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Behavioural adjustment in seizure-free epilepsy patients on monotherapy

Open ArchivePublished:February 13, 2008DOI:https://doi.org/10.1016/j.seizure.2007.12.002

      Summary

      Purpose

      Risk of depression, anxiety, and reduced quality of life is elevated in epilepsy patients, due to a range of factors including aetiology, structural brain lesions, seizure worry, epilepsy surgery, hereditary factors, psychosocial factors, and possible adverse effects of antiepileptic drugs (AEDs). Studies on the relationships between epilepsy-related variables and behavioural adjustment have been mainly conducted on patients with persisting seizures, whereas the present study investigated behavioural function in epilepsy patients seizure-free for more than 2 years on monotherapy.

      Methods

      Adults with epilepsy on AED monotherapy and without epileptic seizures for at least 2 years (n = 126) were assessed with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), in addition to MRI and EEG.

      Results

      Group analysis found mean MMPI-2 scores on all the clinical and content scales to be within the normal range. Abnormally elevated scores on scales measuring aspects of depression, health-related concerns, low self-esteem, negative treatment indicators, and physical complaints were recorded in a higher proportion of patients than would normally be expected. Multiple regression analysis showed that MRI pathology was a significant predictor for an abnormally poor score on the low self-esteem scale, and that epilepsy onset ≤18 years was a significant predictor of abnormally poor score on the work interference scale.

      Discussion

      Although most seizure-free epilepsy patients show normal behavioural adjustment, a higher proportion than expected obtained scores suggesting depression, low self-esteem, and health-related concerns. Both neurobiological and psychosocial factors may explain different aspects of problems with behavioural adjustment.

      Keywords

      Introduction

      Behavioural adjustment problems in epilepsy, with focus on depression, anxiety, quality of life (QOL), and stigma, have been highlighted in numerous studies. Recent studies confirm a moderate to high frequency of depression (ranging between 19 and 60%) in patients with epilepsy.
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      Prevalence of psychopathology in Dutch epilepsy inpatients: a comparative study.
      • Kanner A.M.
      Depression in epilepsy: a frequently neglected multifaceted disorder.
      • Boylan L.S.
      • Flint L.A.
      • Labovitz D.L.
      • Jackson S.C.
      • Starner K.
      • Devinsky O.
      Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy.
      • Grabowska-Grzyb A.
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      Risk factors for depression in patients with epilepsy.
      The rate of mood disorders in epilepsy has been reported to be higher than in other medical conditions, such as diabetes and asthma.
      • Blum D.
      • Reed M.
      • Metz A.
      Prevalence of major affective disorders and manic/hypomanic symptoms in persons with epilepsy: a community survey.
      Among the most important risk factors for depression in patients with epilepsy are: complex partial seizures, absence of secondary generalized tonic–clonic seizures (GTCS), drug resistance, lack of occupational activity,
      • Grabowska-Grzyb A.
      • Jedrzejczak J.
      • Naganska E.
      • Fiszer U.
      Risk factors for depression in patients with epilepsy.
      epileptic focus in the temporal lobe of the dominant hemisphere and neuropsychological evidence of frontal lobe dysfunction,
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      Cerebral metabolism and depression in patients with complex partial seizures.
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      • Trimble M.R.
      Psychiatric profiles and patterns of cerebral blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion related to the laterality of the epilepsy.
      negative impact of anticonvulsant drugs,
      • Hessen E.
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      • Reinvang I.
      • Gjerstad L.
      Slight improvement in mood and irritability after anti-epileptic drug withdrawal. A controlled study in mono-therapy patients.
      • Brendt D.A.
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      • Varma R.R.
      Phenobarbital treatment and major depressive disorder in children with epilepsy.
      • Ketter T.A.
      • Post R.M.
      • Theodore W.H.
      Positive and negative psychotropic effects of antiepileptic drugs in patients with seizure disorders.
      and psychosocial factors.
      • Hermann B.
      • Wyler A.R.
      Depression, locus of control and epilepsy surgery.
      The prevalence of anxiety disorders in epilepsy has been found to be as high as that of mood disorders, or even higher. Swinkels et al.
      • Swinkels W.A.
      • Kuyk J.
      • de Graaf E.H.
      • van Dyck R.
      • Spinhoven P.
      Prevalence of psychopathology in Dutch epilepsy inpatients: a comparative study.
      reported a prevalence of anxiety disorders in epilepsy patients of 25%, and 19% for mood disorders, and in specialist settings, the occurrence of anxiety disorders may exceed 50%.
      • Ettinger A.B.
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      • Nolan E.E.
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      • Vitale S.A.
      • Andriola M.R.
      • et al.
      Symptoms of depression and anxiety in pediatric epilepsy patients.
      • Jones J.E.
      • Hermann B.P.
      • Barry J.J.
      • Gilliam F.
      • Kanner A.M.
      • Meador K.J.
      Clinical assessment of Axis I psychiatric morbidity in chronic epilepsy: a multicenter investigation.
      Seizure frequency has been linked with severity of anxiety in some studies,
      • Jacoby A.
      • Baker G.A.
      • Steen N.
      • Potts P.
      • Chadwick D.W.
      The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. community study.
      and the risk of anxiety seems to be higher in focal epilepsies than general epilepsies.
      • Marsh L.
      • Rao V.
      Psychiatric complications in patients with epilepsy. A review.
      Some groups have found an association with left temporal lobe involvement.
      • Andelman F.
      • Fried I.
      • Neufeld M.Y.
      Quality of life self-assessment as a function of lateralization of lesion in candidates for epilepsy surgery.
      The highest frequency of psychopathology, including both anxiety and depression, is found in patients with persistent refractory epilepsy.
      • Kanner A.M.
      Depression in epilepsy: a frequently neglected multifaceted disorder.
      • Hermann B.P.
      • Seidenberg M.
      • Bell B.
      Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression.
      • Kanner A.M.
      • Soto A.
      • Gross-Kanner H.
      Prevalence and clinical characteristics of postictal psychiatric symptoms in partial epilepsy.
      In patients with refractory epilepsy, symptoms of depression and seizure worry have been found to be the most important factors affecting QOL.
      • Loring D.W.
      • Meador K.J.
      • Lee G.P.
      Determinants of quality of life in epilepsy.
      Another major problem for epilepsy patients is stigmatisation, which is reported to be experienced by approximately 50%, and have been correlated with feelings of anxiety, depression and also long-term health problems, injuries and reported side-effects of antiepileptic drugs (AEDs).
      • Baker G.A.
      • Brooks J.
      • Buck D.
      • Jacoby A.
      The stigma of epilepsy: a European perspective.
      Approximately 70% of patients with recent onset epilepsy become seizure-free, either without medication or on AEDs.
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      • Kwan P.
      • Sander J.W.
      The natural history of epilepsy: en epidemiological view.
      Most studies of behavioural adjustment and QOL have been conducted on patients with active epilepsy (continuing to experience seizures), and relatively few studies have investigated these phenomena in patients with well-controlled epilepsy. Engelberts et al.
      • Engelberts N.H.J.
      • Klein M.
      • van der Ploeg M.H.
      • Heimans J.J.
      • Jolles J.
      • Kasteleijn-Nolst Trenite D.G.A.
      Cognition and health-related quality of life in chronic well-controlled patients with partial epilepsy on carbamazepine monotherapy.
      found that patients with localization-related epilepsy, well-controlled on carbamazepine monotherapy, had unimpaired health-related QOL in comparison with controls matched by age, gender, and education. Uijl et al.
      • Uijl S.G.
      • Uiterwaal C.S.M.P.
      • Aldenkamp A.P.
      • Carpay J.A.
      • Doelman J.C.
      • Keizer K.
      • et al.
      A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs.
      conducted a cross-sectional study of subjective complaints in epilepsy patients whose symptoms were well-controlled with AED monotherapy (85%), or polytherapy (15%). QOL was measured by questionnaire (Qoilie-10) and personality traits by Symptom Checklist 90 (SCL-90). Moderate to severe subjective complaints were reported by 67% of these patients on the Qoilie-10 questionnaire. Cognitive complaints were most common, and were primarily associated with AED polytherapy, and high scores on psycho-neuroticism on the SCL-90.
      To our knowledge, previous studies have not focused on entirely seizure-free epilepsy patients. Thus, the aim of this study was to describe behavioural function in such a group, and to analyse possible predictors for problems with behavioural adjustment, including age at epilepsy onset, seizure variety, duration of seizure freedom, EEG-findings, MRI pathology, and AED treatment. A subgroup of patients with idiopathic generalized epilepsy (IGE) was described separately; as these have no confounding variables from cerebral lesions and thus may be a good model for studying the effect of epilepsy on behavioural function.
      Based on the good cognitive outcome results reported in the study by Hessen et al.,
      • Hessen E.
      • Lossius M.I.
      • Reinvang I.
      • Gjerstad L.
      Predictors of neuropsychological impairment in seizure-free epilepsy patients.
      which included the same group of seizure-free epilepsy patients as participated in the present study, our main hypothesis was that this group, unlike patients with active epilepsy, would show behavioural adjustments similar to those observed in the general population.

      Methods

      Selection of patients—inclusion/exclusion criteria

      The patients described in the present paper were participants in a large study investigating the withdrawal of AEDs in seizure-free epilepsy patients on monotherapy. They were selected on basis of clinical criteria from the epilepsy registry at the Akershus University Hospital and from six neurological outpatient clinics in the Oslo area: They should have a diagnosis of epilepsy (at least two unprovoked seizures), be between 18 and 67 years old and seizure-free on monotherapy for at least 2 years at the time of inclusion. Excluded were patients with the following characteristics: juvenile myoclonus epilepsy (JME), poly-pharmacy, paroxysmal epileptiform activity in patients with primarily generalized epilepsy, mental retardation, two prior withdrawal attempts, pregnant or seeking pregnancy, progressive neurological disease, other serious disease which may influence the health status of the patient in the study period and co-medication (except post menopausal hormone substitution, antihypertensive, ASA and thyroxin).
      Initially, 241 patients seemed to fulfil the inclusion criteria, and were invited to participate in the study. Of these patients, 17 (7%) did not respond to the invitation, 32 (13%) declined to participate, 13 (5%) still had seizures, 20 (8%) fulfilled other exclusion criteria, and 1 had an acute disease. Thus, of the initial 241 patients, 83 (34%) were not eligible or did not wish to participate. The relatively large number of patients that did not wish to participate (32) must be viewed against the background that this study was part of a larger study of AED withdrawal in seizure-free epilepsy patients on monotherapy. Therefore, the patients that declined to participate, primarily did so due to fear of seizure relapse and the potential consequences of seizure relapse (e.g. loss of driver's license). Of the remaining 158 patients, 126 (80%) agreed to answer the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and were included in the present study.

      Behavioural assessment

      Behavioural function was evaluated with The Norwegian Edition of MMPI-2.
      • Butcher J.N.
      • Dahlstrom W.G.
      • Graham J.R.
      • Tellegen A.
      • Kaemmer B.
      MMPI-2: manual for administration and scoring.
      • Butcher J.N.
      • Dahlstrom W.G.
      • Graham J.R.
      • Tellegen A.
      • Kaemmer B.
      MMPI-2: Norwegian edition.
      Norwegian normative data were used to score data from the MMPI-2.
      • Butcher J.N.
      • Dahlstrom W.G.
      • Graham J.R.
      • Tellegen A.
      • Kaemmer B.
      MMPI-2: Norwegian edition.
      All test results were converted to T-scores, a normally distributed scale with a mean score of 50 and standard deviation (S.D.) of 10. Both the 10 standard clinical scales and the 15 content scales from the MMPI-2
      • Butcher J.N.
      • Dahlstrom W.G.
      • Graham J.R.
      • Tellegen A.
      • Kaemmer B.
      MMPI-2: manual for administration and scoring.
      were used as outcome measures. Definition of abnormal function was T-scores equal to or greater than 65 on the different subscales.

      Statistical analysis

      Statistical analyses were performed with the Statistical Package for Social Sciences for Windows (SPSS, version 12.0). First, descriptive statistics of the demographic, clinical and behavioural characteristics of the patient population were computed. Odds ratios for occurrence of abnormal scores on the MMPI-2 were estimated with logistic regression analysis. To assess possible predictors for abnormal scores, variables of importance were tested first in a logistic univariate model, and then in a multivariate logistic model. Behavioural adjustment was dichotomised, with the categories normal and abnormal as the dependent variable. A series of independent t-tests were then performed comparing behavioural function between subgroups of patients defined by clinical variables. As the MMPI-2 subtests are not independent, a Bonferroni correction was not considered appropriate, as this method is highly conservative and has the potential to miss real differences between the groups.
      • Bland J.M.
      • Altman D.G.
      Multiple significance tests: the Bonferroni Method.

      Results

      Demographic and clinical characteristics

      Demographic data and clinical information of the 126 study patients are presented in Table 1. The demographic characteristics of patients with and without IGE were similar. There were no demographic differences between the 158 patients included in our study of cognitive function in seizure-free epilepsy patients
      • Hessen E.
      • Lossius M.I.
      • Reinvang I.
      • Gjerstad L.
      Predictors of neuropsychological impairment in seizure-free epilepsy patients.
      and the 126 patients in the present study. Cognitive function was also similar between these two groups of study patients, with the exception of somewhat poorer scores from the patients participating in this study in two tests: delayed visual memory
      • Wechsler D.
      Wechsler memory scale—revised manual.
      : T = 49.0 versus T = 53.0 (p = 0.016), and COWA (word fluency)
      • Benton A.L.
      • de Hamsher K.S.
      Multilingual aphasia examination.
      : T = 38.5 versus T = 43.0 (p = 0.020).
      Table 1Demographic and clinical characteristics of study patients
      Demographic and clinical variablesAll study patients (n = 126)Patients without IGE (n = 102)Patients with IGE (n = 24)
      Mean age (S.D.)39 (11.9)39 (11.6)38 (13.2)
      Female (%)67 (53)55 (54)12 (50)
      Education years (S.D.)13.2 (2.8)13.2 (2.8)13.2 (2.9)
      Work (%)123 (98)99 (97)24 (100)
      Retirement/disability benefit (%)3 (2)3 (3)0
      Epilepsy onset ≤18 years (%)43 (34)36 (35)7 (29)
      Seizure-free >5 years (%)83 (66)65 (64)18 (75)
      Duration of seizure freedom years (S.D.)9.8 (3.8)10.0 (4.2)9.8 (3.7)
      Partial seizures (%)91 (72)91 (89)0
      Generalized seizures (%)34 (27)10 (10)24 (100)
      Idiopathic generalized epilepsy (%)24 (19)024 (100)
      Presence of GTCS (%)30 (24)9 (9)21 (88)
      Unclassified seizures1 (1)1 (1)0
      Known etiology (%)33 (26)33 (32)0
      MRI pathology (1 tesla) (%)29 (24)23 (23)6 (26)
      Normal neurological status (%)117 (93)95 (93)22 (92)
      Carbamazepine (%)80 (63)67 (66)13 (54)
      Valproate (%)25 (20)18 (18)7 (29)
      Phenytoin (%)12 (10)9 (9)3 (13)
      Phenobarbital (%)3 (2)2 (2)1 (4)
      Lamotrigine (%)6 (5)6 (6)0
      Epileptiform activity on the EEG (%)51 (41)41 (41)10 (42)
      AED within therapeutic range (%)99 (79)81 (80)18 (75)
      Differences in the groups with and without IGE regarding seizure characteristics, aetiology, and medication are shown in Table 1. Apart from these differences, the IGE and non-IGE groups were similar, with regard to seizure debut, duration of seizure freedom, epileptiform EEG activity, and AEDs within therapeutic range. The positive MRI-findings in the IGE group were unspecific and not related to the epilepsy.

      Behavioural function

      Information about behavioural function in the total patient group, and in the groups with and without IGE, is given Table 2. Profiles of the clinical scales and the content scales for the whole group are shown in Figure 1, Figure 2.
      Table 2Mean (S.D.) MMPI-2 T-scores for all study patients and for patients with and without IGE
      All study patients (S.D.) n = 126Patients without IGE (S.D.) n = 102Patients with IGE (S.D.) n = 24
      Clinical scales
       L56.6 11.0)56.4 (11.2)57.3 (10.7)n.s.
       F55.4 (12.2)55.7 (12.1)54.3 (12.5)n.s.
       K49.3 (11.4)49.1 (11.2)50.1 (12.4)n.s
       Hypochondriasis (Hs)58.0 (11.9)58.4 (12.5)56.2 (10.7)n.s.
       Depression (D)59.0 (12.3)59.2 (12.4)58.0 (12.2)n.s.
       Hysteria (Hy)54.7 (11.4)54.7 (11.8)54.7 (9.6)n.s.
       Psychopathic deviate (Pd)48.4 (10.0)48.5 (10.0)48.3 (10.0)n.s.
       Masculinity–Femininity (Mf)49.0 (10.0)48.9 (10.1)49.2 (9.7)n.s.
       Paranoia (Pa)50.1 (10.2)50.2 (10.4)49.4 (9.5)n.s.
       Psychastenia (Pt)53.7 (11.6)54.4 (11.5)50.9 (12.0)n.s.
       Schizophrenia (Sc)54.3 (12.0)54.6 (11.5)53.0 (14.2)n.s.
       Hypomania (Ma)50.3 (10.5)50.1 (10.6)51.2 (10.1)n.s.
       Social introversion (SI)54.8 (11.8)55.6 (12.2)51.4 (9.5)n.s.
      Content scales
       Anxiety (ANX)52.8 (12.1)53.2 (11.8)51.3 (13.3)n.s
       Fears (FRS)51.2 (11.6)51.2 (11.5)51.3 (12.1)n.s.
       Obsessions (OBS)51.1 (11.3)51.4 (11.1)49.6 (11.9)n.s.
       Depression (DEP)53.7 (12.7)53.7 (12.8)53.8 (12.5)n.s.
       Health concerns (HEA)58.7 (12.6)59.2 (12.7)56.3 (12.0)n.s.
       Bizarre Mentation (BIZ)50.3 (10.7)50.6 (10.9)49.2 (10.1)n.s
       Anger (ANG)48.3 (9.7)48.3 (9.6)48.3 (10.5)n.s
       Cynicism (CYN)51.1 (11.4)51.4 (11.8)50.3 (9.9)n.s
       Antisocial practices (ASP)50.8 (10.2)51.2 (10.3)49.0 (9.5)n.s
       Type A (TPA)47.6 (11.6)48.1 (10.6)45.3 (15.2)n.s
       Low self-esteem (LSE)55.8 (14.3)56.1 (14.4)54.6 (13.9)n.s.
       Social discomfort (SOD)52.7 (11.6)53.3 (12.2)50.3 (8.9)n.s.
       Family problems (FAM)49.5 (12.3)49.2 (12.1)50.9 (13.0)n.s.
       Work interference (WRK)53.3 (13.7)53.6 (13.2)52.0 (15.7)n.s.
       Negative treatment indicators (TRT)55.5 (15.3)55.8 (15.0)54.1 (16.6)n.s.
      p < 0.05.
      Figure thumbnail gr1
      Figure 1MMPI-2 mean T-scores, clinical scales.
      Figure thumbnail gr2
      Figure 2MMPI-2 mean T-scores, content scales.
      Scores on all the clinical scales and content scales were within the normal range. The scores were close to one standard deviation above the normative mean on the hypochondriasis (Hs) scale (all patients: T = 58.0, without IGE: T = 58.4, IGE: T = 56.2), on the depression (D) scale (all patients: T = 59.0, without IGE: T = 59.2, IGE: T = 58.0) and on the health concerns (HEA) scale (all patients: T = 58.7, without IGE: T = 59.2, IGE: T = 56.3). On the other scales, the scores were close to the normative mean. On several of the scales, the percentage of patients with T-scores in the pathological range (T ≥ 65) were rather high, compared with the expected 7% in the normative group (Table 3): 33% for the D scale, 29% for the HEA scale, 25% for the low self-esteem (LSE), 24% for the negative treatment indicators (TRT) scale, and 24% for the Hs scale. In addition, 27% of the patients scored T ≥ 65 on the L scale. There were no significant differences between the non-IGE and the IGE group.
      Table 3Frequency of T-scores ≥65 (abnormal function) in the total patient sample and for patients with IGE and without IGE
      All study patients (S.D.) n = 126Patients without IGE (S.D.) n = 102Patients with IGE (S.D.) n = 24
      Clinical scales
       L n (%)34 (27)27 (27)7 (29)n.s.
       F n (%)22 (18)19 (19)3 (13)n.s.
       K n (%)11 (9)8 (8)3 (13)n.s
       Hypochondriasis (Hs) n (%)30 (24)25 (25)5 (21)n.s.
       Depression (D) n (%)41 (33)33 (32)8 (33)n.s.
       Hysteria (Hy) n (%)26 (21)19 (19)7 (29)n.s.
       Psychopathic deviate (Pd) n (%)9 (7)8 (8)1 (4)n.s.
       Masculinity–Femininity (Mf) n (%)9 (7)8 (8)1 (4)n.s.
       Paranoia (Pa) n (%)10 (8)8 (8)2 (8)n.s.
       Psychastenia (Pt) n (%)23 (18)20 (20)3 (13)n.s.
       Schizophrenia (Sc) n (%)25 (20)19 (19)6 (25)n.s.
       Hypomania (Ma) n (%)17 (14)14 (14)3 (13)n.s.
       Social introversion (SI) n (%)21 (17)18 (18)3 (13)n.s.
      Content scales
       Anxiety (ANX) n (%)18 (14)13 (13)5 (21)n.s
       Fears (FRS) n (%)18 (14)15 (15)3 (13)n.s.
       Obsessions (OBS) n (%)14 (11)12 (12)2 (8)n.s.
       Depression (DEP) n (%)24 (19)19 (18)5 (21)n.s.
       Health concerns (HEA) n (%)36 (29)31 (30)5 (21)n.s.
       Bizarre mentation (BIZ) n (%)14 (11)12 (12)2 (8)n.s
       Anger (ANG) n (%)7 (6)5 (5)2 (8)n.s
       Cynicism (CYN) n (%)18 (14)16 (16)2 (8)n.s
       Antisocial practices (ASP) n (%)13 (10)11 (11)2 (8)n.s
       Type A (TPA) n (%)8 (6)6 (6)2 (8)n.s
       Low self-esteem (LSE) n (%)31 (25)26 (26)5 (21)n.s.
       Social discomfort (SOD) n (%)23 (18)21 (21)2 (8)n.s.
       Family problems (FAM) n (%)16 (13)11 (11)5 (21)n.s.
       Work interference (WRK) n (%)24 (19)21 (21))3 (13)n.s.
       Negative treatment indicators (TRT) n (%)30 (24)24 (24)6 (25)n.s.
      p < 0.05.

      Prediction of abnormally elevated scores on the LSE and work interference (WRK) scales in the total patient sample and for patients with and without IGE

      Variables of importance were tested in a logistic univariate model. T-score ≥65 for all the clinical and content scales were entered individually as dependent variables. The independent variables included MRI pathology, epileptiform activity on EEG, presence of GTCS, presence of IGE, complex partial seizures, epilepsy onset at age <18 years, duration of seizure freedom >5 years, and AED within therapeutic range. Significant predictors for abnormally elevated scores were only demonstrated for the total patient sample, on two of the dependent variables (Table 4). Multiple regression analysis showed that MRI pathology was a significant predictor for abnormally poor score on the LSE scale (OR = 1.20, p = 0.008), and that epilepsy onset ≤18 years was a significant predictor of abnormally poor score on the WRK scale (OR = 3.35, p = 0.021).
      Table 4Predictors of behavioural disturbance in epilepsy patients seizure-free for more than 2 years on monotherapy
      VariableUnivariate analysisMultivariate analysis
      ORpOR95% CIp
      Low self-esteem (LSE) T-score ≥65
       MRI pathology1.200.0041.201.05–1.360.008
       Epileptiform activity on EEG1.900.111.650.75–3.640.22
       Epilepsy onset ≤18 years1.870.142.010.78–5.220.15
       Presence of GTCS0.540.250.620.19–2.060.43
       AED within therapeutic range1.250.34
       Complex partial seizure1.410.45
       Idiopathic generalized epilepsy0.770.63
       Duration of seizure freedom >5 years1.080.86
      Work interference (WRK) T-score ≥65
       Epilepsy onset ≤18 years2.840.0253.351.20–9.330.021
       MRI pathology1.130.061.130.98–1.300.09
       Epileptiform activity on EEG1.670.141.120.45–2.780.81
       AED within therapeutic range1.160.191.490.53–4.210.45
       Duration of seizure freedom >5 years0.650.35
       Idiopathic generalized epilepsy0.550.37
       Complex partial seizure1.540.42
       Presence of GTCS0.810.70

      Discussion

      The main findings of the present study were as follows:
      • (1)
        The mean scores on the clinical and content scales were within the normal range.
      • (2)
        The subscales Hs, D and HEA had group scores close to one standard deviation above the normative mean.
      • (3)
        Contrary to that which was expected, the percentage of patients with abnormally elevated scores (T ≥ 65) were considerably higher than in the normative group being 33% for the D scale, 29% for the HEA scale, 25% for the LSE, 24% for the TRT and 24% for the Hs scale, as compared with 7% in normative group.
      • (4)
        Multiple regression analysis showed that MRI pathology was a significant predictor for abnormally poor score on the LSE scale and that epilepsy onset ≤18 years was a significant predictor of abnormally poor score on the WRK scale.
      • (5)
        A large group of epilepsy patients, who had been seizure-free for a minimum of 2 years, had average durations of education and employment status similar to those of the population mean.
      To our knowledge previous studies of behavioural adjustment in epilepsy have not focused on exclusively seizure-free patients. Our study included sufficient patients (n = 126) to enable statistically valid investigation of relationships between medical variables of importance and behavioural function.
      The results are relevant for patients that fulfilled the inclusion criteria. There is reason to believe that the patients participating in this study are representative of the majority of seizure-free epilepsy patients,
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      • Lossius M.I.
      • Stavem K.
      • Gjerstad L.
      Predictors for recurrence of epileptic seizures in a general epilepsy population.
      however, the findings are not valid for all seizure-free epilepsy patients, as persons with poly-pharmacy,
      • Meador K.J.
      Cognitive outcomes and predictive factors in epilepsy.
      paroxysmal epileptiform activity with primarily generalized epilepsy,
      • Aldenkamp A.
      • Arends J.
      The relative influence of epileptic EEG discharges, short non-convulsive seizures, and type of epilepsy on cognitive function.
      mental retardation, and progressive neurological disease were excluded from the study.
      There has been some contention regarding the validity of MMPI and MMPI-2 in detecting abnormal behaviour in patients with epilepsy. The concern is that patients with epilepsy may have falsely exaggerated MMPI-2 scale scores, due to endorsement of disease-related items. Thus, Nelson et al.
      • Nelson L.D.
      • Elder J.T.
      • Groot J.
      • et al.
      Personality testing and epilepsy: comparison of two MMPI-2 correction procedures.
      suggest cautious interpretation of standard MMPI-2 scores in patients with epilepsy, based on a study of patients with mainly intractable epilepsy. Dikmen et al.
      • Dikmen S.
      • Herrmann B.P.
      • Wilensky A.J.
      • Tehrani P.
      • Grant A.C.
      Validity of the Minnesota Multiphasic Personality Inventory (MMPI) to psychopathology in patients with epilepsy.
      however, found that MMPI is sensitive to behavioural abnormalities in patients with different seizure categories. A study by Modrego et al.
      • Modrego P.J.
      • Pina M.A.
      • Galindo M.
      • Minguez J.
      Study of psychopathology in patients with chronic non-lesional epilepsy: a Minnesota Multiphasic Personality Inventory profile controlled study.
      also supports the validity of MMPI for detection of abnormal behaviour in patients with chronic non-lesional epilepsy. Compared with the Diagnostic and Statistical Manual of Mental Disorders-Version Four (DSM-IV) criteria, the MMPI correctly identified personality disorders, especially depression and paranoid personality. In an overview of behavioural and cognitive assessments in clinical trials of AEDs, Baker and Marson
      • Baker G.A.
      • Marson A.G.
      Cognitive and behavioural assessments in clinical trials: what type of measure?.
      reported that the MMPI was the most commonly used test of behavioural function, and was able to detect changes in more than half of the trials in which it was used. This represents a higher degree of sensitivity than other behavioural methods that have been utilised in clinical trials. Questioning the validity of MMPI-2 in studies of persons with intractable epilepsy or ongoing seizure activity is somewhat irrelevant in the context of this study, as all the patients were seizure-free.
      A relatively large proportion of the patients had elevated score (T ≥ 65) on the L scale. Scores in this range can be typical for persons who lack insight into their own behaviour, who deny common human faults, or who are trying to create a favourable impression of themselves. Thus, the rather high frequency of elevated L scores may suggest underreporting of problems in the present group of patients. However, the group with T-scores ≥65 on the L scale (n = 34) and the group with T-scores <65 (n = 92), had similar scores on 9 of the 10 clinical subscales. Significantly lower scores for patients with an elevated L score was only evident on the social introversion (SI) scale, T = 50.4 versus T = 56.5 (p = 0.009). Consequently, there seems to be no indication that the high occurrence of elevated L scores caused significantly changed scores on the MMPI-2.
      On the basis of Norwegian normative data, the mean T-scores for all the clinical and content scales on MMPI-2 were within the normal range. The subscales Hs, D, and HEA had mean scores close to one standard deviation above the normative mean, and the proportion of patients with abnormally elevated scores (T ≥ 65) were considerably above the proportion expected based on the normative group. Patients with T-score ≥65 on the D scale typically exhibit a depressed mood. Patients with scores in the same range on the HS scale are described as excessively concerned about vague physical symptoms, while patients with similar HEA scores are worried about their health, especially with regard to physical symptoms. Abnormally elevated scores on the LSE scale are associated with poor self-esteem, and similar scores on the TRT scale are typical for persons with a negative or pessimistic outlook on treatment possibilities.
      • Greene R.L.
      The MMPI-2. An interpretive manual.
      The high frequency of abnormally elevated scores on these, and other, subscales (Table 3) was contrary to expected as based upon the good cognitive outcomes obtained in our previous study of the same patients.
      • Hessen E.
      • Lossius M.I.
      • Reinvang I.
      • Gjerstad L.
      Predictors of neuropsychological impairment in seizure-free epilepsy patients.
      The results of the present study may resemble those from studies of patients with active epilepsy, that find moderate to high frequency of depression,
      • Swinkels W.A.
      • Kuyk J.
      • de Graaf E.H.
      • van Dyck R.
      • Spinhoven P.
      Prevalence of psychopathology in Dutch epilepsy inpatients: a comparative study.
      • Kanner A.M.
      Depression in epilepsy: a frequently neglected multifaceted disorder.
      • Boylan L.S.
      • Flint L.A.
      • Labovitz D.L.
      • Jackson S.C.
      • Starner K.
      • Devinsky O.
      Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy.
      • Grabowska-Grzyb A.
      • Jedrzejczak J.
      • Naganska E.
      • Fiszer U.
      Risk factors for depression in patients with epilepsy.
      seizure worry and reduced QOL,
      • Loring D.W.
      • Meador K.J.
      • Lee G.P.
      Determinants of quality of life in epilepsy.
      and anxiety.
      • Swinkels W.A.
      • Kuyk J.
      • de Graaf E.H.
      • van Dyck R.
      • Spinhoven P.
      Prevalence of psychopathology in Dutch epilepsy inpatients: a comparative study.
      • Ettinger A.B.
      • Weisbrot D.M.
      • Nolan E.E.
      • Gadow K.D.
      • Vitale S.A.
      • Andriola M.R.
      • et al.
      Symptoms of depression and anxiety in pediatric epilepsy patients.
      • Jones J.E.
      • Hermann B.P.
      • Barry J.J.
      • Gilliam F.
      • Kanner A.M.
      • Meador K.J.
      Clinical assessment of Axis I psychiatric morbidity in chronic epilepsy: a multicenter investigation.
      The average duration of education of the patient group was similar to the population mean in Norway, for persons between 30 and 39 years, and 2% of the patients were either receiving disability benefit or had retired, which is less than the expected 6% for a similar age group in Norway.
      • Rikstrygdeverket
      Pensjonsstatistikk.
      The groups of patients with IGE and the heterogeneous group without IGE had similar education durations and work status.
      Although all the mean MMPI-2 scores in this study were within the normal range, the frequency of patients with abnormally elevated scores on several depression-related subscales, were clearly above expected, based on normative data. The literature suggests that neurobiological,
      • Grabowska-Grzyb A.
      • Jedrzejczak J.
      • Naganska E.
      • Fiszer U.
      Risk factors for depression in patients with epilepsy.
      • Wiegartz P.
      • Seidenberg M.
      • Woodard A.
      • Gidal B.
      • Hermann B.
      Co-morbid psychiatric disorder in chronic epilepsy: recognition and etiology of depression.
      • Bromfield E.B.
      • Altshuler L.
      • Leiderman D.B.
      Cerebral metabolism and depression in patients with complex partial seizures.
      • Schmitz E.B.
      • Moriarty J.
      • Costa D.C.
      • Ring H.A.
      • Trimble M.R.
      Psychiatric profiles and patterns of cerebral blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion related to the laterality of the epilepsy.
      iatrogenic,
      • Hessen E.
      • Lossius M.I.
      • Reinvang I.
      • Gjerstad L.
      Slight improvement in mood and irritability after anti-epileptic drug withdrawal. A controlled study in mono-therapy patients.
      • Brendt D.A.
      • Crumine P.K.
      • Varma R.R.
      Phenobarbital treatment and major depressive disorder in children with epilepsy.
      • Ketter T.A.
      • Post R.M.
      • Theodore W.H.
      Positive and negative psychotropic effects of antiepileptic drugs in patients with seizure disorders.
      and psychosocial
      • Grabowska-Grzyb A.
      • Jedrzejczak J.
      • Naganska E.
      • Fiszer U.
      Risk factors for depression in patients with epilepsy.
      • Hermann B.
      • Wyler A.R.
      Depression, locus of control and epilepsy surgery.
      dimensions constitute main risk factors for depression in epilepsy. Although the present study does not provide any clear answers regarding risk factors for depression in seizure-free epilepsy patients, the results may indicate some possible clues.
      With regard to neurobiological risk factors, depression appears to be elevated in patients with seizures of left temporal lobe origin and with neurophysiological and neuropsychological evidence of frontal lobe dysregulation.
      • Bromfield E.B.
      • Altshuler L.
      • Leiderman D.B.
      Cerebral metabolism and depression in patients with complex partial seizures.
      • Schmitz E.B.
      • Moriarty J.
      • Costa D.C.
      • Ring H.A.
      • Trimble M.R.
      Psychiatric profiles and patterns of cerebral blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion related to the laterality of the epilepsy.
      However, the theory of left-sided involvement has been challenged by Quiske et al.,
      • Quiske A.
      • Helmstaedter C.
      • Lux S.
      Depression in patients with temporal lobe epilepsy is related to mesial temporal sclerosis.
      who found a similar predominance of depressive symptoms in both left and right-sides pathologies. The patients in the present study had been seizure-free for 2 years or more, and were therefore not directly comparable with patients in those studies with patients with persistent seizures and verified neurophysiological and neuropsychological abnormalities. However, the finding that MRI pathology was a significant predictor for abnormally poor score on the LSE scale does suggest that a depression-related phenomenon, like low self-esteem, may be associated with neurobiological factors in seizure-free epilepsy patients also.
      With regard to iatrogenic risk factors for depression, the relationship between AEDs and mood have been discussed, and particularly that phenobarbital has been associated with increased risk of depression in comparison with carbamazepine.
      • Brendt D.A.
      • Crumine P.K.
      • Varma R.R.
      Phenobarbital treatment and major depressive disorder in children with epilepsy.
      In the present study most of the patients were treated with carbamazepine, and only 3 patients received phenobarbital. In the randomised, double-blinded, and placebo-controlled withdrawal study by Hessen et al.,
      • Hessen E.
      • Lossius M.I.
      • Reinvang I.
      • Gjerstad L.
      Slight improvement in mood and irritability after anti-epileptic drug withdrawal. A controlled study in mono-therapy patients.
      based on the same group of patients as in this study, only slightly elevated depression scores were related to the use of AEDs. On the depression scale (DEP) withdrawal resulted in an improvement of 4.1 T-scores (p = 0.012). Therefore, it is probable that treatment with AEDs contributes slightly to the high frequency of depressed patients, but it seems unlikely that AED treatment alone can explain these results.
      With regard to psychosocial risk factors for depression in epilepsy a theme associated with the nature of epilepsy has been discussed in the literature. It involves the fact that patients with epilepsy experience random seizures over which they have minimal control. This has been discussed in the context of the concepts of external locus of control and the concept of learned helplessness, and have been found to apply to the epilepsy–depression relation.
      • Hermann B.
      • Wyler A.R.
      Depression, locus of control and epilepsy surgery.
      • Hermann B.P.
      • Trenerry M.R.
      • Colligan R.C.
      Learned helplessness, attributional style and depression in epilepsy.
      Also the perception of stigma, which affects approximately 50% of people with epilepsy
      • Baker G.A.
      • Brooks J.
      • Buck D.
      • Jacoby A.
      The stigma of epilepsy: a European perspective.
      have been shown to have a positive relationship with affective disorders.
      • Hermann B.P.
      • Trenerry M.R.
      • Colligan R.C.
      Learned helplessness, attributional style and depression in epilepsy.
      Although the present seizure-free patients probably have less seizure worry, less feeling of external locus of control, and less experience of stigma than patients with persistent seizures, it is probable that these psychosocial elements also have influence on these patients and the rather high frequency of depressive symptoms and health-related concerns. This may be particularly relevant in the study patients that were included in a trial with the aim to withdraw their medication. This is a sensitive situation which may have contributed to the level of seizure worry and health-related concerns.
      Early epilepsy onset (≤18 years) was significantly associated with abnormally poor score on the WRK scale. Scores in this range are typical for persons who report impaired working ability, poor self-confidence, lack of energy, and a tendency to give up easily when facing a problem.
      • Greene R.L.
      The MMPI-2. An interpretive manual.
      It is difficult to explain this finding, and both neurobiological and psychosocial factors may be of relevance. Studies have indicated interruption of brain maturation in epilepsy with seizure debut in childhood.
      • Huttenlocher P.R.
      • Hapke R.J.
      A follow-up study of intractable seizures in childhood.
      • Bjornaes H.
      • Stabell K.
      • Henriksen O.
      • Loyning Y.
      The effects of refractory epilepsy on intellectual functioning in children and adults: a longitudinal study.
      In addition, adverse psychosocial experiences related to seizures and seizure worry during childhood and adolescence may have a negative influence on the development of self-confidence.

      Conclusions

      Group analysis of epilepsy patients, seizure-free for more than 2 years, found mean MMPI-2 scores within the normal range, and in addition an average duration of education and employment status similar to the population mean. Contrary to expected, the proportion of patients with abnormally elevated scores on scales measuring aspects of depression, health-related concerns, low self-esteem, negative treatment indicators, and physical complaints were clearly above that which would normally be expected. Multiple regression analysis showed that MRI pathology was a significant predictor for an abnormally poor score on the low self-esteem scale, and that epilepsy onset ≤18 years was a significant predictor of an abnormally poor score on the work interference scale.

      Conflict of interest

      The authors report no conflict of interest.

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