarding triggers and avoidance behaviors. Second, the generalizability of the results may be affected by the relatively small sample size, with a predominance of females, and from a tertiary center, where patients present with more severe and resistant cases. Additionally, this cohort had a relatively high proportion of patients with a comorbid diagnosis of PNES and epilepsy, confirmed by video-EEG monitoring, displaying both epileptic activity and events not correlated with epileptic activity. The study was performed in a tertiary epilepsy center adjacent to a neuropsychiatric clinic that specializes in treatment of PNES, which may have contributed to the relatively high prevalence of PNES in our cohort. Thus, the high prevalence of seizure phobia in this study could be the result of case selection bias, where a high number of patients with comorbid PNES were included. Further research in larger populations should be conducted. Finally, a history of ictal injuries or traumatic seizures was not assessed in the current study. This could have added valuable information regarding etiology and differential diagnosis and should be included in future studies.

      5. Conclusion

      Seizure phobia is a distinct clinical entity which may be more widespread than assumed, and is closely related to comorbid psychiatric disorders, rather than to neurological attributes of epilepsy. It is important that the medical personnel caring for PWE will be able to recognize this condition and will make efforts to manage its expression by means of education, psychosocial interventions and possibly changes in medications. The unique characteristics of the disorder, coupled with the implications of being diagnosed with epilepsy, calls for further research to evaluate the clinical qualities and etiology of seizure phobia. Development of appropriate screening tools and implementation of effective treatment interventions is warranted for individual patients, combined with large-scale population-targeted psychoeducation, aimed to mitigate the risk of developing seizure phobia in PWE.

      Declaration of Competing Interest

      None.

      Acknowledgements

      None.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Appendix. Supplementary materials

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