Fatigue in epilepsy: A systematic review and meta-analysis

  • Oh-Young Kwon
    Affiliations
    Department of Neurology and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
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  • Hyeong Sik Ahn
    Affiliations
    Institute for Evidence-Based Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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  • Hyun Jung Kim
    Correspondence
    Corresponding author at: Institute for Evidence-Based Medicine, Department of Preventive Medicine, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Fax: +82 2 2286 1342.
    Affiliations
    Institute for Evidence-Based Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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Open ArchivePublished:November 16, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.006

      Highlights

      • Degree of fatigue was higher in adult patients with epilepsy than in healthy adults.
      • Frequency of fatigue was 47.1% in adult patients with epilepsy.
      • Fatigue was more frequent in epilepsy patients than controls or general population.
      • Depression and sleep-related problems affected fatigue in epilepsy patients.
      • Fatigue in epilepsy patients was closely correlated with depression.

      Abstract

      Purpose

      To estimate the frequency and strength of fatigue in epilepsy patients.

      Methods

      The MEDLINE, EMBASE, COCHRANE, Web of Science, and SCOPUS databases were searched, and hand-searched data were added. For inclusion, the studies had to be original research articles that included fatigue data from adult epilepsy patients. The strength was estimated using studies reporting fatigue scores of standardized inventories for the patients and healthy controls. The fatigue frequency was estimated based on studies reporting the number of fatigue events in patients. We also investigated risk factors for fatigue and the correlation of depression with fatigue in epilepsy patients.

      Results

      Of 25,613 abstracts screened, we included 12 articles or proceedings with distinctive data. The Fatigue Severity Scale (FSS) was the most commonly used inventory for fatigue in epilepsy patients. Four studies compared FSS scores between 499 epilepsy patients and 295 healthy controls. The overall mean difference in the FSS scores was significant. Seven of the 12 studies reported the frequency of fatigue determined by the FSS for 700 epilepsy patients. As stated by the studies, the overall frequency of fatigue was 47.1%. The risk factors for fatigue in epilepsy patients were depression, sleep-related impairment, and sleep quality. Of the 12 studies, 7 revealed a significant correlation between depression and fatigue.

      Conclusions

      Fatigue is common in epilepsy patients and is closely correlated with depression. The identification and management of fatigue and its risk factors, especially depression, is mandatory for the management of epilepsy.

      Keywords

      1. Introduction

      Epilepsy patients frequently complain of fatigue. Fatigue is the mental and/or physical experience of extreme and persistent tiredness, weakness, or exhaustion [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ]. The complaint of fatigue is more common in epilepsy patients than in the general population according to a population-based study [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ]. This trend was also observed between epilepsy patients and healthy volunteers in a hospital-based study [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ]. In addition, in another hospital-based study, fatigue inventory scores were higher in epilepsy patients than in healthy volunteers and in patients with multiple sclerosis, migraine, and radiculopathy [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ].
      Although the mechanism of fatigue remains unclear, it can be assumed that depression is associated with fatigue. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, fatigue may be a symptom of major depressive disorder [
      • American Psychiatric Association
      Diagnostic criteria from DSM-IV-TR.
      ]. Fatigue is prominent, especially when depression is atypical [
      • Arnold L.M.
      Understanding fatigue in major depressive disorder and other medical disorders.
      ]. In addition, fatigue is a common prodromal symptom in patients suffering their first major depressive episode [
      • Fava G.A.
      • Grandi S.
      • Canestrari R.
      • Molnar G.
      Prodromal symptoms in primary major depressive disorder.
      ]. Since depression is commonly comorbid in epilepsy patients [
      • Kwon O.Y.
      • Park S.P.
      Depression and anxiety in people with epilepsy.
      ], the association between depression and fatigue should be explored to understand and ameliorate fatigue in epilepsy patients.
      A crucial problem related to fatigue is that it may precipitate a single or multiple seizures in patients with established epilepsy [
      • Ferlisi M.
      • Shorvon S.
      Seizure precipitants (triggering factors) in patients with epilepsy.
      ,
      • Balamurugan E.
      • Aggarwal M.
      • Lamba A.
      • Dang N.
      • Tripathi M.
      Perceived trigger factors of seizures in persons with epilepsy.
      ]. Therefore, a better understanding of fatigue in epilepsy patients is mandatory for effective patient management. From this viewpoint, it may be clinically valuable to evaluate the degree and frequency of fatigue in epilepsy patients based on meta-analysis and systematic review. The aim of this study was to determine the significance of fatigue in epilepsy patients in terms of degree and frequency by estimating the overall effect sizes and to examine the risk factors for fatigue, including depression, in patients.

      2. Methods

      2.1 Search strategy

      The search strategy was established by the coauthors, including systematic review expertise in referring to key articles. We used common keywords related to epilepsy, quality of life (QOL), sleep, and fatigue in epilepsy patients. The keywords used were: ‘epilepsy,’ ‘epilepsies,’ ‘epileptic,’ ‘seizure disorder,’ ‘seizure disorders,’ ‘life quality,’ ‘quality of life,’ ‘fatigue,’ ‘chronic fatigue syndrome,’ ‘mental fatigue,’ ‘exhaustion,’ ‘lassitude,’ ‘hypersomnolence,’ ‘idiopathic,’ ‘somnolence,’ ‘disorders of excessive somnolence,’ ‘daytime somnolence,’ ‘somnolence,’ ‘sleep,’ and ‘drowsiness’ for exposure factors. The search strategy is provided as Appendix A of this review.
      We searched the electronic databases MEDLINE, EMBASE, COCHRANE, Web of Science, and SCOPUS (from inception to March 2016). The search was performed on March 9, 2016. We also manually examined other bibliographies to avoid missing pertinent articles. No restrictions were placed on the time of publication or language. The references, including articles and proceedings, were exported and managed using EndNote X7.5 [
      Endnote X7.5.
      ].

      2.2 Study selection

      To identify suitable studies for this review on fatigue in epilepsy, two reviewers (OY Kwon and HJ Kim) separately examined the titles and abstracts of the searched studies. Abstracts that were clearly based on cases or case series were excluded at this stage. The initial screening was wide to obtain all studies pertinent to this review. The two reviewers also independently re-screened the full-length articles or proceedings of the abstracts captured in the first screening. When there was a disagreement between the two reviewers, the disagreement was addressed by discussion or consultation with a third author (HS Ahn). In cases with the same data from multiple articles and proceedings, we selected the study containing the most detailed description of the methods and results. Since one author of this review was an author of a study included in this review (OY Kwon), another author of this review (HJ Kim) confirmed the objectiveness of the study to eliminate the probable conflict of interest.
      Although we initially planned to include epidemiological studies of both population-based and hospital-based studies in this review, few population-based studies were available. Prospective cohort studies and case-control studies were also limited. Articles were included if they met the following criteria: studies that evaluated fatigue in epilepsy patients, studies on adult epilepsy patients, original studies, hospital-based or population-based studies, and studies with a cohort or cross-sectional design. We included only adult studies because fatigue in children and adolescents are much more complex and manifest differently. In a study investigating fatigue in adolescent epilepsy patients using the Checklist Individual Strength (CIS) questionnaire, the levels of fatigue were significantly lower than in adult normative samples. Abstracts and unpublished studies were also considered. The following data were extracted: study information (author, year), population demographics (age, location), condition information (data sources, condition definition, total number of participants), population size, and reported estimates (frequency of fatigue, scores of the questionnaires).

      2.3 Data synthesis and analysis

      The overall mean difference of Fatigue Severity Scale (FSS) score and fatigue frequency determined by the FSS, and 95% confidence intervals (CIs) were calculated. All statistical analyses were performed using Comprehensive Meta-Analysis (version 2.2.064; Biostat, Englewood, NJ, USA). The meta-analysis software also calculated the Cochrane Q statistic and I2. We used the Cochrane Q statistic and I2 to assess study heterogeneity. If the I2 value was greater than 50%, the included studies were considered substantially heterogeneous. If the p value was less than 0.01 in the Cochrane Q statistics, the null hypothesis was rejected and the studies were considered heterogeneous.

      3. Results

      3.1 Identification of relevant studies

      Fig. 1 shows a flow diagram of how we identified relevant studies. In total, 43,067 articles were identified by searching five databases and by hand-searching relevant bibliographies: 6537 from MEDLINE, 15,281 from EMBASE, 720 from COCHRANE, 7499 from Web of Science, 13,030 from SCOPUS, and one from hand-searching. We excluded 17,456 duplicate articles and an additional 25,423 articles that did not satisfy the selection criteria. We reviewed the full texts of the remaining 191 articles and excluded 179 articles with reference to the selection criteria. After full text review, 12 articles were finally included in this study.
      Fig. 1
      Fig. 1Flow diagram for the identification of relevant studies. In total, 43,068 articles were identified by searching five databases and by hand-searching relevant bibliographies. We excluded 17,455 duplicate articles and an additional 25,422 articles that did not satisfy the selection criteria. We reviewed the full texts of the remaining 191 articles and excluded 179 articles. After reviewing the full texts, 12 articles were included in this study.

      3.2 Characteristics of studies included in the final analyses and review

      Table 1 presents the characteristics of the 12 enrolled studies. All 12 included studies were cross-sectional designs. Ten of the 12 studies were hospital-based studies investigating fatigue or QOL in epilepsy patients using standard questionnaires [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Another was a population-based study [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ] and the remaining study was a survey using an online platform [
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ]. Among the 12 studies, 9 were published as articles [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ], and the remaining 3 studies were conference proceedings [
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ]. The years of publication ranged from 1999 to 2016. Seven of the twelve studies reported summary data on the age of epilepsy patients, with the mean age of participants ranging from 34.3 to 39.8 years [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Three of the twelve studies reported summary data on the age of healthy controls, with the mean age ranging from 35.6 to 47.8 years [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Three studies were performed in Turkey, three in Canada, two in South Korea, one in the US, one in Brazil, one in France, and one was based on an online platform survey.
      Table 1Characteristics of the included studies in the final analyses and review.
      Study (author, year)
      The enrolled studies were sorted by fatigue inventories used, reporting patterns, and years in which the studies were done.
      Country, continentData sourceStudy designInventory for fatigueControlsSample sizeReport of scoreReport of frequencyMean age of epilepsy patientsPredictors for fatigue based on multiple regressionCorrelation with depression
      Hernandez-Ronquillo et al.
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      Canada, North AmericaNeurological clinicCross-sectional studyFSS, FSI, FAIHV, MS, migraine, radiculopathyEpilepsy: 67, HV: 34, MS: 30, migraine: 19, radiculopathy: 7YesNoNo dataNot doneYes
      Kwon and Park
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      South Korea, Eastern AsiaEpilepsy clinicCross-sectional studyFSSHVEpilepsy: 270, HV: 200YesRecruited39.8Sleep-related impairment, depressionYes
      Soyuer et al.
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      Turkey, Western AsiaEpilepsy clinicCross-sectional studyFSSHVEpilepsy: 73, HV: 31YesEpilepsy: yes. HV: no35.64Not doneYes
      Ettinger et al.
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      USA, North AmericaMedical centerCross-sectional studyFSSHV, depressionEpilepsy: 89, HV: 30, depression: 26YesYes35.1Not doneYes
      Kim and Ha
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      South Korea, AsiaEpilepsy clinicCross-sectional studyFSSNoneEpilepsy: 39YesYes38.3Seizure frequencyNo data about depression
      Senol et al.
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      Turkey, Western AsiaEpilepsy clinicCross-sectional studyFSSNoneEpilepsy: 103NoYes34.3Not doneNot done
      Naqvi et al.
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      Canada, North AmericaEpilepsy clinicCross-sectional studyFSSNoneEpilepsy: 56NoYesNo dataDepressionYes
      Erdogan et al.
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      Turkey, Western AsiaEpilepsy clinicCross-sectional studyFSSNoneEpilepsy: 70NoYesNo dataNot doneNo data about depression
      De La Loge et al.
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      Onlie platformPatietLikeMe® platformCross-sectional studySelf reportNoneEpilepsy: 2135NoYesNo dataNot doneNo data about depression
      Neves and Gomes
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      Brazil, South AmericaNeurological clinicCross-sectional studyVsSF-36NoneEpilepsy: 98YesNo39.74Depression, quality of sleepYes
      Hamelin et al.
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      France, EuropeEpilepsy clinicCross-sectional studyFISNoneEpilepsy: 279NoYes39Not doneYes
      Téllez-Zenteno et al.
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      Canada, North AmericaPopulation-basedCross-sectional studyDoor-to-door surveyGeneral populationCanadian community: 130,883NoYesNo dataNot doneNo data about depression
      FSS: Fatigue Severity Scale, FSI: Fatigue Symptom Index, FAI: Fatigue Assessment Inventory, HV: healthy volunteer, MS: multiple sclerosis, VsSF-36: vital subscale of 36-Item Short Form Health Survey, FIS: Fatigue Impact Scale.
      a The enrolled studies were sorted by fatigue inventories used, reporting patterns, and years in which the studies were done.
      Various inventories were used for the evaluation of fatigue depending on the studies. Eight studies used the FSS [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ,
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ]. Therefore, the FSS was the most commonly used inventory. Five of the eight studies reported the FSS scores of epilepsy patients [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. In addition, four provided the FSS scores of healthy controls, so we were able to use the four studies to compare FSS scores between epilepsy patients and healthy controls [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. One of the four studies, which reported FSS scores in both epilepsy patients and healthy controls, also provided the FSS scores of other neurological diseases, such as multiple sclerosis, migraine, and radiculopathy [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ]. The authors of that study validated the other two inventories simultaneously with the FSS in epilepsy patients. These inventories were the Fatigue Symptom Inventory (FSI) and the Fatigue Assessment Inventory (FAI) [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ]. One study among the eight studies with the FSS score included control patients with depression [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ].
      Six of the eight studies that used the FSS presented the fatigue frequency in epilepsy patients based on cut-off points of the FSS scores [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. However, the number of healthy controls with fatigue was declared in only one study [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ]. That study also had depressed controls and provided the frequency of fatigue in all study groups: epilepsy patients, controls with depression, and healthy controls [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ]. One author of this review is also an author of another study that used the FSS, which did not provide the number of healthy controls with fatigue. Thus, we could also examine the fatigue frequency in both epilepsy patients and healthy controls by re-examining the raw data of that study [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ].
      Four studies did not use the FSS [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ], and one of them applied the Medical Outcomes Study 36-Item Short Form Health Survey (MOS SF-36). As a fatigue inventory, the authors used the vitality subscale (VsSF-36) of the MOS SF-36 [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. That study evaluated fatigue in epilepsy patients and investigated the relationship of daytime sleepiness, sleep quality, and depression with fatigue. Another study used the Fatigue Impact Scale (FIS) [
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ] to evaluate fatigue in epilepsy patients at different time points (i.e., the interictal and postictal periods) and to investigate the effects of depression, sleepiness, and epilepsy factors on fatigue. The authors reported the FIS scores of epilepsy patients in the absence of a control group. Another study was a population-based study based on the Canadian Health Survey. The purpose of the study was to compare the prevalence of chronic somatic conditions between epilepsy patients and the general population. The authors performed a door-to-door health survey to obtain information on epilepsy and fatigue [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ]. The last study that did not use the FSS was performed using an online platform (PatientsLikeMe®) [
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ]. Epilepsy patients freely used the platform, and they recorded, monitored, and shared sociodemographic and clinical features of their disease conditions. They also completed thePatient Reported Outcomes instrument. The authors investigated fatigue via the online self-report portion of the platform.
      Four of the 12 included studies proposed risk factors for fatigue in epilepsy patients using multiple regression analyses [
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Seven of the twelve studies showed a correlation between the depression inventory score and fatigue inventory score [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ].

      3.3 Scores of fatigue inventories

      Seven studies provided scores from fatigue inventories [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Four studies yielded FSS scores in both epilepsy patients and healthy controls [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The FSS consists of nine items assessing fatigue, with each item having a scale from 0 to 7 [
      • Krupp L.B.
      • LaRocca N.G.
      • Muir-Nash J.
      • Steinberg A.D.
      The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.
      ]. The final FSS values range from 0 to 7 because the total score of the nine items is divided by the number of items. The FSS score was higher in epilepsy patients than in healthy controls in all four studies. The overall mean difference was estimated using the fixed effect model: 0.794 with a 95% CI of 0.587–1.001 (Fig. 2).
      Fig. 2
      Fig. 2Comparison of the overall Fatigue Severity Scale (FSS) score between epilepsy patients and healthy controls. The FSS score was higher in epilepsy patients than in healthy controls in all four studies in the comparison between 499 epilepsy patients and 295 healthy controls. The overall mean difference in FSS scores estimated using the fixed effect model was 0.794 out of a total score of 7. The 95% confidence interval (CI) was 0.587–1.001.
      One study provided FSI and FAI scores, as well as an FSS score to validate the scales for clinical use [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ]. The authors adapted the scales to epilepsy patients and other patients with multiple sclerosis, migraine, and radiculopathy. For comparison, the authors also applied the scales to healthy volunteers. The fatigue scores of all three instruments in all disease subgroups were statistically different compared with the healthy volunteers. There were no comparisons among the disease subgroups in the study.
      Another study used the VsSF-36 scores of epilepsy patients in the absence of controls [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. For comparison, the authors used data from a different study: a dissertation. The dissertation explored headache and QOL in professional bus drivers in Rio De Janeiro, which is where the authors’ study was performed [
      • Carneiro L.M.
      Prevalência da cefaléia e suas consequências na qualidade de vida de motoristas de uma empresa de transporte coletivo urbano [dissertation].
      ]. The authors compared the scores of epilepsy patients with those of drivers with chronic headaches. The VsSF-36 scores did not differ significantly between the two groups.
      The last of the seven studies with a fatigue score used the FIS as a fatigue inventory [
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ] with no controls. They found that epilepsy patients had high chronic fatigue scores regardless of the type of epilepsy, seizure frequency, or number of antiepileptic drugs. FIS scores were significantly higher in the postictal than the interictal period, and were positively correlated with the Beck Depression Inventory and Epworth Sleepiness Scale scores.

      3.4 Frequency of fatigue

      Seven hospital-based studies provided the number of fatigue events in epilepsy patients based on FSS score cut-off points [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The frequency of fatigue in epilepsy patients across seven studies reporting on 700 persons ranged from 43.8% to 50.0%. The overall event rate estimated using the fixed effects model was 0.471, and its 95% CI was 0.434–0.508 (Fig. 3). In a different study, the event rate of fatigue in epilepsy patients was determined based on a self-reported database obtained using the online platform PatientsLikeMe® [
      • De La Loge C.
      • Dimova S.
      • Durgin T.
      • Phillips G.
      • Mueller K.
      • Lafosse C.
      • et al.
      Patientslikeme® epilepsy community: factors affecting quality of life.
      ]. The fatigue rate was 0.500 (1068/2135). This event rate was similar to that of hospital-based studies.
      Fig. 3
      Fig. 3Overall frequency of fatigue among epilepsy patients. Seven studies provided the number of fatigue events in epilepsy patients using FSS-score cut-off points. The frequency of fatigue in epilepsy patients across the seven studies reporting on 700 persons ranged from 43.8% to 50.0%. The overall event rate estimated using the fixed effects model was 0.471 and its 95% CI was 0.434–0.508.
      We identified event rates of healthy controls using raw data in one of the seven studies; the rates of epilepsy patients and healthy controls were 0.441 (119/270) and 0.315 (63/200), respectively. Therefore, the frequency ratio (FR) of fatigue between epilepsy patients and healthy controls in the study was 1.4 [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ]. Another study also showed the event rates of fatigue in epilepsy patients, healthy controls, and controls with depression. The rates were 0.438 (39/89), 0.167 (5/30), and 0.500 (13/26), respectively. Thus, the FR between epilepsy patients and healthy controls was 2.6, and the frequency of fatigue in epilepsy patients was similar to that in depressive patients [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ]. The Canadian population-based survey provided the prevalence ratio (PR) between epilepsy patients and the general population. The PR was 4.1 with a 95% CI of 2.8–5.7 [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ].
      Taken together, the frequency of fatigue in epilepsy patients was 47.1% with a 95% CI of 43.4%–50.8%; the FR of epilepsy patients was 1.4 or 2.6 times higher than that of healthy adults and the PR of the patients was 4.1 times higher than that of the general population. The wide distribution of the FR and PR may be due to the variability of controls in each study.

      3.5 Correlation between fatigue and depression

      Seven studies found significant correlation coefficients between depression inventory scores and fatigue inventory scores [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The paired combinations between fatigue inventories and depression inventories varied according to each individual study (Table 2). The FSS was employed most commonly to evaluate fatigue; five of the seven studies used the FSS as a fatigue inventory [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Another study used the VsSF-36 [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ], and the remaining study used FIS to evaluate fatigue [
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ]. The most commonly used inventory for the evaluation of depression was the BDI. Four of the seven studies used the BDI as a depression inventory [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Another two studies used the Center for Epidemiologic Studies Depression Scale [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ], and the remaining study used the Neurological Disorders Depression Inventory for Epilepsy [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ] to evaluate depression. The correlation coefficients of the five studies that used the FSS ranged from 0.497 to 0.60. The correlation coefficient of the study that used both the FIS and BDI was 0.7348 [
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ]. The correlation coefficient of the study that used both the VsSF-36 and BDI was −0.660 [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Since vitality is greater when the VsSF-36 score is higher, there is a negative correlation between the VsSF-36 and BDI scores (Table 2).
      Table 2Studies that provided correlation coefficients between depression inventory and fatigue inventory scores.
      Study (author, year)Fatigue inventoryDepression inventoryCorrelation coefficient (r)p
      Hernandez-Ronquillo et al.
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      FSSBDI0.52<0.01
      Kwon and Park
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      FSSNDDI-E0.497 <0.001
      Soyuer et al.
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      FSSBDI0.636 <0.01
      Ettinger et al.
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      FSSCES-D0.60.001
      Naqvi et al.
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      FSSCES-D0.58 <0.01
      Neves and Gomes
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      VsSF-36BDI−0.660<0.0001
      Hamelin et al.
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      FISBDI0.7348<0.0001

      3.6 Risk factors for fatigue

      In 4 of 12 studies [
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ], multiple regression analyses were performed to investigate the risk factors for fatigue in epilepsy patients. The significant risk factors were depression [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ], sleep-related impairment [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ], and sleep quality [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Depression was a significant risk factor for fatigue in all three studies that included depression as a variable in their multiple analyses [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Among the epilepsy-related factors, seizure frequency was a significant risk factor for fatigue in one study [
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ]. However, that study did not include enough variables: psychosocial factors and sleep-related problems were not included in the multiple regression analysis. It is especially problematic that the authors did not include depression as a variable in their analysis, which has been strongly correlated with fatigue in other studies [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Controlled confounders included age, sex, job, driver’s license, marital status, age at onset, household income, number of AEDs, duration of epilepsy, seizure control, seizure type, cause of seizures, seizure focus, depression, anxiety, sleep quality, excessive daytime sleepiness, co-administration of psychiatric drugs, EEG findings, and MRI findings.

      3.7 Evaluation of heterogeneity

      We evaluated study heterogeneity using Cochrane Q statistics and I2 among the four studies that provided FSS scores in both epilepsy patients and healthy controls [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ] and among the seven studies that provided frequencies of fatigue in epilepsy patients [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Since fewer than 10 studies were included in the evaluations, we did not obtain funnel plots to show publication bias.
      The first four studies were highly heterogeneous. The Cochrane Q statistics and I2 were 30.020 (p = 0.000) and 90.007%, respectively. The forest plot of the four studies also presented the heterogeneity (Fig. 2). However, we used the fixed effects model to estimate the overall FSS score and 95% CI since the designs of the studies were not clinically heterogeneous. We intended to explore the causes of heterogeneity based on careful review of the studies. Two of the four studies had strict exclusion criteria [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ], but the other two studies did not establish exclusion criteria [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Therefore, the effects of other severe conditions, excluding epilepsy, were controlled in the former two studies. The studies were Kwon’s [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ] and Ettinger’s [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ]. In Kwon’s study, epilepsy patients were excluded in cases where the patient had severe neurological diseases and/or other medical diseases. In Ettinger’s study, patients were excluded if they had mental retardation, cerebral palsy, and/or progressive central nervous system disorders. The mean differences in the FSS scores between epilepsy patients and healthy controls in the two studies were smaller than those of Hernandez-Ronquillo’s [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ] and Soyuer’s studies [
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The mean differences in the former two studies were 0.400 and 0.760, respectively, and those in the latter two studies were 1.600 and 2.230, respectively (Fig. 2).
      Furthermore, Souyer’s study, which had the largest mean difference, had the lowest mean FSS score and standard deviation of healthy controls among the studies (Table 3). The mean FSS score and standard deviation (SD) were 1.5 and 0.35, respectively. The mean ± SD of the FSS score of healthy controls was 2.6 ± 1.1, 2.7 ± 1.3, and 2.91 ± 1.06 in the other three studies, respectively, in the order of Hernandez-Ronquillo’s, Kwon’s, and Ettinger’s studies. The mean age of the healthy controls in Souyer’s study was also the youngest age among the four studies (Table 3). The mean age of the study was 35.61 years old, and those of the other two studies were 40.3 and 47.8 years old, respectively, for Kwon’s and Ettinger’s study. There was no information on age in Heranandez-Ronquillo’s study. Thus, the healthy controls in Souyer’s study may have been healthier and had fewer factors that induced fatigue than those included in the other three studies.
      Table 3Descriptive statistics of the four studies included in estimation of the overall mean difference in Fatigue Severity Scale (FSS) scores between epilepsy patients and healthy controls.
      EpilepsyControl
      FSS scoreSample numberMean ageFSS scoreSample numberMean age
      MeanSDMeanSD
      Hernandez-Ronquillo et al.
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      4.21.567No data2.61.134No data
      Kwon and Park
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      3.11.527039.82.71.320040.3
      Soyuer et al.
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      3.731.817335.641.50.353135.61
      Ettinger et al.
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      3.671.58935.12.911.063047.8
      SD: standard deviation.
      Among the seven studies in which the event rate of fatigue was provided based on cut-off scores of the FSS, the heterogeneity was low [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The Cochrane Q statistics and I2 were 7.392 (p = 0.286) and 18.833%, respectively (Fig. 3). There was no heterogeneity among the five studies in which the correlations between the FSS scores and the depression inventory scales were presented [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The Cochrane Q statistics and I2 were 3.330 (p = 0.504) and 0.000%, respectively.

      3.8 Study quality assessment

      The methodological quality of the studies included in the meta-analysis of the mean difference in FSS scores was assessed based on the Newcastle–Ottawa Scale [

      Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. [Accessed 4 March 2016].

      ]. The results of the assessment are summarized in Supplemental Table S1. The risk of bias in the studies included in the meta-analyses of the event rates of fatigue and/or the correlation between fatigue and depression were evaluated based on the Quality in Prognosis Studies tool [
      • Hayden J.A.
      • van der Windt D.A.
      • Cartwright J.L.
      • Cote P.
      • Bombardier C.
      Assessing bias in studies of prognostic factors.
      ]. The results of the evaluation are summarized in Supplemental Table S2.

      4. Discussion

      This review showed that the degree of fatigue was higher in adult epilepsy patients than in healthy adults [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The estimated overall frequency of fatigue in epilepsy patients was 47.1% [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Erdogan F.
      • Soyuer F.
      • Senol V.
      • Arman F.
      Effects of fatigue on the quality of life of epilepsy patients.
      ,
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Senol V.
      • Soyuer F.
      • Arman F.
      • Ozturk A.
      Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. The frequency or prevalence of fatigue was 1.4–4.1 times higher in epilepsy patients than in healthy controls or the general population [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ].
      Determining the prevalence or frequency of fatigue precisely is problematic, even in population-based studies. The prevalence of fatigue in the general population is 22% in Norway and 38% in England [
      • Loge J.H.
      • Ekeberg O.
      • Kaasa S.
      Fatigue in the general Norwegian population: normative data and associations.
      ,
      • Pawlikowska T.
      • Chalder T.
      • Hirsch S.R.
      • Wallace P.
      • Wright D.J.
      • Wessely S.C.
      Population based study of fatigue and psychological distress.
      ]. These two studies used the Fatigue Questionnaire to measure fatigue. In a Norwegian study that used the FSS, the prevalence of fatigue in the general population was found to be 23.1% [
      • Lerdal A.
      • Wahl A.
      • Rustoen T.
      • Hanestad B.R.
      • Moum T.
      Fatigue in the general population: a translation and test of the psychometric properties of the Norwegian version of the fatigue severity scale.
      ]. In the working population of the Netherlands, fatigue was measured using the Checklist Individual Strength questionnaire, and its prevalence was 22% [
      • Bultmann U.
      • Kant I.
      • Kasl S.V.
      • Beurskens A.J.
      • van den Brandt P.A.
      Fatigue and psychological distress in the working population: psychometrics, prevalence, and correlates.
      ]. The fatigue frequency of healthy controls was reported in two studies in our review: 16.7% and 31.5%, respectively. Therefore, the prevalences of fatigue in general population were 22–38%, and the frequencies of fatigue in healthy controls were 16.7–31.5% [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ].
      The prevalence or frequency of fatigue may vary according to sociodemographic, cultural and linguistic factors. Moreover, the diversity among fatigue inventories may influence the variation in prevalence or frequency. Therefore, the FR and PR between epilepsy patients and healthy controls or the general population in a single dataset facilitate investigation of fatigue in epilepsy patients. The fatigue frequency was compared between epilepsy patients and healthy controls in two studies, with FRs of 1.4 and 2.6, respectively [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ]. The FR may also be affected by the characteristics of the healthy controls. The FSS was used as the fatigue inventory in those two studies. In a Canadian population-based study, a door-to-door survey was performed, and the PR between epilepsy patients and the general population was 4.1 [
      • Téllez-Zenteno J.F.
      • Matijevic S.
      • Wiebe S.
      Somatic comorbidity of epilepsy in the general population in Canada.
      ].
      To determine the prevalence of fatigue precisely, several prerequisites regarding the research framework are needed. The research should be population-based, involving randomized sampling, and should be conducted by interviews using validated inventories. In the future, to determine the difference in fatigue prevalence between epilepsy patients and the general population, a comparison in the same community with the prerequisites is required.
      To investigate the risk factors for fatigue in epilepsy patients, four studies among the studies included in this review performed multiple regression analyses with many variables [
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. However, the analysis of one of these studies was inadequate because the authors did not include depression, other psychosocial factors, or sleep-related factors as variables in their analysis [
      • Kim K.
      • Ha Y.S.
      Factors influencing on fatigue in patients with epilepsy.
      ]. According to the results of the former three studies, depression, sleep-related impairment, and sleep quality were significant risk factors. In all three studies, depression was a significant risk factor [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ].
      The bidirectional relationship between depression and epilepsy is well established. Depression is frequently comorbid in epilepsy patients, and the frequency of the comorbidity is 9–37% [
      • Kwon O.Y.
      • Park S.P.
      Depression and anxiety in people with epilepsy.
      ]. As we discussed, all three studies that included depression in their multiple regression analyses revealed that depression was a significant risk factor for fatigue in epilepsy patients [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. To highlight this, seven of twelve studies included in this review showed a significant correlation between depression and fatigue [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. Taken together, depression is frequently comorbid with epilepsy and is a major risk factor for fatigue in epilepsy patients. This suggests that to reduce their fatigue we should be aware of depression in epilepsy patients.
      Many studies implicated depression as a major risk factor for comorbid problems in epilepsy patients, and the impact was stronger than that of seizure-related factors. The negative influence of depressive symptoms on the QOL of epilepsy patients is stronger than that of seizure control, and explains more variance in their QOL than any other seizure-related or demographic factors [
      • Choi-Kwon S.
      • Chung C.
      • Kim H.
      • Lee S.
      • Yoon S.
      • Kho H.
      • et al.
      Factors affecting the quality of life in patients with epilepsy in Seoul, South Korea.
      ,
      • Tracy J.I.
      • Dechant V.
      • Sperling M.R.
      • Cho R.
      • Glosser D.
      The association of mood with quality of life ratings in epilepsy.
      ]. One study showed that the QOL was better even in drug-resistant epilepsy patients when they did not have affective symptoms than in well-controlled epilepsy patients with affective symptoms. This also suggests that depression is more influential than seizure-related factors, including seizure control, in reducing the QOL of epilepsy patients [
      • Park S.P.
      • Song H.S.
      • Hwang Y.H.
      • Lee H.W.
      • Suh C.K.
      • Kwon S.H.
      Differential effects of seizure control and affective symptoms on quality of life in people with epilepsy.
      ].
      This tendency for depression in epilepsy patients with fatigue was also observed in the investigations included in this review. Depression was found to be a significant risk factor for fatigue in epilepsy patients, while seizure-related factors were not [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Epilepsy patients may be more depressive if their seizures are not controlled sufficiently [
      • O’Donoghue M.F.
      • Goodridge D.M.
      • Redhead K.
      • Sander J.W.
      • Duncan J.S.
      Assessing the psychosocial consequences of epilepsy: a community-based study.
      ,
      • Kwon O.Y.
      • Park S.P.
      Frequency of affective symptoms and their psychosocial impact in Korean people with epilepsy: a survey at two tertiary care hospitals.
      ]. Depression caused by poor seizure control may ultimately make patients feel more fatigued, and the resulting fatigue may precipitate seizures [
      • Ferlisi M.
      • Shorvon S.
      Seizure precipitants (triggering factors) in patients with epilepsy.
      ,
      • Balamurugan E.
      • Aggarwal M.
      • Lamba A.
      • Dang N.
      • Tripathi M.
      Perceived trigger factors of seizures in persons with epilepsy.
      ]. Overall, a vicious cycle of depression, fatigue, and poor seizure control can occur, and the cycle may be aggravated if the pathway is not interrupted. For these reasons, physicians of epilepsy patients should be aware of the fatigue and attempt to reduce the patients’ depression.
      Several studies have reported a correlation between fatigue and depression [
      • Hernandez-Ronquillo L.
      • Moien-Afshari F.
      • Knox K.
      • Britz J.
      • Tellez-Zenteno J.F.
      How to measure fatigue in epilepsy? The validation of three scales for clinical use.
      ,
      • Ettinger A.B.
      • Weisbrot D.M.
      • Krupp L.B.
      • Coyle P.K.
      • Jandorf L.
      • Devinsky O.
      Fatigue and depression in epilepsy.
      ,
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ,
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ,
      • Naqvi R.
      • McLachlan R.S.
      • Matijevic S.
      • Burneo J.G.
      Fatigue is a common symptom in epilepsy.
      ,
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ,
      • Soyuer F.
      • Erdoğan F.
      • Şenol V.
      • Arman F.
      The relationship between fatigue and depression, and event-related potentials in epileptics.
      ]. These studies used the FSS, VsSF-36 and FIS as fatigue inventories and the BDI, NDDI-E and CES-D as depression inventories. The NDDI-E does not include any item associated with fatigue [
      • Gilliam F.G.
      • Barry J.J.
      • Hermann B.P.
      • Meador K.J.
      • Vahle V.
      • Kanner A.M.
      Rapid detection of major depression in epilepsy: a multicentre study.
      ]. However, on careful inspection, we found that problems considered by several items in the BDI and CES-D depression inventories were very similar to items in the FSS, VsSF-36 and FIS fatigue inventories [
      • Krupp L.B.
      • LaRocca N.G.
      • Muir-Nash J.
      • Steinberg A.D.
      The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.
      ,
      • Brown L.F.
      • Kroenke K.
      • Theobald D.E.
      • Wu J.
      Comparison of SF-36 vitality scale and Fatigue Symptom Inventory in assessing cancer-related fatigue.
      ,
      • Fisk J.D.
      • Ritvo P.G.
      • Ross L.
      • Haase D.A.
      • Marrie T.J.
      • Schlech W.F.
      Measuring the functional impact of fatigue: initial validation of the fatigue impact scale.
      ]. The items ask about working, sexual activity and motivation. Although the fatigue inventories inquire about the problems induced by fatigue while the depression inventories inquire about those induced by a depressed mood, the patients may consider them to be the same questions [
      • Beck A.T.
      • Ward C.H.
      • Mendelson M.
      • Mock J.
      • Erbaugh J.
      An inventory for measuring depression.
      ,
      • Radloff L.S.
      The CES-D scale a self-report depression scale for research in the general population.
      ]. In addition, the 17th item of the BDI directly enquires about fatigue [
      • Beck A.T.
      • Ward C.H.
      • Mendelson M.
      • Mock J.
      • Erbaugh J.
      An inventory for measuring depression.
      ]. In our results, the correlations between the FSS, VsSF-36 or FIS and BDI or CES-D were stronger than that between the FSS and NDDI-E (Table 2). Therefore, there may be some interaction between the scores of fatigue inventories and depression inventories. Consequently, the tendency for depression in patients with fatigue could have been subject to bias.
      One study performed a multiple regression analysis, which indicated that sleep-related impairment is a crucial risk factor for fatigue in epilepsy patients [
      • Kwon O.Y.
      • Park S.P.
      Interictal fatigue and its predictors in epilepsy patients: a case-control study.
      ]. Another study, in which multiple regression analysis was not performed, revealed that fatigue in epilepsy patients was correlated with daytime sleepiness by showing a significant correlation coefficient [
      • Hamelin S.
      • Kahane P.
      • Vercueil L.
      Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey.
      ]. Thus, the two studies both showed that daytime sleepiness was associated with fatigue in epilepsy patients. However, another study that performed multiple regression analysis provided a different viewpoint. That study showed that sleep quality rather than daytime sleepiness was a significant risk factor for fatigue [
      • Neves G.
      • Gomes M.D.
      Fatigue in patients with epilepsy and its association with depression and sleep quality.
      ]. Our review indicates that few studies have explored the relationship between sleep problems and fatigue; the number of studies was not sufficient to perform a meta-analysis. Further studies are required to establish the relationship based on meta-analysis.
      There are some limitations of this study. First, the quality of studies included in this review varied. Specifically, various inventories for fatigue were used. Some studies used a subscale of an inventory, an online platform, or a door-to-door survey. In addition, some studies included healthy controls, whereas other studies did not. Second, the patterns of reporting results were variable. The most suitable studies for our review were studies reporting both inventory scores and fatigue frequencies in both epilepsy patients and healthy controls. However, only a limited number of studies provided both the scores and fatigue frequency. In addition, some studies provided the scores and/or frequencies only in epilepsy patients but not in healthy controls while others did not provide fatigue frequencies. Because of these problems, we used a limited number of studies to perform the meta-analysis of fatigue strength in epilepsy patients and healthy controls and performed the one-arm meta-analyses for fatigue frequency in epilepsy patients only. We expect that more studies will report event rates for healthy controls in the future, which will allow us to perform a meta-analysis comparing the fatigue frequency between epilepsy patients and healthy controls and increase the meta-analysis quality. Third, according to the results of this review, no epilepsy-specific inventory for fatigue has been developed to date. The depression inventories used in the studies included in this review, with the exception of the NDDI-E, are also not epilepsy-specific. Because most of the inventories used in the selected articles were not epilepsy-specific, there may be the potential for bias. Lastly, we cannot confirm the causality between each risk factor for fatigue. Since the study designs included in this review were cross-sectional, the studies did not clarify causality. Therefore, further studies with a cohort-study design are required to explore the association between fatigue and epilepsy.

      5. Conclusions

      Although there are some limitations, our review shows that fatigue is more frequent and more severe in adult epilepsy patients than in healthy adults, and can be induced by depression and sleep problems. Physicians who care for epilepsy patients should pay attention to patients’ fatigue, and understand that depression and sleep problems may aggravate or provoke fatigue.

      Conflict of interest statement

      The authors report no financial interests or potential conflicts of interest related to the present study, except the following. Because one author of this review was an author of a study included in this review (OY Kwon), another author of this review (HJ Kim) confirmed the objectiveness of the study to eliminate the probable conflict of interest.

      Acknowledgment

      This work was supported by the Gyeongsang National University Fund for Professors on Sabbatical Leave , 2016.

      Appendix A.

       Search strategy

       MEDLINE

      “Epilepsy”[Mesh] 137993.
      epilepsy[tiab] OR Epilepsies[tiab] OR “Seizure Disorder”[tiab] OR “Seizure Disorders”[tiab] OR Epileptic[tiab] 101387
      1 OR 2 162723
      “Quality of Life”[Mesh] OR “Fatigue”[Mesh] OR “Fatigue”[Mesh:NoExp] OR “Mental Fatigue”[Mesh] OR “Disorders of Excessive Somnolence”[Mesh:NoExp] OR “Hypersomnolence, Idiopathic”[Mesh] 155464
      “Life Qualities”[tiab] OR “Life Quality”[tiab] OR “quality of life”[tiab] OR “fatigue”[tiab] OR “Lassitude”[tiab] OR “Hypersomnolence”[tiab] OR “Somnolence”[tiab] OR “Hypersomnolence”[tiab] OR “sleep”[tiab] 352271
      4 OR 5 403604
      3 AND 6 8364]
      7 NOT (“review”[Publication Type] OR “review literature as topic”[MeSH Terms]) 6537

       EMBASE

      ‘epilepsy’/exp 198526
      epilepsy:ab,ti OR Epilepsies:ab,ti OR ‘Seizure Disorder’:ab,ti OR ‘Seizure Disorders’:ab,ti OR Epileptic:ab,ti 141476
      1 OR 2 219296
      ‘quality of life’/exp OR ‘fatigue’/de OR ‘chronic fatigue syndrome’/exp OR ‘exhaustion’/exp OR ‘lassitude’/exp OR ‘daytime somnolence’/exp OR ‘drowsiness’/exp OR ‘somnolence’/exp 501993
      ‘Life Qualities’:ab,ti OR ‘Life Quality’:ab,ti OR ‘quality of life’:ab,ti OR ‘fatigue’:ab,ti OR ‘Lassitude’:ab,ti OR ‘Hypersomnolence’:ab,ti OR ‘Somnolence’:ab,ti OR ‘Hypersomnolence’:ab,ti OR ‘sleep’:ab,ti 510240
      4 OR 5 719247
      3 AND 6 20229
      7 NOT ‘review’/it 16470
      8 NOT (‘animal experiment’/de OR ‘animal model’/de OR ‘human tissue’/de OR ‘nonhuman’/d e) 15281

       COCHRANE

      1. MeSH descriptor: [Epilepsy] explode all Trees 2465
      2. epilepsy or Epilepsies or “Seizure Disorder” or “Seizure Disorders” or Epileptic:ti,ab,kw (Word variations have been searched) 4710
      3. OR 2 5160
      4. MeSH descriptor: [Quality of Life] explode all Trees 17710
      5. MeSH descriptor: [Fatigue] explode all Trees 2065
      6. MeSH descriptor: [Fatigue] this term only 1987
      7. MeSH descriptor: [Mental Fatigue] explode all Trees 94
      8. MeSH descriptor: [Disorders of Excessive Somnolence] this term only 215
      9. MeSH descriptor: [Hypersomnolence, Idiopathic] explode all Trees 4
      10. 4 OR 5 OR 6 OR 7 OR 8 OR 9 19516
      11. “Life Qualities” or “Life Quality” or “quality of life” or “fatigue” or “Lassitude” or “Hypersomnolence” or “Somnolence” or “Hypersomnolence” or “sleep”:ti,ab,kw (Word variations have been searched) 70153
      12. 10 OR 11 70153
      13. 3 AND 12 810
      14. 13/TRIALS 720

       Web of Science

      TOPIC: (epilepsy OR Epilepsies OR “Seizure Disorder” OR “Seizure Disorders” OR Epileptic) OR TITLE: (epilepsy OR Epilepsies OR “Seizure Disorder” OR “Seizure Disorders” OR Epileptic) 123124
      2. TOPIC: (“Life Qualities” OR “Life Quality” OR “quality of life” OR “fatigue” OR “Lassitude” OR “Hypersomnolence” OR “Somnolence” OR “Hypersomnolence” OR “sleep”) OR TITLE: (“Life Qualities” OR “Life Quality” OR “quality of life” OR “fatigue” OR “Lassitude” OR “Hypersomnolence” OR “Somnolence” OR “Hypersomnolence” OR “sleep”) 495244
      3. 1 AND 2 8659
      4. 3/REVIEW EXCLUDE 7499

       SCOPUS

      1. INDEXTERMS (“Epilepsy”) 141888
      2. TITLE-ABS-KEY (epilepsy OR epilepsies OR “Seizure Disorder” OR “Seizure Disorders” OR epileptic) 183625
      3. 15 OR 2 183625
      4. INDEXTERMS (“Quality of Life” OR “Fatigue” OR “Fatigue” OR “Mental Fatigue‘ OR “Disorders of Excessive Somnolence’ OR ‘Hypersomnolence, Idiopathic’) 482899
      5. TITLE-ABS-KEY (“Life Qualities” OR “Life Quality” OR “quality of life” OR “fatigue” OR “Lassitude” OR “Hypersomnolence” OR “Somnolence” OR “Hypersomnolence” OR “sleep”) 853458
      6. 4 OR 5 853458
      7. 3 AND 6 16534
      8. 7/ARTICLES 13030
      Total: 43067
      Duplicates: 17455
      Final: 25612

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