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Pre-ictal heart rate changes: A systematic review and meta-analysis

Open ArchivePublished:January 08, 2018DOI:https://doi.org/10.1016/j.seizure.2018.01.003

      Highlights

      • The pooled incidence of pre-ictal heart rate increase (HRI) was 36/100 seizures.
      • Higher HRI estimates were found in TLE, adults and people on AEDs.
      • Pre-ictal HR reduction incidence was 0.5% in the paediatric population.
      • Bias and methods assessment disclosed limitations in the evidence-base.
      • Monitoring of HR changes could be attempted to early identify seizures.

      Abstract

      Purpose

      To estimate the incidence of pre-ictal heart rate (HR) manifestations and to identify clinical and study-related factors modulating the estimate.

      Methods

      We searched articles recording concurrent pre-ictal EEG and HR in adults and children with epilepsy. Pre-ictal HR changes were classified as HR reduction (HRR) or increase (HRI). Studies reporting the total number of seizures and the number of seizures with pre-ictal HR changes were included in a random-effects meta-analysis. A random-effects meta-regression was used to identify variables affecting study heterogeneity.

      Results

      Thirty studies, including 1110 participants and 2957 seizures, were included. The meta-analysis showed a pooled incidence of pre-ictal HRI of 36/100 seizures (95% CI 22–50). The pre-ictal HRI incidence was 44/100 seizures (95% CI 33–55) in studies including temporal lobe epilepsy, 55/100 seizures (95% CI 41–68) in studies enrolling adults and 35/100 seizures (95% CI 16–58) when patients on antiepileptic drugs were included. The meta-regression showed that the age group, the length of the pre-ictal period, the incidence of ictal tachycardia and the time of onset of the pre-ictal HRI had a significant impact on estimates variability. The pooled incidence of pre-ictal HRR was 0/100 seizures (95% CI 0–1).

      Conclusion

      Review of bias evaluation and methods assessment disclosed several major limitations in the evidence-base. HR monitoring could be valuable to identify seizures prior to their apparent onset, opening the possibility to early interventions. Additional effort is necessary to delineate the target population who might benefit from its use and the mechanisms sustaining the pre-ictal cardiac changes.

      Keywords

      1. Introduction

      The alterations provoked by epileptic seizures on cardiac rate and rhythm have been recognized for more than 70 years [
      • Erikson T.
      Cardiac activity during epileptic seizures.
      ,
      • Gastaut H.
      So-called psychomotor and temporal epilepsy: a critical study.
      ]. Ictal cardiac changes have been attributed either to the activation of cortical structures connected to the autonomic centres, or to peripheral mechanisms regulating reflex responses, driving various cardiac manifestations [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ]. Although a reduction of the heart rate (HR) can occur, the most commonly observed pattern associated with seizures is represented by an increased HR [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ]. Ictal tachycardia (IT) has been reported in up to 80% of all seizures and in 82% of people with epilepsy on average [
      • Eggleston K.S.
      • Olin B.D.
      • Fischer R.S.
      Ictal tachycardia: the head-heart connection.
      ], while ictal bradycardia (IB) is commonly considered a rare event, manifesting in less than 5% of epilepsy patients [
      • Devinsky O.
      Effects of seizures on autonomic and cardiovascular function.
      ,
      • Baumgartner C.
      • Lurger S.
      • Leutmezer F.
      Autonomic symptoms during epileptic seizures.
      ]. The possibility to detect alterations of cardiac parameters during a seizure has led to consider the HR as a potential extra-cerebral seizure biomarker [
      • Eggleston K.S.
      • Olin B.D.
      • Fischer R.S.
      Ictal tachycardia: the head-heart connection.
      ]. In comparison to other more invasive measurements, HR assessment has the potential of providing a reliable and easily measurable signal which may be recorded continuously in a daily life environment. In addition, HR alterations have been reported to occur early during a seizure or even pre-ictally [
      • Jansen K.
      • Lagae L.
      Cardiac changes in epilepsy.
      ], demonstrating a theoretical role in seizure prediction. However, studies investigating ictal and pre-ictal HR changes have yielded controversial results and our understanding of the mechanism supporting these alterations is still limited [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ]. In fact, the frequency of ictal HR manifestations in patients with epilepsy varies considerably across studies and estimates range between 38 and 100% for IT and <5 and 66.7% for IB [
      • Sevcencu C.
      • Struijk J.J.
      Autonomic alterations and cardiac changes in epilepsy.
      ,
      • Eggleston K.S.
      • Olin B.D.
      • Fischer R.S.
      Ictal tachycardia: the head-heart connection.
      ], with higher variability when a pre-ictal onset is considered. This variance likely reflects differences in measurements along with clinical variables, including epilepsy and seizure type, age groups, use of antiepileptic drugs (AEDs), lobe of seizure onset and presence of cardiac co-morbidities. In addition, methodological issues can also be responsible for the mixed findings, including methods used to assess seizure onset and to define HR changes. Understanding the distribution of pre-ictal HR alterations and the temporal relation between these changes and seizure activity might represent a pivotal point to shed new light on the mechanisms shaping the ictal autonomic changes and influencing seizure spreading patterns. Moreover, this could also help to explore the utility of this measure as a seizure detection tool and to identify the target population who might benefit from its use. We aimed to perform a meta-analysis to assess the incidence of pre-ictal HR alterations and to identify clinical and study-related factors modulating this phenomenon.

      2. Methods

      This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Handbook guidelines [
      • Moher D.
      • Liberat A.
      • Tetzlaff J.
      • Altman D.G.
      The PRISMA Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ,
      • Higgins J.
      • Green S.
      Cochrane Handbook for systematic reviews of interventions version 5.1.0. (updated March 2011).
      ].

      2.1 Criteria for considering studies for this review

      Retrospective and prospective studies (case-control, cohort or case series) recording concurrent pre-ictal EEG and HR in adults and children with epilepsy were considered for inclusion. Studies focusing on neonatal seizures only were excluded. Pre-ictal HR changes were classified as HR reduction (HRR) or increase (HRI) as compared to the baseline HR. Methods used to measure the HR and definitions of HR alterations were extracted and considered as separate variables assessed in the meta-regression as potential sources of between studies heterogeneity.

      2.2 Search methods for identification of studies

      A systematic search with no language restrictions was carried-out to identify all relevant published and unpublished studies. The search strategy included the terms “epilepsy”, “heart rate”, “ictal tachycardia” and “ictal bradycardia” and is reported in Appendix S1. The search was conducted from the first date available (1958) up to May 30, 2017 in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). The search strategies for each database were based on the strategy developed for MEDLINE, taking into account the differences in controlled vocabulary and syntax rules. In addition to the electronic searches, we hand-searched reference lists of all available review articles and primary studies and hand-searched the references quoted in the most recent congress proceedings (e.g. International Epilepsy Congress, European Congress on Epileptology).

      2.3 Data collection and analysis

      Two review authors (EB and AB) independently assessed the titles and abstracts of all the studies identified by the electronic searching or hand-searching. Full texts of potentially relevant studies were obtained and screened. We resolved any disagreements concerning study inclusion and exclusion by discussion. For each study included, two review authors (EB and AB) independently extracted the following data on an ad-hoc created data collection form: study design (prospective, retrospective) and setting (inpatients, outpatients); demographic and clinical data of the population (number of patients, age group, gender, type of epilepsy, drug-resistance, cardiac comorbidities, AEDs administration/withdrawal during the recording); number of seizures recorded, seizure type and focus (including focus side), definition of seizure onset (EEG, clinical, either EEG or clinical); EEG characteristics: type (scalp, intracranial), number of electrodes used (standard, non-standard), duration (continuous, intermittent, number of hours recorded), use of video recording; HR assessment methods (automatic versus manual count of R–R intervals or QRS complexes or beats) and length of ECG epoch used for HR analysis (in seconds); duration of the pre-ictal period assessed (in seconds); number of seizures presenting with ictal HR change (IT, IB and definitions adopted) and ictal HR peak/minimum reached; number of seizures with pre-ictal HR change (pre-ictal HRI and HRR) and onset time (seconds before seizure onset).

      2.4 Quality assessment

      The quality of included studies was evaluated using a standard assessment tool, that was slightly re-adapted (Appendix S2), and included sample representativeness, condition assessment, and statistical methods [
      • Fiest K.M.
      • Sauro K.M.
      • Wiebe S.
      • Patten S.B.
      • Kwon C.S.
      • Dykeman J.
      • et al.
      Prevalence and incidence of epilepsy. A systematic review and meta-analysis of international studies.
      ]. Each study was given a quality score of 0 to 8 based on fulfilment of the quality criteria. The quality score was considered as a separate variable in the meta-regression.
      For studies included in the meta-analysis, two review authors (EB and AB) independently assessed the study methods and the risk of bias related to them. The following domains were considered and compared across studies: definition of HR change, definition of pre-ictal period, time interval used to calculate the HR change, assessment of onset of HR change.

      2.5 Data synthesis and analysis

      Studies reporting the total number of seizures recorded and the number of seizures with pre-ictal HR changes (including 0), were included in a meta-analysis.
      Pre-ictal HRI and pre-ictal HRR were separately analysed. In addition, meta-analysis was separately fitted according to epilepsy type, age group and AEDs administration/withdrawal, when these variables were specified by an adequate number of studies. We used the ‘metaprop_one’ command in Stata 14.0 to estimate crude incidence rates along with their 95% confidence intervals (CI) and we expressed the estimates as the number of seizures with pre-ictal HR changes per 100 seizures. We reported the pooled, weighted estimate generated by random-effects models. To handle the studies with zero events, we used Freeman–Tukey double arcsine transformation which stabilizes the variance of the proportion restricting the 95% CI within the range of 0 and 1, even in the presence of zero events [
      • Sweeting M.J.
      • Sutton A.J.
      • Lambert P.C.
      What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data.
      ]. As a sensitivity analysis, the pooling process was repeated after the successive removal of incidence studies judged at high risk of bias in all the domains considered. The I2 was used to quantify the magnitude of between-study heterogeneity and the Cochrane Q statistic was calculated to determine significance. Publication bias was investigated statistically using Begg’s and Egger’s tests. To determine the influence of the clinical variables and of the study-level factors on the observed variability, we used random-effects meta-regression. We regressed one variable at a time. Significance level was established at p < 0.05. All analyses were performed using STATA version 14.0 (StataCorp, College Station, TX, U.S.A.).

      3. Results

      3.1 Study selection and quality assessment

      The search of electronic databases yielded 1130 references (Fig. 1). One additional study was identified by hand-searching. After duplicates and non-relevant studies were removed, the titles and abstracts of the remaining studies were reviewed and the full-text of 98 articles with potentially relevant studies was assessed. Finally, 30 published studies were considered eligible for qualitative synthesis. All the included studies assessed the occurrence of pre-ictal HRI, while pre-ictal HRR was investigated in 20 studies only. The characteristics of all the 30 studies included are summarized in Table 1 and more extensively detailed in Table S1 (Supporting information). Quality assessment revealed a median study quality score of 6/8 (range 1–8).
      Fig. 1
      Fig. 1Flowchart of the study selection process. HRI: heart rate increase; HRR: heart rate reduction.
      Table 1Characteristics of the included studies (N = 30).
      StudiesNo. of ParticipantsAge groupEpilepsy typeNo. of seizuresSeizures with pre-ictal HRI (N, %)Seizures with pre-ictal HRR (N, %)
      Van Buren et al. [
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ]
      13AdultsTLE2019 (95.0)None
      Blumhardt et al. [
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ]
      26AdultsTLE7435 (47.3)None
      Keilson et al. [
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ]
      45Adults and childrenFocal and Gen106NRNone
      Cumulative data only (number and% of seizures not reported).
      Galimberti et al. [
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ]
      50Adults and childrenFocal90NoneNone
      Vaughn et al. [
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ]
      12Adults and childrenFocal and Gen446 (13.6)None
      Novak et al. [
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ]
      12AdultsTLENRNRNA
      Schernthaner et al. [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ]
      41AdultsFocal12786 (67.7)None
      Saleh et al. [
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ]
      27AdultsTLE267 (26.9)NA
      Wilder-Smith et al. [
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ]
      37AdultsFocal37NRNone
      Cumulative data only (number and% of seizures not reported).
      Kirchner et al. [
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ]
      21AdultsTLE216 (13.6)None
      Zijlmans et al. [
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ]
      81Adults and childrenFocal28165 (23.1)NR
      Leutmezer et al. [
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ]
      58AdultsFocal145110 (75.9)None
      Di Gennaro et al. [
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ]
      68AdultsTLE257134 (52.1)None
      Mayer et al. [
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ]
      20ChildrenTLE7220 (27.8)3 (4.2%)
      De Oliveira et al. [
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ]
      27AdultsTLE59None
      Cumulative data only (number and% of seizures not reported).
      None
      Cumulative data only (number and% of seizures not reported).
      Standridge et al. [
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ]
      58ChildrenFocal and Gen24418 (7.4)6 (2.4%)
      Nilsen et al. [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ]
      38AdultsFocal38NRNA
      Toth et al. [
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ]
      31AdultsFocal31None
      Cumulative data only (number and% of seizures not reported).
      NA
      Surges et al. [
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ]
      25AdultsTLE50None
      Cumulative data only (number and% of seizures not reported).
      NA
      Calandra-Buonaura et al. [
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ]
      10Adults + 1 childNFLE45NRNA
      Behbahani et al. [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ]
      12AdultsFocal133NRNA
      Jansen et al. [
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ]
      35ChildrenFocal and Gen8025 (31.3)3 (3.75%)
      Chen et al. [
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ]
      81Adults and childrenFocal181NRNR
      Kato et al. [
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ]
      21AdultsTLE7727 (35.1)None
      Behbahani et al. [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ]
      24AdultsFocal232NRNA
      Chen et al. [
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ]
      102Adults and childrenFocal202NRNone
      Cumulative data only (number and% of seizures not reported).
      Hampel et al. [
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ]
      37AdultsFocal45None
      Cumulative data only (number and% of seizures not reported).
      NA
      Jaychandran et al. [
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ]
      42AdultsFocal57NRNR
      Moridani et al. [
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]
      7NRFocal11NRNA
      Whealy et al. 2017 [
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ]
      49Children and teensTLE17265 (38.0)1 (1%)
      Gen: generalised; HRI: heart rate increase; HRR: heart rate reduction; NA: not assessed; NFLE: nocturnal frontal lobe epilepsy; NR: not reported; TLE: temporal lobe epilepsy
      a Cumulative data only (number and% of seizures not reported).

      3.2 Pre-ictal HRI

      3.2.1 Summary of characteristics of the studies

      Thirty studies, enrolling 1110 people living with epilepsy (39.0% female; 38.2% male; 22.8% not reported) and a total of 2957 seizures, assessed the occurrence of pre-ictal HRI. Eighteen included adults [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ], four children only [
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ], and seven both adults and children [
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ,
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ]. The age group was not reported in one study [
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. Fourteen studies included people with different type of focal epilepsy [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ], 11 TLE [
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ], four a combined sample of focal and generalized epilepsy [
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ], and one nocturnal frontal lobe epilepsy (NFLE) [
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ]. Fifteen studies included drug-resistant patients [
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ], three non-refractory patients and 12 did not report if patients were drug-resistant or not [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. In ten studies people continued to receive their AEDs during the recording [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ], while treatment was withdrawn in six studies [
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ], and 14 did not report the AEDs status. Twenty-one studies included complex partial seizures (CPS) alone or in combination with other seizure types [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ,
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ]. The definition of the pre-ictal and ictal periods was based on seizure onset, identified by clinical [
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ], EEG [
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ], or either clinical and EEG manifestations [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ]. It was not reported in five studies [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. All the studies used scalp EEG, with five studies also including intracranial EEG [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ]. The majority were based on prolonged EEG recording, using a standard number of electrodes and additional video recording. Only studies published before 1997 used less electrodes than standard [
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ]. HR assessment was specified in 23 studies, and it was either manual (nine studies) [
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ], or automatic (14 studies) [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ,
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. The mean time-epoch considered for HR assessment was on average 23.1 s (±23.3; range 5–60) and a mean pre-ictal period of 99.2 s prior to seizure onset (±156.5; range 15–600) was assessed. One study considered multiple pre-ictal periods, starting from 240 min before seizures onset [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ].

      3.2.2 Frequency of ictal and pre-ictal HRI

      The mean baseline HR was 74.35 bpm (±4.8; range 65.9–86.4). Although all the studies described the occurrence of IT, only 18 studies clearly reported its frequency, giving a cumulative incidence of 1556/2957 seizures (52.6%) [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ]. The remaining eight reported the occurrence of IT without specifying the frequency [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ], while four did not report any quantitative data [
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. The mean ictal HR peak was 116.5 bpm (±27.0; range 81.2–201.0), demonstrating a mean increase of 56.8% as compared to the baseline HR. Pre-ictal HRI was found in 623/2957 seizures (21.1%) and it was reported in 14 studies [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ], while no pre-ictal change was found in five studies [
      • Toth V.
      • Hejjel L.
      • Fogarasi A.
      • Gyimesi C.
      • Orsi G.
      • Szucs A.
      • et al.
      Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ]. The remaining eleven studies did not report the number of seizures with pre-ictal HRI, although they commented on its occurrence and onset time [
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ,
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ,
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ,
      • Moridani M.K.
      • Farhadi H.
      Heart rate variability as a biomarker for epilepsy seizure prediction.
      ]. The median onset time of pre-ictal HRI was 10.7 s prior to seizure onset (IQR 5–60), with one study reporting HR increase from 30 min before [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Pre-ictal heart rate variability assessment of epileptic seizures by means of linear and non-linear analyses.
      ].

      3.2.3 Clinical variables and pre-ictal HRI

      In five studies [
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Hampel K.G.
      • Jahanbekam A.
      • Elger C.E.
      • Surges R.
      Seizure-related modulation of systemic arterial blood pressure in focal epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ], seizures originating from the mesial temporal lobe were more often associated with pre-ictal HRI as compared to lateral and extra-temporal onset, with two studies reporting more significant pre-ictal HRI in right-sided mesial seizures [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ]. Only one study observed that pre-ictal changes were more frequent in patients with lateral TLE [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ]. One study investigating NFLE reported a pre-ictal HR increase, although physiological arousal was also associated with a similar HR alteration [
      • Calandra-Buonaura G.
      • Toschi N.
      • Provini F.
      • Corazza I.
      • Bisulli F.
      • Barletta G.
      • et al.
      Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology.
      ]. Seizures of frontal origin were also associated with a lower pre-ictal HR compared to temporal lobe seizures [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ].
      Seven studies included focal seizures exclusively and six [
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Novak V.
      • Reeves L.A.
      • Novak P.
      • Low P.A.
      • Sharbrough F.W.
      Time-frequency mapping of R–R interval during complex partial seizures of temporal lobe origin.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ], reported the occurrence of pre-ictal HRI while one did not observe any alterations [
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ]. Patients with secondarily generalized tonic-clonic (SGTC) seizures were associated with increased pre-ictal HR in one study compared to those with localized seizures only [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ]. However, this finding was not confirmed in another study using a paired design methodology [
      • Surges R.
      • Scott C.A.
      • Walker M.
      Enhanced QT shortening and persistent tachycardia after generalized seizures.
      ]. Although male gender was more often associated with HRI [
      • Behbahani S.
      • Dabanloo N.J.
      • Nasrabadi A.M.
      • Dourado A.
      Gender-related differences in heart rate variability of epileptic patients.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ], no data were available on the influence of gender on HRI onset time. The peri-ictal HR pattern was considered consistent or predictable in the same patient across multiple seizures in 2 studies [
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ], while no stereotyped HR behaviour and high intra-individual variability was observed in another study [
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ].

      3.2.4 Meta-analysis

      Fifteen studies analysing pre-ictal HRI were considered eligible for the meta-analysis [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ]. For studies included in the meta-analysis, the quality assessment yielded higher scores (7/8). The assessment of study methods and risk of bias is detailed in Table 2. A high variety in the four methodological domains considered was demonstrated across studies, and the risk of bias was frequently rated as unclear or high. The pooled incidence of pre-ictal HRI was 36/100 seizures (95% CI 22–50) (Fig. 2A), with a significant between study heterogeneity (I2 = 97.25%, Q p-value = 0.000). Egger’s and Begg’s test were not significant (p = 0.74, p = 0.92 respectively) indicating a low risk of publication bias. The analysis performed according to epilepsy type (Fig. 3A) showed that studies including TLE had a pre-ictal HRI incidence of 44/100 seizures (95% CI 33–55) while the incidence was 36/100 seizures (95% CI 6–75) for studies including mixed focal types and 16/100 seizures (95% CI 4–34) for those including generalized and focal epilepsy combined. Studies including adults presented with an incidence rate of 55/100 seizures (95% CI 41–68) while the incidence was 25/100 seizures (95% CI 9–44) for studies including children and 9/100 seizures (95% CI 0–33) for studies including both children and adults (Fig. 3B). Studies including patients recorded while on AED treatment had a pooled incidence rate of 35/100 seizures (95% CI 16–58) as compared to 22/100 seizures (95% CI 4–47) for those studies including patients withdrawing the treatment (Fig. 3C). The treatment status was not reported in 5 studies [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Saleh T.
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Temporallappenepilepsien.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ].
      Table 2Methods and risk of bias of studies included in the meta-analysis (N = 15) (For interpretation of the references to colour in the table legend, the reader is referred to the web version of this article.).
      Risk of bias assessment: red = high risk of bias, yellow = unclear risk of bias, green = low risk of bias. Risk of bias assessment criteria: Definition of HR change: Baseline not defined or overlapping with pre-ictal periods (high risk of bias), Unclear HRI definition (unclear risk of bias), Well defined HR change (low risk of bias). Definition of pre-ictal period: ≤30 seconds or not defined (high risk of bias), >30 and <60 seconds (unclear risk of bias), ≥60 seconds (low risk of bias). Time interval to calculate HR change: Fixed time interval (average of RR intervals) ≥ 10 sec or not defined (high risk of bias), Fixed time interval (average of RR intervals) <10 sec (unclear risk of bias), Dynamic (instant RR intervals plot) (low risk of bias). HR change onset time: Not reported (high risk of bias), Time interval of HR change as per definition (unclear risk of bias), Exact onset (first instant HR change) reported (low risk of bias). Bpm: beat per minute; CIs: confidence intervals; HR: heart rate; HRI: heart rate increase; HRR: heart rate reduction.
      Fig. 2
      Fig. 2Cumulative incidence of pre-ictal heart rate increase (HRI) (A) and pre-ictal heart rate reduction (HRR) (B).
      Fig. 3
      Fig. 3Cumulative incidence of pre-ictal heart rate increase (HRI) by epilepsy type (A), age group (B) and AEDs status during the recording (C).
      The meta-regression (Table S2, Supporting information) showed that, among clinical variables, the age group of study participants had a significant impact on variability of studies (p = 0.004), accounting for 23.44% of the observed heterogeneity. Among methodological covariates, the length of the pre-ictal period during which the HR was assessed (p = 0.016), explained an additional 33.44% of the observed heterogeneity, with higher incidence in studies using a longer time frame (60 s or more). In addition, the pre-ictal HRI estimates were significantly correlated with the IT frequency (p = 0.004) and with the time of onset of the pre-ictal changes (p = 0.04), and higher pre-ictal estimates were reported in studies observing higher IT estimates or earlier HRI presentations (Fig. 4). Finally, the sensitivity analysis demonstrated comparable results when two studies considered at high risk of bias in all the domains were excluded (pre-ictal HRI incidence 36/100 seizures, 95% CI 23–49; I2 = 96.58%, Q p-value = 0.000) and the meta-regression found no effect of study quality on the estimates of the pre-ictal HR (p = 0.2).
      Fig. 4
      Fig. 4Meta-regression bubble plot showing the variation of the incidence of pre-ictal heart rate increase (HRI) regressed against the (A) proportion of seizures with ictal tachycardia (IT) and the (B) time of onset of pre-ictal HRI reported in the studies included.

      3.3 Pre-ictal HRR

      Twenty studies investigated the presence of pre-ictal HRR. IB was reported in 88/2346 seizures (3.7%) and was observed in 13 studies [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Wilder-Smith E.
      • Lim S.H.
      Heart rate changes during partial seizures: a study amongst Singaporean patients.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Jaychandran R.
      • Chaitanya G.
      • Satishchandra P.
      • Bharath R.D.
      • Thennarasu K.
      • Sinha S.
      Monitoring pre-ictal; changes in hert rate variability, oxygen saturation and blood pressure in epilepsy monitoring unit.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Zijlmans M.
      • Flanagan D.
      • Gotman J.
      Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign.
      ,
      • Chen W.
      • Guo C.L.
      • Zhang P.S.
      • Liu C.
      • Qiao H.
      • Zhang J.G.
      • et al.
      Heart rate changes in partial seizures: analysis of influencing factors among refractory patients.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ]. One study reported pre-ictal HR reduction without commenting about subsequent IB [
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ], and six studies did not observe any IB [
      • Blumhardt L.D.
      • Smith P.E.
      • Owen L.
      Electrocardiographic accompaniments of temporal lobe epileptic seizures.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • De Oliveira G.R.
      • Gondim F.A.
      • Hogan R.E.
      • Rola F.H.
      Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Chen W.
      • Zhang P.S.
      • Guo C.L.
      • Zhang S.J.
      • Zeng X.W.
      • Meng F.G.
      Comparison of heart rate changes with ictal tachycardia seizures in adults and children.
      ,
      • Keilson M.J.
      • Hauser W.A.
      • Magrill J.P.
      Electrocardiographic changes during electrographic seizures.
      ]. The mean baseline HR was 76.2 bpm (±4.9; range 69.5–86.4) and the mean ictal HR minimum was 62.2 bpm (±13.4; range 50.0–76.5), demonstrating a mean decrease of 18.4% as compared to the baseline HR. Pre-ictal HRR was observed in 13/2346 seizures (0.5%) and was reported in four studies, exclusively including a paediatric population [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ]. Two studies included patients with refractory TLE [
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ], one reporting a mild pre-ictal bradycardia progressing into IT in seizure originating from the lateral temporal areas or from the right hemisphere [
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ]. The other two studies included a mixed sample of focal and generalized epilepsy [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ], one describing changes in left focal seizures only [
      • Nilsen K.B.
      • Haram M.
      • Tangedal S.
      • Sand T.
      • Brodtkorb E.
      Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy?.
      ]. Time of onset of the pre-ictal changes was not reported.

      3.3.1 Meta-analysis

      Twelve studies analysing pre-ictal HRR were considered eligible for the meta-analysis [
      • Schernthaner C.
      • Lindinger G.
      • Pötzelberger K.
      • Zeiler K.
      • Baumgartner C.
      Autonomic epilepsy – the influence of epileptic discharges on heart rate and rhythm.
      ,
      • Leutmezer F.
      • Schernthaner C.
      • Lurger S.
      • Pötzelberger K.
      • Baumgartner C.
      Electrocardiographic changes at the onset of epileptic seizures.
      ,
      • Van Buren J.M.
      Some autonomic concomitants of ictal automatism: a study of temporal lobe attacks.
      ,
      • Kirchner A.
      • Pauli E.
      • Hilz M.J.
      • Neundörfer B.
      • Stefan H.
      Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy.
      ,
      • Di Gennaro G.
      • Quarato P.P.
      • Sebastiano F.
      • Esposito V.
      • Onorati P.
      • Grammaldo L.G.
      • et al.
      Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures.
      ,
      • Kato K.
      • Jin K.
      • Itabashi H.
      • Iwasaki M.
      • Kakisaka Y.
      • Aoki M.
      • et al.
      Earlier tachycardia onset in right than left mesial temporal lobe seizures.
      ,
      • Mayer H.
      • Benninger F.
      • Urak L.
      • Plattner B.
      • Geldner J.
      • Feucht M.
      EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy.
      ,
      • Whealy M.
      • Wirrel E.
      • Wong-Kisiel L.
      • Nickels K.
      • Payne E.T.
      Prevalence and risk factors of peri-ictal autonomic changes in children with temporal lobe seizures.
      ,
      • Standridge S.M.
      • Holland K.D.
      • Horn P.
      Cardiac arrhythmias and ictal events within and epilepsy monitoring unit.
      ,
      • Jansen K.
      • Varon C.
      • Van Huffel S.
      • Lagae L.
      Peri-ictal ECG changes in childhood epilepsy: implications for detection systems.
      ,
      • Galimberti C.A.
      • Marchioni E.
      • Barzizza F.
      • Manni R.
      • Sartori I.
      • Tartara A.
      Partial epileptic seizures of different origin variably affect cardiac rhythm.
      ,
      • Vaughn B.V.
      • Quint S.R.
      • Tennison M.B.
      • Messenheimer J.A.
      Monitoring heart period variability changes during seizures II. Diversity and trends.
      ]. The pooled incidence of pre-ictal HRR was 0/100 seizures (95% CI 0–1) (Fig. 2B), with a significant between study heterogeneity (I2 = 49.26%, Q p-value = 0.03). Egger’s and Begg’s test were not significant (p = 0.99, p = 0.11 respectively) indicating a low risk of publication bias.

      4. Discussion

      This systematic review and meta-analysis of the incidence of pre-ictal HR changes demonstrated a pooled pre-ictal HRI incidence of 36/100 seizures, with a median onset of HR manifestations of 10.7 (IQR 5–60) seconds prior the clinical or EEG signs. Higher estimates were found for studies including patients with TLE (44/100 seizures), adults (55/100 seizures) and people on AEDs (35/100 seizures). Using data reported in the literature, we identified an incidence of 0.5/100 seizures of pre-ictal HRR, reported exclusively in the paediatric population and a pooled incidence of 0/100 seizures through the meta-analysis. However, the evaluation of study methods and the assessment of the risk of bias disclosed important factors influencing the results obtained across studies and limiting the validity of the pooled estimates. Although we decided a-priori not to apply any study inclusion restriction based on IT and IB definitions and favoured the terms HRI and HRR, the great variety of definitions and threshold adopted across the studies have likely influenced the frequencies reported. HR alterations may be more easily detected when a lower threshold is considered and might depend on the baseline HR set as reference. Similarly, the possibility to detect HR alteration may depend on the length of the pre-ictal period assessed, with very short pre-ictal time-windows hampering a sensitive detection, as also highlighted in the meta-regression and further commented below. Finally, methods enabling an instant HR calculation and the identification of the exact onset of HR changes might be more appropriate as compared to methods based on arbitrary time intervals, subject to length-dependent averaging effects. Another consideration is essential to carefully interpret the results of this review. Although the mechanisms supporting cardiovascular changes in epilepsy are largely unknown, there is evidence of the involvement of cortical structures, constituting the central autonomic network (CAN, including the amygdala and the insular cortex), and of adaptive cardiovascular reflexes triggered by ictal manifestations, especially motor [
      • Benarroch E.E.
      The central autonomic network: functional organization, dysfunction and perspective.
      ]. It has been previously suggested that the variable ictal cardiac alterations reported across studies (IT, IB, combined IT/IB and oscillatory HR patters) may reflect the different contribution of the central and peripheral autonomic pathways driving distinct cardiac manifestations [
      • Sevcencu C.
      • Struijk J.J.