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Altered responsiveness in psychogenic nonepileptic seizures and its implication to underlying psychopathology

Open AccessPublished:October 13, 2017DOI:https://doi.org/10.1016/j.seizure.2017.10.011

      Highlights

      • Altered responsiveness during PNES is a common semiological sign.
      • It is associated to experiential avoidance, affect intolerance and lower resilience.
      • It was not explained by level of dissociation, history of trauma or PTSD.
      • Prior exposure to models of loss of consciousness may contribute to its development.

      Abstract

      Purpose

      Altered responsiveness during psychogenic nonepileptic seizures (PNES) is a distinct semiological feature that may signal a psychological vulnerability. We hypothesized that altered responsiveness is related to difficulties with emotion tolerance, experiential avoidance, difficulty coping, dissociation and trauma and prior experiences of loss of awareness.

      Methods

      71 patients with video-EEG confirmed PNES were divided into two groups based on their responsiveness at the time of the captured event during long-term monitoring. Demographic information, clinical history and self-rated questionnaires highlighting psychopathology were compared between the groups.

      Results

      47 patients (66%) had altered responsiveness during their captured event. Married or partnered subjects were more represented in the altered responsiveness group. Experiential avoidance, as measured by the Acceptance and Action Questionnaire-II, and affect intolerance, as measured by the Affective Style Questionnaire, were significantly higher in the altered responsiveness group. The Connor Davidson Resilience Scale was significantly higher among intact responsiveness subjects. Subjects with altered responsiveness were more likely to have a family history of seizures, comorbid headaches, and loss of consciousness (LOC) during traumatic brain injury. There were no differences in measures of dissociation, somatization, mood or anxiety, or presence of psychiatric comorbidities, including PTSD or history of trauma.

      Conclusion

      Altered responsiveness during PNES is a marker of lower emotional resilience or ability to tolerate emotions among patients with PNES. Emotion management may be an important therapeutic target for these patients. Prior experiences with LOC also contribute to the presence of altered responsiveness. Trauma and dissociation did not differentiate responsiveness during PNES.

      Keywords

      1. Introduction

      Psychogenic nonepileptic seizures (PNES) are seizure-like attacks that are due to a presumed underlying psychological etiology, and they are considered a subtype of conversion disorder in the DSM-5 [
      • American Psychiatric Association
      Diagnostic and Statistical Manual of Mental disorders.
      ]. PNES are the most common condition mistaken for epilepsy, and a substantial percentage of patients evaluated for uncontrolled seizures are ultimately diagnosed with PNES [
      • Benbadis S.R.
      • O’Neill E.
      • Tatum W.O.
      • Heriaud L.
      Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center.
      ].
      Semiology refers to the study of signs in a disease. In the case of PNES, presence of typical semiological features is primarily determined through objective observation of a typical episode. Diagnostic certainty is achieved when typical semiology is observed during video-EEG (v-EEG) monitoring with no accompanying electrographic features suggestive of epilepsy [
      • LaFrance Jr., W.C.
      • Baker G.A.
      • Duncan R.
      • Goldstein L.H.
      • Reuber M.
      (a) Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League Against Epilepsy Nonepileptic Seizures Task Force.
      ]. Therefore, the semiology of each PNES event has an important role in predicting diagnosis. Semiology also has safety implications and some studies have linked certain semiological signs to prognosis [
      • Arain A.M.
      • Hamadani A.M.
      • Islam S.
      • Abou-Khalil B.W.
      Predictors of early seizure remission after diagnosis of psychogenic nonepileptic seizures.
      ,
      • Chen D.K.
      • Izadyar S.
      • Wisdom N.M.
      • Collins R.L.
      • Franks R.
      • Hrachovy R.A.
      Intact vs impaired ictal sensorium: does it affect outcome of psychogenic nonepileptic events following disclosure of diagnosis.
      ,
      • Reuber M.
      • Pukrop R.
      • Bauer J.
      • Helmstaedter C.
      • Tessendorf N.
      • Elger C.E.
      Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients.
      ].
      In epilepsy, semiology provides helpful localizing information, especially when a seizure focus needs to be identified for surgical treatment. In contrast, what semiology suggests about underlying psychopathology in PNES is not known. Very few studies have focused on the relationship between semiology and psychopathology, as the latter is generally identified through a comprehensive neuropsychiatric evaluation. However, if clear correlations can be established between semiological features and the psychopathology underlying PNES then semiology may confer clinical and prognostic information which could inform treatment.
      There is currently limited data linking semiological features to underlying psychopathology. The few studies that have addressed semiology being linked to psychopathology showed that the ‘catatonic’ subtype (referring to motionless unresponsive episodes) had a more benign personality profile in the Minnesota Multiphasic Personality Inventory II (MMPI-II), with no clinical elevations, and lower ratings of pessimism compared to ‘motor’ subtypes [
      • Griffith N.M.
      • Szaflarski J.P.
      • Schefft B.K.
      • Isaradisaikul D.
      • Meckler J.M.
      • McNally K.A.
      • et al.
      Relationship between semiology of psychogenic nonepileptic seizures and Minnesota Multiphasic Personality Inventory profile.
      ,
      • Griffith N.M.
      • Smith K.M.
      • Schefft B.K.
      • Szaflarski J.P.
      • Privitera M.D.
      Optimism, pessimism, and neuropsychological performance across semiology-based subtypes of psychogenic nonepileptic seizures.
      ].
      The psychopathology underlying PNES has been suggested to imply a dissociative and avoidant response to hyperarousal [
      • Goldstein L.H.
      • Mellers J.D.C.
      Ictal symptoms of anxiety, avoidance behavior and dissociation in patients with dissociative seizures.
      ]. Compared to normative data, PNES patients have demonstrated lower acceptance of their emotional states [
      • Uliaszek A.A.
      • Prensky E.
      • Baslet G.
      Emotion regulation profiles in psychogenic non-epileptic seizures.
      ]. An impairment in the ability to tolerate and integrate emotional states is therefore a reasonable hypothetical underlying psychopathological mechanism in PNES.
      While subjective report of impairment of consciousness is common in PNES, studies suggest that impairment of consciousness tends to be less pronounced in PNES than in epilepsy [
      • Reuber M.
      • Kurthen M.
      Consciousness in non-epileptic attack disorder.
      ]. Lack of responsiveness during a PNES event indicates that relatedness to the environment is temporarily “shut down”, either partially or entirely, and it is an observation that patients and caregivers use to infer impairment of consciousness. Pathological dissociation has been implicated as one mechanism in altered responsiveness in PNES [
      • Reuber M.
      • Kurthen M.
      Consciousness in non-epileptic attack disorder.
      ]. Based on the mechanisms enumerated above in PNES in general, altered responsiveness may imply higher degrees of dissociation, affective intolerance and tendency to avoid emotional states.
      In this study, we describe and analyze two subgroups of PNES subjects: those with and without altered responsiveness during their events. Our objectives are to: 1) identify demographic, social and clinical differences between the two subgroups; and 2) identify differences in measures of emotion regulation between the two subgroups.
      We hypothesized that those PNES subjects with altered responsiveness during their episodes had, at the time of diagnosis, a decreased ability to tolerate their emotional states, compared to those PNES subjects without altered responsiveness. Patients with altered responsiveness would therefore score lower in scales measuring affect tolerance, and would score higher in scales of experiential avoidance, dissociation and have higher frequency of post-traumatic stress disorder (PTSD) and/or traumatic experiences. Measures that describe specific styles of managing emotional states will likely confirm affect intolerance as a feature that more clearly distinguish those PNES patients where ability to respond becomes compromised (as opposed to other affective styles such as concealing or adjusting that are unlikely to be tied to this specific semiological feature). Similarly, measures of experiential avoidance and dissociation will likely distinguish this subgroup of patients with altered responsiveness in PNES.
      We also hypothesized that PNES subjects with altered responsiveness would be more likely to have more frequent exposure to other models of altered consciousness such as personal or family history of epilepsy and/or loss of consciousness (LOC) during traumatic brain injury (TBI).

      2. Methods

      2.1 Subjects

      Seventy-one adult patients with v-EEG confirmed PNES were consecutively and prospectively recruited during their diagnostic long-term monitoring (LTM) admission, or during their first outpatient neuropsychiatric evaluation (if such evaluation had not taken place during the LTM admission). Subjects with comorbid documented epilepsy (as verified by interictal EEG suggestive of active epilepsy and/or as per the expert opinion of the treating epileptologist) were allowed in the study.
      Recruitment took place at Brigham and Women’s Hospital in Boston, Massachusetts, between January 2013 and May 2015. All subjects provided informed consent for research participation in accord with the local internal review board (IRB).
      Subjects were divided into two groups based on their level of responsiveness during the captured event during their diagnostic v-EEG. Altered responsiveness was defined as the patient not responding (verbally or otherwise) and not remembering three words given to them during at least one of their v-EEG captured events.

      2.2 Measures

      Data on demographic and clinical factors were obtained with a semi-structured neuropsychiatric interview by a single neuropsychiatrist (GB). Self-rating questionnaires were used to obtain measures of psychopathology and underlying psychological mechanisms. These data were collected during the initial neuropsychiatric evaluation.
      Demographic variables obtained during the interview include location of evaluation, age, sex, ethnicity, years of education, marital status and employment status. Clinical variables obtained during the interview include comorbid documented epilepsy, intellectual disability, history of a prior diagnosis of PNES, family history of epilepsy, age of onset of PNES, delay in diagnosis, frequency of events, reported duration of usual event, reported duration of longest event, reported number of symptoms per event, history of TBI (and presence of LOC during TBI). Psychiatric clinical variables obtained during the interview include active major depression, active post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder, subjective cognitive complaints, borderline personality disorder, past suicide attempts, family psychiatric history and history of trauma/abuse.

      2.3 Self-report questionnaires

      The Beck Depression Inventory-II (BDI-II) is a 21-item self-report scale that measures depressive symptoms over the preceding 2 weeks and was developed to assess DSM-IV depressive symptoms [
      • Beck A.T.
      • Steer R.A.
      • Brown G.K.
      Manual for the Beck Depression Inventory II.
      ]. The BDI-II has been shown to have good internal consistency, with a coefficient α of 0.91 for an outpatient population [
      • Beck A.T.
      • Steer R.A.
      • Ball R.
      • Ranieri W.
      Comparison of Beck Depression Inventories IA and II in psychiatric outpatients.
      ].
      The Dissociative Experiences Scale (DES) is a 28-item self-report questionnaire designed to assess the current degree of dissociative experiences using an 11-point multiple-choice response format that ranges from 0% to 100% [
      • Bernstein E.
      • Putnam F.W.
      Development, reliability and validity of a dissociation scale.
      ]. Higher scores indicate likelihood of a dissociative disorder. Factor analysis has identified subscales that specifically distinguish clinical categories, depersonalization/derealization, amnestic dissociation and absorption and imaginative involvement. Internal consistency of the DES was shown to be quite high; in 16 studies, the mean coefficient α was 0.93 [
      • Van I.Jzendoorn M.
      • Schuengel C.
      The measurement of dissociation in normal and clinical populations: meta-analytic validation of the Dissociative Experiences Scale (DES).
      ].
      The depression, anxiety and stress symptoms scale (DASS) is a 42-item self-report questionnaire that measures depression (DASS-D), anxiety (DASS-A), and stress (DASS-S) levels over the preceding week [
      • Lovibond S.H.
      • Lovibond P.F.
      Manual for the Depression Anxiety Stress Scales.
      ]. The DASS subscales (anxiety and depression, respectively) have been shown to correlate highly with the Beck anxiety inventory (r = 0.81) and Beck Depression Inventory (r = 0.74) [
      • Lovibond P.F.
      • Lovibond S.H.
      The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories.
      ]. We only scored those items specific for the anxiety and stress subscales since depression severity was already captured with the BDI-II. In this study we selected to use the BDI-II rather than the Depression subscale of the DASS as a measure of depression because the BDI-II is consistently given to all patients admitted to our LTM unit and therefore readily available for most of them.
      The Patient Health Questionnaire 15 (PHQ-15) is a 15-item self-rated instrument that assesses the level of distress caused by different somatic symptoms over the preceding 4 weeks; severity is rated as 0 (“not at all bothered”), 1 (“bothered a little”), or 2 (“bothered a lot”) [
      • Kroenke K.
      • Spitzer R.L.
      • Williams J.B.W.
      The PHQ-15: validity of a new measure for evaluating somatic symptom severity.
      ]. The PHQ-15 has shown acceptable internal reliability across different ethnic groups (coefficient α = 0.79) and has been found to be associated with medically unexplained symptoms and psychological distress [
      • Interian A.
      • Allen L.A.
      • Gara M.A.
      • Escobar J.I.
      • Diaz-Martinez A.M.
      Somatic complaints in primary care: further examining the validity of the Patient Health Questionnaire (PHQ-15).
      ].
      The Acceptance and Action Questionnaire-II (AAQ-II) is a 7-item self-report questionnaire that measures psychological inflexibility, or experiential avoidance [
      • Hayes S.C.
      • Strosahl K.D.
      • Wilson K.G.
      • Bissett R.T.
      • Pistorello J.
      • Toarmino D.
      • et al.
      Measuring experiential avoidance: a preliminary test of a working model.
      ]. Experiential avoidance is a concept derived from Acceptance and Commitment Therapy (ACT), a subtype of mindfulness-based psychotherapy, and posits that psychopathology is the result of patients’ rigidly and excessively ‘avoiding’ situations or stimuli that may be uncomfortable. Internal consistency is good, with a mean coefficient α of 0.84 from a variety of sample populations. Higher rates of psychological inflexibility, as measured by the AAQ-II, predict mental health problems and work absences [
      • Bond F.W.
      • Hayes S.C.
      • Baer R.A.
      • Carpenter K.M.
      • Guenole N.
      • Orcutt H.K.
      • et al.
      Preliminary psychometric properties of the Acceptance and Action Questionnaire-II: a revised measure of psychological inflexibility and experiential avoidance.
      ].
      The Affective Style Questionnaire (ASQ) is a 20-item self-report questionnaire that measures individual differences in emotion regulation. Three general strategies to handle emotional reactions are identified and supported by factor analysis of this questionnaire: 1) adjust affect to adapt to the situation, 2) conceal affect and 3) tolerate and accept emotions. There is no total score for the scale, since the three subscales show specific and distinct styles of managing affective states. The internal consistency for each subscale is satisfactory [
      • Hofmann S.G.
      • Kashdan T.B.
      The affective style questionnaire: development and psychometric properties.
      ].
      The Connor Davidson Resilience Scale (CD-RISC) is a 25-item self-report questionnaire that measures a subject’s resilience in the face of difficult life situations, also related to stress coping ability. The scale has been used in a number of clinical and non-clinical populations. The scale has sound psychometric properties, including a coefficient α of 0.89 for a general population sample [
      • Connor K.M.
      • Davidson J.R.
      Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC).
      ].

      2.4 Statistical analysis

      IBM SPSS software version 23.0 was used to perform chi-square analyses for categorical variables and analysis of variance (ANOVA) for continuous variables between the two groups. The Shapiro-Wilk test was used to test for normal distribution. Deviations from normality are noted in the tables when applicable. ANOVAs are considered to be robust enough to moderate deviations from normality under the central limit theorem.

      3. Results

      3.1 Group allocation

      Of the 71 PNES subjects prospectively recruited, 47 (66%) showed evidence of altered responsiveness during PNES episodes versus 24 (34%) who did not. The following analyses compared these two groups of PNES subjects.

      3.2 Demographic variables

      There was no difference between the altered versus intact responsiveness groups in terms of the location of evaluation, age at time of evaluation, sex, ethnicity or years of education. There was a significant difference in married/living-in partner status with a greater percentage in the group with altered responsiveness. (Table 1).
      Table 1Demographic variables.
      Demographic VariableAltered responsiveness (n = 47; 66%)Intact responsiveness (n = 24; 34%)Statisticsp
      Location first evaluationPearson Chi-Sq = 1.3650.29
      DF 1
       EMUn = 42 (89.4%)n = 19 (79.2%)
       Outpatientn = 5 (10.6%)n = 5 (20.8%)
      Age at time of first evaluationmean = 38.15 (SD 11.23)mean = 39.13 (SD 14.26)F = 0.10.75
      95% CI 34.85–41.4495% CI 33.10–45.15DF 1
      Sex (female)n = 42 (91.7%)n = 22 (89.4%)Pearson Chi-Sq = 0.0951.00
      DF 1
      EthnicityPearson Chi-Sq = 4.1250.25
      DF 3
       Whiten = 38 (80.9%)n = 18 (75%)
       Blackn = 6 (12.8%)n = 3 (12.5%)
       Hispanicn = 3 (6.4%)n = 1 (4.2%)
       Othern = 0 (0%)n = 2 (8.3%)
      Years of educationmean = 13.00 (SD 2.54)mean = 13.73 (SD 3.27)F = 1.0750.31
      95% CI 12.26–13.7595% CI 12.35–15.11DF 1
      Marital statusPearson Chi-Sq = 14.4830.006
      p<0.05.
      DF 4
       Never marriedn = 12 (25.5%)n = 9 (37.5%)
       Marriedn = 17 (36.2%)n = 7 (29.2%)
       Living-in partnern = 14 (29.8%)n = 0 (0%)
       Separated/divorcedn = 4 (8.5%)n = 7 (29.2%)
       Widown = 0 (0%)n = 1 (4.2%)
      Employment StatusPearson Chi-Sq = 9.0460.06
      p=0.051–0.1.
      DF 4
       Employed full timen = 10 (21.3%)n = 3 (12.5%)
       Employed part timen = 7 (14.9%)n = 2 (8.3%)
       Unemployedn = 12 (25.5%)n = 6 (25%)
       Disabledn = 18 (38.3%)n = 9 (37.5%)
       Studentn = 0 (0%)n = 4 (16.7%)
      EMU = epilepsy monitoring unit.
      * p < 0.05.
      ^ p = 0.051–0.1.

      3.3 Clinical variables

      There was no difference between the altered versus intact responsiveness groups in terms of delay in diagnosis, frequency of events per week, age of onset, percentage of comorbid documented epilepsy, previous PNES diagnosis, or history of TBI (Table 2, Fig. 1). Comorbid documented epilepsy was diagnosed in 5 subjects in the altered responsiveness group (10.6%) and 4 subjects in the intact responsiveness group (16.7%), a difference that was not statistically significant and consistent with previous descriptions of PNES populations [
      • Wong V.S.S.
      • Salinsky M.
      Neurologic and medical factors.
      ]. The usual duration of events and the reported duration of the longest event were both significantly longer in the intact responsiveness group, although these variables were not normally distributed. Subjects with altered responsiveness had a greater number of reported symptoms per event. Family history of seizures was more common in those with altered responsiveness (53.2%) compared to those with intact responsiveness (20.8%) (p = 0.01). Intellectual disability was identified in 14.9% of the altered responsiveness group but in none of the patients with intact responsiveness, which showed a trend towards significance (p = 0.09). Among those who reported a history of TBI, LOC during TBI was reported in 96% of the 25 subjects with altered responsiveness and in 52.9% of the 17 subjects with intact responsiveness (p = 001). These findings support our hypothesis that prior exposure to LOC, including family history of epilepsy and a prior LOC during a TBI, increases the likelihood of altered responsiveness during a PNES event. Headaches were significantly more common in the altered responsiveness group (83.0% versus 58.3%, p = 0.04), but the difference did not reach statistical significance for other pain syndromes. There were no statistically significant differences in psychiatric clinical variables between the two groups, although there was trend towards a higher frequency of panic disorder among the altered (48.9%) versus intact responsiveness group (25%) (p = 0.07) (Fig. 2). Rates of trauma or abuse history or active PTSD symptoms did not differ between the two responsiveness groups.
      Table 2Clinical variables.
      Clinical VariablesAltered responsiveness (n = 47)Intact responsiveness (n = 24)F-valueDFp
      mean (SD)95% CImean (SD)95% CI
      Delay in diagnosis (months)63.75 (104.30)
      Not normally distributed.
      33.13–94.3880.07 (152.71)
      Not normally distributed.
      14.03–146.10.27610.60
      Frequency of events per week11.94 (23.78)
      Not normally distributed.
      4.96–18.9221.74 (71.05)
      Not normally distributed.
      −8.26 to 51.740.74110.39
      Usual duration of event (min)6.62 (9.70)
      Not normally distributed.
      3.77–9.4743.18 (85.08)
      Not normally distributed.
      7.24–79.118.57610.01
      p<0.05.
      Duration of longest event (min)25.33 (54.33)
      Not normally distributed.
      9.01–41.66390.47 (1023.17)
      Not normally distributed.
      −41.58 to 822.525.77610.02
      p<0.05.
      Age of onset32.58 (12.27)28.97–36.1831.58 (15.89)24.87–38.300.08510.77
      Number of symptoms per event7.64 (2.10)
      Not normally distributed.
      7.03–8.255.42 (2.19)4.49–6.3417.64210.00
      p<0.05.
      a Not normally distributed.
      * p < 0.05.

      3.4 Self-report questionnaires

      None of the scales measuring severity of depression, anxiety, stress, somatic complaints or dissociation differed between the two responsiveness groups (Table 3). Separate analysis of the DES subscales showed no difference between the groups. The AAQ-II was significantly higher in the altered responsiveness (28.98, SD 12.15) compared to the intact responsiveness group (21.56, SD 10.61) (p = 0.04). This indicates higher degree of psychological inflexibility or experiential avoidance in those patients who do not respond during their events. Of the three subscales in the ASQ, the Tolerating subscale was significantly lower in the altered responsiveness (13.83; SD 3.70) versus intact responsiveness group (16.71; SD 3.50) (p = 0.01). This indicates that those patients not responding during their events have at baseline lower ability to tolerate their emotions. The ability to adjust to or to conceal emotional states did not differ between the two responsiveness groups. These results support our initial hypotheses of a decreased ability to tolerate intense emotional states among those PNES patients with altered responsiveness, which leads to more experiential avoidance. Finally, the CD-RISC was higher among those PNES patients with intact responsiveness (67.88; SD 17.31) compared to those with altered responsiveness (55.98; SD 18.14) (p = 0.03).
      Table 3Self-report questionnaires.
      QuestionnairesAltered responsivenessIntact responsivenessF-valueDFp
      nMean (SD)95% CInMean (SD)95% CI
      BDI-II2518.68 (11.61)13.89–23.471516.13 (12.85)9.02–23.250.41610.52
      DASS-A3115.63 (9.86)
      Not normally distributed.
      12.01–19.241713.59 (9.21)8.85–18.320.49310.49
      DASS-S3117.31 (12.18)12.84–21.781714.59 (9.86)9.52–19.660.62110.44
      PHQ-153013.03 (6.20)10.72–15.351712.65 (6.30)9.41–15.890.04210.84
      DES2217.10 (11.74)11.90–22.311511.99 (12.85)4.87–19.111.56810.22
      AAQ-II3128.98 (12.15)24.53–33.441721.56 (10.61)16.11–27.014.47110.04
      p<0.05.
      ASQ – Concealing2926.62 (6.03)24.33–28.911624.31 (7.36)20.39–28.241.29110.26
      ASQ – Adjusting3116.32 (5.15)14.43–18.211617.88 (5.01)15.21–20.540.97810.33
      ASQ – Tolerating3013.83 (3.70)12.45–15.211716.71 (3.50)14.91–18.504.47110.01
      p<0.05.
      CDRS2955.98 (18.14)49.08–62.881767.88 (17.31)58.98–76.784.76610.03
      p<0.05.
      Because not all measures could be obtained in all subjects, the n is shown for each measure.
      a Not normally distributed.
      * p < 0.05.

      4. Discussion

      Event semiology plays a key role in making the diagnosis of PNES [
      • LaFrance Jr., W.C.
      • Baker G.A.
      • Duncan R.
      • Goldstein L.H.
      • Reuber M.
      (a) Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League Against Epilepsy Nonepileptic Seizures Task Force.
      ]. Semiology also has safety implications, particularly altered responsiveness. For instance, if a patient becomes unresponsive or loses motor control without a prolonged period of warning symptoms during their PNES episodes, patients should follow the same driving restrictions as those with active epilepsy.
      Semiology provides important diagnostic information to help support a diagnosis of PNES, and the way consciousness may be altered in PNES can be a significant differentiating semiological feature. Consciousness is a difficult experience to define and measure, and two specific components have been described as part of it: arousal and awareness of content. Neurological conditions may present with similarly decreased arousal and awareness (such as in coma or generalized seizures), variable arousal and preserved awareness of content (such as in complex partial seizures with vivid experiential phenomena), or apparent awake state and impaired awareness of purposeful actions (such as in sleepwalking) [
      • Cavanna A.E.
      • Shah S.
      • Eddy C.M.
      • Williams A.
      • Rickards H.
      Consciousness: a neurological perspective.
      ]. In PNES, level of arousal was shown to be significantly higher than in generalized seizures, and subjective awareness was significantly higher than in temporal lobe seizures. When compared to an epilepsy group, PNES subjects had greater level of arousal and more vivid subjective experiences during their events [
      • Ali F.
      • Rickards H.
      • Bagary M.
      • Greenhill L.
      • McCorry D.
      • Cavanna A.E.
      Ictal consciousness in epilepsy and nonepileptic attack disorder.
      ]. The degree to which these different components of consciousness are altered provides information differentiating PNES from epileptic seizures using patients’ responses during their events and descriptions of their experiences.
      The role of semiology in predicting outcome in PNES is less clear at this time. One study showed that those patients with altered responsiveness during PNES reported the same or worse intensity and frequency of their events at two follow-up periods of up to 9 months [
      • Chen D.K.
      • Izadyar S.
      • Wisdom N.M.
      • Collins R.L.
      • Franks R.
      • Hrachovy R.A.
      Intact vs impaired ictal sensorium: does it affect outcome of psychogenic nonepileptic events following disclosure of diagnosis.
      ]. Other studies have shown that those patients with more vigorous movements tend to have less favorable outcomes [
      • Arain A.M.
      • Hamadani A.M.
      • Islam S.
      • Abou-Khalil B.W.
      Predictors of early seizure remission after diagnosis of psychogenic nonepileptic seizures.
      ,
      • Reuber M.
      • Pukrop R.
      • Bauer J.
      • Helmstaedter C.
      • Tessendorf N.
      • Elger C.E.
      Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients.
      ,
      • Selwa L.M.
      • Geyer J.
      • Nikakthar N.
      • Brown M.B.
      • Schuh L.A.
      • Drury I.
      Nonepileptic seizure outcome varies by type of spell and duration of illness.
      ].
      Certain semiological signs may offer a clue about the underlying psychopathology [
      • Griffith N.M.
      • Szaflarski J.P.
      • Schefft B.K.
      • Isaradisaikul D.
      • Meckler J.M.
      • McNally K.A.
      • et al.
      Relationship between semiology of psychogenic nonepileptic seizures and Minnesota Multiphasic Personality Inventory profile.
      ,
      • Griffith N.M.
      • Smith K.M.
      • Schefft B.K.
      • Szaflarski J.P.
      • Privitera M.D.
      Optimism, pessimism, and neuropsychological performance across semiology-based subtypes of psychogenic nonepileptic seizures.
      ]. Altered responsiveness during PNES is common. In one study, less than 3% of patients with PNES were both responsive and aware during their episodes [
      • Reuber M.
      • Kurthen M.
      Consciousness in non-epileptic attack disorder.
      ]. Because lack of responsiveness is such a striking feature, we hypothesized that such a sign may be a “raw” signal of an underlying psychopathological process. Our prediction that lack of responsiveness would be associated with lower degree of affect tolerance and higher experiential avoidance was confirmed by our data. However, neither dissociation nor its subcomponents seemed to distinguish PNES patients with altered versus intact responsiveness. This is an interesting and unexpected finding. It may indicate that dissociation, defined as an intrapsychic defense that includes behavioral automatization, compartmentalization and identity alteration/depersonalization [
      • Putnam F.W.
      Dissociation in children and adolescents.
      ], is commonly pervasive across different semiologies in PNES. One possible explanation is that dissociation is present regardless of level of responsiveness, because even during a PNES event with intact responsiveness, there is some degree of compartmentalization and detachment of other somatic or cognitive control functions. Instead, patients’ inability to tolerate their discomfort around affective states as well their tendency to avoid such experiences have a more specific role in leading patients to cognitively disengage from the surrounding environment, as if this altered responsiveness was a ‘protective’ measure against an intolerable experience. Patients with intact responsiveness still experience difficulties managing their emotions, but may be more able to tolerate them. Impairment of consciousness in PNES has previously been suggested to be related to dissociation but other mechanisms may also contribute to alteration of awareness [
      • Roberts N.A.
      • Reuber M.
      Alterations of consciousness in psychogenic nonepileptic seizures: emotion, emotion regulation and dissociation.
      ].
      Because altered responsiveness may provide an indirect, “raw” measure of patients’ baseline response to affective states, this finding may inform certain aspects of treatment. Training in affect tolerance and enhancing psychological flexibility may be especially important treatment targets for those patients with altered responsiveness during PNES. This can be complementary, rather than exclusionary, of the treatments that currently have stronger evidence in the literature for PNES, such as cognitive behavioral therapy (CBT) [
      • LaFrance Jr, W.C.
      • Reuber M.
      • Goldstein L.H.
      (b) Management of psychogenic nonepileptic seizures.
      ].
      The higher baseline resilience ratings in those PNES patients with intact responsiveness may suggest that alteration of responsiveness is linked to more difficulty coping with life struggles in general. Whether this suggests better outcomes in those with intact responsiveness requires a long-term follow-up study.
      We also found that family history of seizures (but not personal history of epilepsy) and LOC during TBI (in the subset of PNES patients who suffered TBI) were more common among the altered responsiveness group. Familiarity with altered awareness may model its involuntary expression in the form of a symptom, as a previously observed or learned behavior. This in no way implies that altered responsiveness is a “voluntary” symptom, but provides support to the “cognitive hierarchy model” hypothesis for conversion disorder [
      • Brown R.J.
      Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model.
      ]. According to this theory, functional neurological symptoms represent an alteration of cognitive schemata of a variety of neurological functions, and cognitive schemata can be highly influenced by prior experiences [
      • Brown R.J.
      Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model.
      ]. We did not investigate if patients with reported family history of seizures had specifically witnessed seizures and, if so, if they indeed included LOC, which would have provided a more direct measure of witnessed LOC contributing to a “disease model”.
      We did not anticipate that marital (or partnered) status would differ between the two responsiveness groups. There may be an interpersonal value to altered responsiveness given its more frequent presence in married (or partnered) patients. We did not screen for presence of witnesses during events in this study, which could have provided a more meaningful and direct measure of the interpersonal function of this symptom.
      Our study has some limitations. While other semiological signs could have been included in the analysis (such as motor phenomena or eye closure), doing so would have created several smaller groups which would have limited our power to detect intergroup differences. Instead, we chose to select one of the most prominent semiological features in PNES and one whose psychopathological significance could potentially guide therapeutic interventions. Some studies have separated “awareness” (able to recall all seizure experience) from “responsiveness” (ability to respond with or without ability to recollect later) [
      • Reuber M.
      • Kurthen M.
      Consciousness in non-epileptic attack disorder.
      ]. Our measure of responsiveness focused on objective observations of lack of response and later ability to recall specific information. It did not specifically distinguish the ability to recall all the seizure activity. Another limitation is the lack of a healthy control group which limits our ability to determine how each PNES subgroup compares to those without major psychopathology. In terms of our statistical analysis, it should be noted that a correction for multiple comparisons was not performed, therefore increasing the risk of type I errors. We consider this to be an exploratory study in a hitherto unstudied area (psychological correlates of altered responsiveness among patients with PNES). As such we believe that it is important to identify potential correlates of altered responsiveness for future studies (to avoid type II errors). The correlations identified in this study should therefore be tested and replicated in future studies. Lastly, the two groups are unequal in distribution given the naturalistic nature of the study. This provides a more realistic picture of how common altered responsiveness in PNES is encountered in clinical practice.
      Semiological signs in PNES should not replace a comprehensive neuropsychiatric examination. Altered responsiveness gives clinicians some clue regarding psychopathology that will steer them to investigate further during the clinical interview. Ultimately, the relationship between altered awareness and different clinical variables is complex and any meaning should be considered in the context of a careful clinical examination.

      5. Conclusion

      The role of semiology of PNES in uncovering underlying psychopathological mechanisms has not been previously explored. Our findings suggest that altered responsiveness in PNES may provide insight into psychopathology as it correlates with lower affect tolerance and acceptance, lower resilience, prior exposure to disease models and it may have interactional value. The presence of altered responsiveness in PNES may therefore help to guide treatment goals, and in particular may support the addition of emotion management skills during therapy. A comprehensive neuropsychiatric evaluation still remains necessary to provide a psychological framework for PNES to inform treatment.
      This research did not receive any specific grant from funding agencies in the public, commercial or non-for-profit sectors.

      Conflict of interest statement

      None.

      Funding

      The authors report that there are no any financial and personal relationships with other people or organizations that could inappropriately influence or bias their work.

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental disorders.
        fifth edition. American Psychiatric Association, Arlington, VA2013
        • Benbadis S.R.
        • O’Neill E.
        • Tatum W.O.
        • Heriaud L.
        Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center.
        Epilepsia. 2004; 45: 1150-1153
        • LaFrance Jr., W.C.
        • Baker G.A.
        • Duncan R.
        • Goldstein L.H.
        • Reuber M.
        (a) Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League Against Epilepsy Nonepileptic Seizures Task Force.
        Epilepsia. 2013; 54: 2005-2018
        • Arain A.M.
        • Hamadani A.M.
        • Islam S.
        • Abou-Khalil B.W.
        Predictors of early seizure remission after diagnosis of psychogenic nonepileptic seizures.
        Epilepsy Behav. 2007; 11: 409-412
        • Chen D.K.
        • Izadyar S.
        • Wisdom N.M.
        • Collins R.L.
        • Franks R.
        • Hrachovy R.A.
        Intact vs impaired ictal sensorium: does it affect outcome of psychogenic nonepileptic events following disclosure of diagnosis.
        Epilepsy Behav. 2012; 24: 30-35
        • Reuber M.
        • Pukrop R.
        • Bauer J.
        • Helmstaedter C.
        • Tessendorf N.
        • Elger C.E.
        Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients.
        Ann Neurol. 2003; 53: 305-311
        • Griffith N.M.
        • Szaflarski J.P.
        • Schefft B.K.
        • Isaradisaikul D.
        • Meckler J.M.
        • McNally K.A.
        • et al.
        Relationship between semiology of psychogenic nonepileptic seizures and Minnesota Multiphasic Personality Inventory profile.
        Epilepsy Behav. 2007; 11: 105-111
        • Griffith N.M.
        • Smith K.M.
        • Schefft B.K.
        • Szaflarski J.P.
        • Privitera M.D.
        Optimism, pessimism, and neuropsychological performance across semiology-based subtypes of psychogenic nonepileptic seizures.
        Epilepsy Behav. 2008; 13: 478-484
        • Goldstein L.H.
        • Mellers J.D.C.
        Ictal symptoms of anxiety, avoidance behavior and dissociation in patients with dissociative seizures.
        J Neurol Neursurg Psychiatry. 2006; 77: 616-621
        • Uliaszek A.A.
        • Prensky E.
        • Baslet G.
        Emotion regulation profiles in psychogenic non-epileptic seizures.
        Epilepsy Behav. 2012; 23: 364-369
        • Reuber M.
        • Kurthen M.
        Consciousness in non-epileptic attack disorder.
        Behav Neurol. 2011; 24: 95-106
        • Beck A.T.
        • Steer R.A.
        • Brown G.K.
        Manual for the Beck Depression Inventory II.
        Psychological Corp, San Antonio, TX1996
        • Beck A.T.
        • Steer R.A.
        • Ball R.
        • Ranieri W.
        Comparison of Beck Depression Inventories IA and II in psychiatric outpatients.
        J Pers Assess. 1996; 67: 588-597
        • Bernstein E.
        • Putnam F.W.
        Development, reliability and validity of a dissociation scale.
        J Nerv Ment Dis. 1986; 174: 491-497
        • Van I.Jzendoorn M.
        • Schuengel C.
        The measurement of dissociation in normal and clinical populations: meta-analytic validation of the Dissociative Experiences Scale (DES).
        Clin Psychol Rev. 1996; 16: 365-382
        • Lovibond S.H.
        • Lovibond P.F.
        Manual for the Depression Anxiety Stress Scales.
        second edition. Psychology Foundation, Sydney1995
        • Lovibond P.F.
        • Lovibond S.H.
        The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories.
        Behav Res Ther. 1995; 33: 335-343
        • Kroenke K.
        • Spitzer R.L.
        • Williams J.B.W.
        The PHQ-15: validity of a new measure for evaluating somatic symptom severity.
        Psychosom Med. 2002; 64: 258-266
        • Interian A.
        • Allen L.A.
        • Gara M.A.
        • Escobar J.I.
        • Diaz-Martinez A.M.
        Somatic complaints in primary care: further examining the validity of the Patient Health Questionnaire (PHQ-15).
        Psychosomatics. 2006; 47: 392-398
        • Hayes S.C.
        • Strosahl K.D.
        • Wilson K.G.
        • Bissett R.T.
        • Pistorello J.
        • Toarmino D.
        • et al.
        Measuring experiential avoidance: a preliminary test of a working model.
        Psychol Rec. 2004; 54: 553-578
        • Bond F.W.
        • Hayes S.C.
        • Baer R.A.
        • Carpenter K.M.
        • Guenole N.
        • Orcutt H.K.
        • et al.
        Preliminary psychometric properties of the Acceptance and Action Questionnaire-II: a revised measure of psychological inflexibility and experiential avoidance.
        Behav Ther. 2011; 42: 676-688https://doi.org/10.1016/j.beth.2011.03.007
        • Hofmann S.G.
        • Kashdan T.B.
        The affective style questionnaire: development and psychometric properties.
        J Psychopathol Behav Assess. 2010; 32: 255-263
        • Connor K.M.
        • Davidson J.R.
        Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC).
        Depress Anxiety. 2003; 18: 76-82
        • Wong V.S.S.
        • Salinsky M.
        Neurologic and medical factors.
        in: Dworetzky B.D. Baslet G. Psychogenic nonepileptic seizures: Towards the Integration of Care. Oxford University Press, New York, NY2017
        • Cavanna A.E.
        • Shah S.
        • Eddy C.M.
        • Williams A.
        • Rickards H.
        Consciousness: a neurological perspective.
        Behav Neurol. 2011; 24: 107-116
        • Ali F.
        • Rickards H.
        • Bagary M.
        • Greenhill L.
        • McCorry D.
        • Cavanna A.E.
        Ictal consciousness in epilepsy and nonepileptic attack disorder.
        Epilepsy Behav. 2010; 19: 522-525
        • Selwa L.M.
        • Geyer J.
        • Nikakthar N.
        • Brown M.B.
        • Schuh L.A.
        • Drury I.
        Nonepileptic seizure outcome varies by type of spell and duration of illness.
        Epilepsia. 2000; 41: 1330-1334
        • Putnam F.W.
        Dissociation in children and adolescents.
        New York, NY, Guilford1997
        • Roberts N.A.
        • Reuber M.
        Alterations of consciousness in psychogenic nonepileptic seizures: emotion, emotion regulation and dissociation.
        Epilepsy Behav. 2014; 30: 43-49https://doi.org/10.1016/j.yebeh.2013.09.035
        • LaFrance Jr, W.C.
        • Reuber M.
        • Goldstein L.H.
        (b) Management of psychogenic nonepileptic seizures.
        Epilepsia. 2013; 54: 53-67
        • Brown R.J.
        Psychological mechanisms of medically unexplained symptoms: an integrative conceptual model.
        Psychol Bull. 2004; 130: 793-812