Scholarly article on topic 'Ictal tachycardia: The head–heart connection'

Ictal tachycardia: The head–heart connection Academic research paper on "Health sciences"

CC BY-NC-ND
0
0
Share paper
Academic journal
Seizure
OECD Field of science
Keywords
{Epilepsy / Tachycardia / Seizure / "Heart rate" / Electrocardiogram / "Seizure detection" / Electroencephalography}

Abstract of research paper on Health sciences, author of scientific article — Katherine S. Eggleston, Bryan D. Olin, Robert S. Fisher

Abstract Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients. Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (e.g., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection. We reviewed 34 articles that reported the prevalence of ictal tachycardia in patients with epilepsy. Scientific literature supports the occurrence of significant increases in heart rate associated with ictal events in a large proportion of patients with epilepsy (82%) using concurrent electroencephalogram (EEG) and electrocardiogram (ECG). The average percentage of seizures associated with significant heart rate changes was similar for generalized (64%) and partial onset seizures (71%). Intra-individual variability was noted in several articles, with the majority of studies reporting significant increase in heart rate during seizures originating from the temporal lobe. Accurate detection of seizures is likely to require an adjustable threshold given the variability in the magnitude of heart rate changes associated with seizures within and across patients.

Academic research paper on topic "Ictal tachycardia: The head–heart connection"

^ ARTICLE IN PRESS

Seizure xxx (2014) xxx-xxx

ELSEVIER

Contents lists available at ScienceDirect

Seizure

journal homepage www.elsevier.com/locate/yseiz

Review

Ictal tachycardia: The head-heart connection

Katherine S. Eggleston a'*, Bryan D. Olina, Robert S. Fisherb

a Cyberonics, Inc., Houston, TX 77058, United States

b Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, United States

ARTICLE INFO

ABSTRACT

Article history:

Received 17 January 2014

Received in revised form 21 February 2014

Accepted 22 February 2014

Keywords:

Epilepsy

Tachycardia

Seizure

Heart rate

Electrocardiogram

Seizure detection

Electroencephalography

Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients. Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (e.g., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection. We reviewed 34 articles that reported the prevalence of ictal tachycardia in patients with epilepsy. Scientific literature supports the occurrence of significant increases in heart rate associated with ictal events in a large proportion of patients with epilepsy (82%) using concurrent electroencephalogram (EEG) and electrocardiogram (ECG). The average percentage of seizures associated with significant heart rate changes was similar for generalized (64%) and partial onset seizures (71%). Intra-individual variability was noted in several articles, with the majority of studies reporting significant increase in heart rate during seizures originating from the temporal lobe. Accurate detection of seizures is likely to require an adjustable threshold given the variability in the magnitude of heart rate changes associated with seizures within and across patients.

© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

Epilepsy affects 65 million people worldwide. Despite available treatments, more than 1 million people still suffer from seizures that severely limit their daily activities and quality of life. Most medical therapies for epilepsy consist of daily regimens of anti-epileptic drugs and/or electrical stimulation provided by medical devices such as VNS Therapy®. Once a clinical seizure starts, rescue medications can be administered in an attempt to disrupt progression of a given seizure and manage seizure emergencies, such as prolonged, repetitive seizures, or status epilepticus. However, rescue medications, for example rectal diazepam, are not appropriate for all patients, require caregiver administration, and may have undesirable side effects. Automatic and non-invasive delivery of treatment prior to or at the onset of a clinical

* Corresponding author at: Clinical and Regulatory Strategic Planning, Cyberonics, Inc., 100 Cyberonics Boulevard, Houston, TX 77058, Unites States. Tel.: +1 800 332 1375/+1 281 228 7523; fax: +1 281 283 5598.

E-mail address: Katherine.eggleston@cyberonics.com (K.S. Eggleston).

seizure may provide patients with epilepsy peace of mind and increased control over their seizures.

Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (i.e., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Cardiac signals are robust, easy to record, and algorithms can be adapted to individual patients based on predetermined heart rate changes in response to epileptic seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection.

Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients.

The parasympathetic and sympathetic systems act in concert to maintain homeostasis and regulate key visceral functions such as heart rate. In particular, the anterior cingulate, insular, posterior orbito-frontal, and the pre-frontal cortices play key roles in influencing the autonomic nervous system at the cortical level

http://dx.doi.org/10.1016/j.seizure.2014.02.012

1059-1311/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 3.0/).

along with the amygdala and hypothalamus.1,2 In patients with epilepsy, ictal discharges that occur in or propagate to these structures can lead to increased sympathetic outflows, impacting autonomic function. Research involving experimental stimulation of various neural structures suggests that the propagation of epileptic discharges to the right insular cortex is a primary driver of sympathetic-parasympathetic changes that influence heart rate.3 Although sympathetic responses such as sinus tachycardia are the most common changes that occur during seizures, parasympathetic responses such as bradycardia can also occur if the ictal discharges propagate to cortical regions governing depressor responses.1

Sinus tachycardia characteristically refers to a heart rate that exceeds the normal range for a resting heart rate. The upper threshold of a normal heart rate depends on and decreases with age, however no standard definition exists. The upper threshold of heart rate for people >15 years of age is commonly considered to be 100 beats per minute (bpm) while the upper threshold for children 6-11 months of age is >169 bpm.4 Ictal tachycardia can be defined as the occurrence of sinus tachycardia either prior to, during, or shortly after the onset of ictal discharges.2 This review describes the prevalence and characteristics of ictal tachycardia in patients with epilepsy as reported in the literature.

2. Methods

A review of the literature was conducted per MEDDEV 2.7.15 to summarize the prevalence of ictal tachycardia in patients with epilepsy as reported in the literature. Only full original peer-reviewed research (no meeting abstracts or review articles) related to the research objective were included. The reference lists of key relevant articles were also searched and additional articles were identified. Known references that were not found in the literature search were also included for completeness. The literature search for this topic was conducted in April 2013 using PubMed (Fig. 1). Three independent searches were conducted using the following keywords: (1) ictal tachycardia (46 primary citations), (2) heart rate variability seizure (79 primary citations) and (3) ictal bradycardia (63 primary citations). The combination of the results of these three searches provided 165 unique citations. Upon review of the abstracts, 19 were review articles (17 were unrelated to ictal tachycardia, 2 were used to identify additional primary articles), 7 were case reports, and 105 were not directly related to ictal tachycardia; the remaining 34 articles were obtained and reviewed. Upon review of the full publications, an additional 10 papers were excluded as they were not directly related to ictal tachycardia. Articles were included if they reported the proportion of patients or seizures that exhibited an increased heart rate or ictal tachycardia. An evaluation of the study design and measures to reduce bias was also performed. For the primary search, 24 clinical articles were identified that reported changes in heart rate associated with epileptic events.6-29 An additional 10 articles that were not identified in the primary search were also included that were either known to the authors or identified as additional references from the primary articles.30-39

3. Results

The 34 articles identified were reviewed and are summarized alphabetically by author's last name in Table 1. The literature was assessed based on several key characteristics that define this clinical phenomenon including the overall prevalence of ictal tachycardia in the patient population, the prevalence of ictal tachycardia by seizure type, as well as potential differential indicators of ictal tachycardia including lobe of seizure onset and lateralization. Consistent with the diverse nature of the epilepsies,

Fig. 1. Literature review of ictal tachycardia.

the results presented here include a range of etiologies, seizure types, patient characteristics, and definitions of ictal tachycardia. The occurrence and magnitude of ictal tachycardia may be influenced by patient and/or disease state characteristics. Thus, in addition to overall summary data, we present results by seizure type, lobe of onset, lateralization, and degree of tachycardia. Finally, the magnitude and timing of the respective changes in heart rate associated with seizure onset are discussed. Defining these characteristics promotes understanding of potential mechanisms of action for ictal tachycardia and also provides insight on patient selection for use and programming of cardiac based seizure detection algorithms.

3.1. Study design

The study designs utilized by the articles reviewed were primarily prospective or retrospective case series of observational

ВВДДЗЕ^И ARTICLE IN PRESS

K.S. Eggleston et al./Seizure xxx (2014) xxx-xxx

Table 1

Ictal tachycardia.

Citation

Study design

Demographics

Definition of ictal tachycardia

Heart rate changes reported

Adjei et al.6

Blumhardt et al.30

Britton et al.7

Calandra-Buonaura et al.8

de Oliveira et al.22

Di Gennaro et al.9

Epstein et al.1

Galimberti et al.3

Garcia et al.1

Isik et al.1

Jeppesen et al.1

Keilsonet al.14

Kerem and Geva32

Case series of patients with pharmaco-resistant epilepsy who underwent intracranial video-EEG monitoring

Case series of consecutive patients with TLE who underwent ambulatory EEG and ECG monitoring, compared to control group

Retrospective case series of consecutive patients diagnosed with ictal bradycardia who underwent scalp EEG monitoring

Prospective case series of patients with NFLE who underwent scalp EEG monitoring, compared to control group

Retrospective case series of patients who underwent video-EEG monitoring

Case series of consecutive patients with medically refractory TLE referred for pre-surgical assessment who underwent video-EEG monitoring

Case series of patients with TLE evaluated with bi-temporal lobe depth electrodes and orbitofrontal subdural electrodes

Case series of patients with ambulatory EEG-ECG recordings that showed at least one partial seizure without secondary generalization Case series of consecutive patients who underwent video-EEG monitoring Case series of consecutive seizures from patients who underwent video-EEG monitoring

Prospective pilot study of patients with TLE who underwent video-EEG monitoring

Retrospective case series of patients with electrographic seizures who underwent ambulatory EEG-ECG monitoring.

Retrospective case series of patients with TLE who underwent video-EEG monitoring

74 Events from 26 pts; mean age 38 ± 10 yrs; 14 TLE, 12 FLE (all pharmaco-resistant); subclinical events

74 Events in 26 pts; mean age 14.9 (range 6-37 yrs); TLE, CPS

60 Events from 13 pts (5 M/8 F); aged 17-73 yrs; diagnosed with ictal bradycardia; TLS

45 Nocturnal frontal lobe seizures from 10 pts (6 M/ 4 F) aged 12-41 yrs diagnosed with NFLE

59 Events from 27 pts (11 M/16 F); mean age 34.9±2 yrs; CPS, SPS, non-epileptic

257 Events from 68 pts (42 M/26 F); mean age 33.2 ± 19 yrs; TLE

27 Events from 5 pts (2 M/ 3 F); age range 22-30 yrs; medically refractory complex partial seizures

100 Events from 50 pts (25 M/25 F); aged 12-61 yrs (mean: 29 ± 11.7); PS

97 Events in 38 pts (18 M/ 20 F); aged 3-53 yrs (mean: 27.5); CPS 47 Seizures (2 GTC, 7 GT, 1 MCT, 37 SPS) from 18 pts (12 M/6 F) age 4 months-19 yrs with intractable epilepsy

Tachycardia: HR >100 bpm

Tachycardia: HR > 120 bpm

Tachycardia: development of a HR >120 beats/min after onset of seizure activity on the EEG None specified

None specified

None specified

None specified

HRsignificant changes defined as no overlap between CIs of baseline and the first 10 s of ictal EEG.

Tachycardia: HR >107.06 bpm

None specified

6 Seizures (1GTC, 4 CPS, 1 SPS) from 3 pts (1 M/2 F) age 35-53 yrs, with TLE

106 Events from 45 pts; aged 4-69 yrs (mean: 25.3); CPS, PG

21 Events from 8 pts, all with TLE

None specified

Tachycardia: HR >100 bpm

None specified

Tachycardia: 4% (n = 3/74) of subclinical patterns arising from left temporal lobe foci; 7.7% (n = 2/26) of patients. HR: weakly increased during and after subclinical event; mean HR of 80 ± 10 bpm before to 82 ± 11 bpm during and 81 ± 10 bpm after subclinical event (p = 0.06). Tachycardia: tachycardia exceeded 120bpm in 61% of seizures, 140 beats/min in 30% of seizures, and 160 bpm in 12% of seizures. Occurred in 92% (n = 24/26) of patients. HR: increased heart rate in 91% of seizures Tachycardia: 23% of pts (n = 3) and 13.3% of seizures (n = 8)

Tachycardia: significant tachycardia occurred during the seizure period compared with the basal period (p < 0.0005). HR absolute values during the pre-ictal period (10 s before onset) did not change compared to the basal period. R-R interval began to decrease significantly 1 second before onset (range 1 s before to 1 s after onset)

HR: 100% of TLS (p < 0.05). Ictal HR was not altered in non-epileptic or simple partial TLS groups; mean HR increased to 109 ± 3.2 bpm (p < 0.05).

HR: HR increase in 92% of epileptic episodes (n = 237/257)

Left TLE: mean HR increased from 75.6 to

79.7 bpm.

Right TLE: mean HR increased from 77.5 to

82.8 bpm.

Tachycardia: 100% of complex partial and simple partial seizures. 1/13 subclinical seizures showed tachycardia. HR: mean HR increased from a baseline of 80-124bpm (55%) when ipsilateral spread was complete, and further increased another 17% when seizures spread bilaterally. HR: ranged from 44 to 186 bpm. Early-HR showed significant increase in 49% of seizures; in 10 of 20 patients who had more than one seizure recorded in the same EEG, seizures showed a variable effect. For all seizures, the difference between mean baseline HR and HR 120 s after seizure onset is 16.5 bpm.

Tachycardia: all seizures showed increase in heart rate. Mean pre-ictal HR=98.43; mean ictal HR = 116.38; difference was significant (p < 0.001). Increase in mean HR was <10 bpm in 42.6% of seizures, 10-19 bpm in 12.8% of seizures, 70 bpm in one patient. No significant difference in HR between temporal and extratemporal seizures Bradycardia: no seizures showed bradycardia (<50 bpm) or decrease in heart rate.

100% of seizures showed reciprocal HR-power peaks between 10 s pre seizure and 24 s post seizure-onset.

Tachycardia: 93% of seizures; average increase in HR was 60% (range 0%-160%). HR: 96% of seizures

Tachycardia: 100% of pts had ictal tachycardia to some degree. Peak HR during seizure ranged from 78 to 171 bpm

Table 1 (Continued )

Citation

Study design

Demographics

Definition of ictal tachycardia

Heart rate changes reported

Leutmezer et al.15

Li and Roche et al.16

Marshall et al.17

Massetani et al.1

Mayer et al.1

Moseley et al.2

Nei et al.21

Nilsen et al.33

Novak et al.3

O'Regan and Brown24

Opherk et al.2

Retrospective case series of consecutive patients who underwent video-EEG monitoring

Retrospective case series of patients with refractory TLE who underwent EEG-ECG monitoring randomly selected from a consecutive list Case series of consecutive patients with temporal lobe seizures who underwent video-EEG monitoring. Case series of patients with TLE who underwent ambulatory EEG-ECG monitoring, compared to control group Retrospective case series of patients with refractory TLE who underwent video-EEG monitoring

145 Events in 58 pts; refractory TLE, extratemporal

61 Events from 20 pts (9 M/11 F); median age 28 yrs; TLE; CPS

12 pts (5 M/7 F); aged 1578 yrs; TLE

6 Events from 65 pts (38 M/27 F); TLE; CPS

72 Events from 20 pts (7 M/13 F); aged 3-17 yrs; drug resistant symptomatic TLE

Prospective case series of patients with suspected partial complex or generalized convulsive seizures who underwent EEG-ECG monitoring

218 Seizures from 76 pts (59.2% M/40.8% F), aged 2-61 yrs; 139 CPS, 41 SG, 12 PG, 26 GTC

Prospective case series of consecutive patients with refractory partial epilepsy who underwent video-EEG monitoring, compared to control group

Case series of patients with partial seizures with ictal impairment of consciousness during video-EEG monitoring Case series of patients who underwent video-EEG monitoring

Prospective cohort of pediatric patients with unstable epilepsy who underwent EEG-ECG monitoring

Retrospective case series of consecutive patients who underwent EEG-ECG monitoring

Tachycardia: ictal HR increase >1 standard deviation ofthe mean pre-ictal HR of all patients

Tachycardia: HR >120bpm

None specified

None specified

Tachycardia: increase of >10bpm above baseline HR

Absolute tachycardia: increase of heart rate above the age-adjusted normal heart rate

Tachycardia: >98th percentile for age Bradycardia <2nd percentile for age

51 Events in 43 pts (25 M/ 18 F); mean age 34 yrs (14-55); intractable partial epilepsy

38 Events from 38 pts (11 M/27 F); mean age 33 yrs; CPS, SG

12 Events from 12 pts (4 M/8 F); aged 19-62 yrs; TLE, CPS

101 Events from 37 pts (20 M/17 F); aged 1.515.5 yrs (median: 7.5 yrs); CPS, AA, PG

102 Events in 41 pts (19 M/22 F); aged 13-69 yrs (mean: 35 yrs); 71 CPS, 27 SG, 4 PG seizures

Tachycardia: HR >100 beat/min

None specified

None specified

HR changes: significant change in HR was more than 10% increase or decrease below the baseline HR.

Tachycardia: HR >100bpm

Tachycardia: 86.9% of seizures. Mean absolute HR increase was 43.2 bpm; relative HR increase was 64.8%. HR: ictal changes preceded EEG seizure onset by 13.7 s in pts with TLE and 8.2 sec in pts with extra-temporal epilepsy. The difference was significant. Tachycardia: 39% of CPS; median tachycardia rate: 140bpm, range (120-180).

Tachycardia: 100%ofpatients; maximum HR during seizures ranged from 120-180 bpm.

Tachycardia: 67% of CPS and 67% of patients (n = 4/6).

Tachycardia: pre-Ictal stage: 28% (n = 20/72) of seizures; 5 of these seizures showed an increase of >30 beats/min. Ictal stage: 98% (n = 71/72) of seizures and in 100% of pt.

HR increase ranged from 16.8 to 99.8 beats/ min (mean 55.6 beats/min) Observed in 100% of patients (n = 20/20) and patients with TLE (n = 9/9). Absolute Tachycardia: 80.6% of CPS Tachycardia: 57% (n =124/217) of seizures; 76% (n = 57/75) of patients; 48% (n = 66/138) of CPS, 81% (n = 33/41) of secondarily GTC seizures, 83% (n =10/12) of PGTC seizures; 58% (n = 15/26) of GT seizures; more common with generalized (73%) than with non-generalized CPS (48%), and in patients who failed >3 AEDs, had normal vs. abnormal neuroimaging, or who had temporal localization of partial seizures without secondary generalization. Linear analysis found significant association with >3 failed AEDs and seizure generalization. Bradycardia: 2% (n = 4/217) of seizures and 5% (n = 4/75) of patients; linear regression found significant association with beta blocker usage and >50 seizures/month. Tachycardia: 53% of patients during the ictal or post-ictal period.

HR: Increased >10 bpm from the pre-ictal to the ictal period in 74% of patients (CPS 74%, GTC 73%)

Tachycardia: CPS were accompanied by a marked tachycardia >140 bpm, P=0.01 that started few seconds before seizure onset and typically progressed to a maximum during seizure.

Tachycardia: 35% (n =14/40) in focal seizures with or without secondary generalization; 57% (n =12/21) in generalized seizures;

Focal seizures: increase in mean ictal heart rate ranged from 13 to 120%. Tachycardia: 100% of generalized seizures, 73% of non-generalized seizures. For all seizures, difference between mean maximum ictal HR and mean ictal onset HR is 34 bpm.

ВВДДЗЕ^И ARTICLE IN PRESS

K.S. Eggleston et al./Seizure xxx (2014) xxx-xxx

Table 1 (Continued)

Citation

Study design

Demographics

Definition of ictal tachycardia

Heart rate changes reported

Rugg-Gunn et al.3'

Schernthaner et al.2

Smith et al.26

Toth et al.27

van Elmpt et al.3

Vaughn et al.3

Walker and Fish3,

Weilet al.28

Wilder-Smith and Lim29

Zijlmans et al.3

Prospective cohort of patients with refractory partial seizures implanted with a loop recorder

Retrospective case series of patients who underwent non-invasive or invasive EEG monitoring

Case series of consecutive patients with complex partial seizures who underwent ambulatory EEG-ECG monitoring

Retrospective case series of consecutive patients with refractory focal epilepsy who underwent video EEG-ECG monitoring

Retrospective case series of patients who were mentally retarded and suffered a severe form of epilepsy and who underwent video EEG-ECG monitoring

Retrospective case series of patients with epilepsy who underwent video EEG-ECG monitoring, compared to control group

Case series of patients with epilepsy who underwent EEG-ECG monitoring

Retrospective case series of patients with partial seizures who underwent EEG-ECG monitoring

Retrospective case series of patients with partial seizures who underwent video EEG-ECG monitoring

Retrospective case series of patients with intractable epilepsy who underwent video EEG-ECG monitoring

377 Events from 20 pts (10 M/10 F); aged 24-56 yrs (median: 40 yrs); refractory PS; all with TLE. 41 pts; TLE, FLE Group I: 30 pts, aged 1946 yrs; 92 seizures recorded by noninvasive electrodes

Group II: 11 pts, aged 2245 yrs; 35 seizures recorded by indwelling electrodes

93 Events from 32 pts (18 M/14 F); aged 15-75 yrs (mean: 36.6); CPS

31 Seizures from 31 pts (14 M/17 F); mean age 35.5 ± 10 yrs; 9 GTC, 15 CPS, and 7 SPS

104 Events from 10 pts (8 M/2 F); aged 21-50 yrs; mental retardation with severe epilepsy; TC, MC, and AA seizures

44 Events from 12 pts (5 M/7 F); aged 4.5-55 yrs; CPS SG, GTC.

79 Seizures from 37 pts (20 M/17 F); aged 14-68 yrs (mean 35.2 yr); 70 CPS, 9 SG tonic or TC seizures 22 Events from 21 pts; (11 M/10 F); median age = 33 yrs; subclinical seizures

37 Events from 37 pts (20 M/17 F);mean age, 44 yrs (range: 18-80 yrs); PS

281 Events from 81 pts (60% F); subclinical (11%), PS (83%), SG (6%); aged 11-64 yrs (mean: 34 yrs)

Tachycardia: Heart rate >140 bpm

Tachycardia: increase of >10 bpm above baseline HR

None specified

None specified

HR: peri-ictal maximum HR was larger than the baseline period +2 S.D., and hold on for at least five QRS complexes

Tachycardia: heart rate increase >15 bpm

None specified

HR changes: defined as maximum frequency/ minimum frequency; increase of 1.8 was considered significant

Tachycardia: increase of >10 bpm over baseline HR

Tachycardia: heart rate >100 bpm

Tachycardia: in 19 patients, all experienced sinus tachycardia during some seizures (maximum 175 bpm)

Tachycardia: Group I: 89.1% of seizures (82/ 92)

Group II: 68.6% of seizures (24/35) Group II: Seizures of temporal lobe origin had mean HR increase

Tachycardia: 74% of seizures were associated with dominant tachycardia; 5% of seizures were associated with dominant but transient effects on HR and rhythm; 19% of seizures were equivocal or negative ictal effects on HR. Observed in 84% of patients (n = 27/32).

Median periictal increase in HR was significant compared to early postictal period (p < 0.001)

HR: increase in 80% of patients and 48% of seizures

Tachycardia: 52% of seizures (n = 23/44) in 83% of patients (n = 10/12) HPV: 13.6% of seizures showed changes in heart period variability (HPV) preceding EEG or behavioral seizure onset. Tachycardia: 6/6 TC, 2/3 tonic, 45/70 CPS Bradycardia: followed a period of apnea in 23 tonic seizures; did not occur in any of the CPS

Tachycardia: 41% of subclinical seizures (n = 9/22). IT was observed more often in seizures of temporal lobe origin (62%) than from extratemporal regions (11%) (p < 0.0018). Observed in 38% of patients (n = 8/21).

Tachycardia: 22% of seizures were associated with moderate sinus tachycardia (20-50% increase); 11% were associated with severe sinus tachycardia (> 50% increase). Increases were seen in 43% of patients (n = 16/37).

Tachycardia: increase of at least 10bpm in 73% of seizures (93% of pts) around seizure onset. In 23% of seizures (49% of pts), the rate increase preceded both electrographic and clinical onset. Occurred in 93% (n = 75/81) of patients.

PT - patient; HR - heart rate; CPS - complex partial seizure; SPS - simple partial seizure; GTC - generalized tonic clonic; TLE - temporal lobe epilepsy; FLE - frontal lobe epilepsy; NFLE - nocturnal frontal lobe epilepsy; bpm - beats per minute; TLS - temporal lobe seizure; IT - ictal tachycardia; SG- secondarily generalized; PG - primary generalized; PS - partial seizure; MC - myoclonic; AA - atypical absence; CI - confidence interval.

data on patients with epilepsy who underwent EEG monitoring (scalp and/or intracranial). Five of the 34 studies utilized ambulatory EEG recordings.14,18,26,30,31 Six studies were conducted prospectively8,13,20,21,24,35 one of which was an interventional study where patients were implanted with a loop recorder to automatically measure changes in heart rate in an outpatient setting.35 Several studies took measures to control selection bias by selecting random16 or consecutive patients7,9,11,12,15,17,21,23,26,27,30 and utilizing a control group.8,18,30,37

3.2. Summary of patient characteristics

The mean age at evaluation was reported in 27 of 34 articles and ranged from 7.5 to 48 years of age with an average of 30 years.6-9,11,12,14,16,18-24,26-31,33,35-39 Five articles reported on pediatric populations (mean age of less than 18 years old),8,12,19,24,30 while eight articles included populations that were exclusively adults (>18).6,10,13,25,29,34-36 The majority of articles (n = 16) included both adult and pediatric popula-

tions.7,8,ii,i4,i6,i7,20,2i,23,26,28,30,3i,33,37-39 Two articles evaluated

exclusively subclinical events.6,28 Most articles (n = 17) reported data on patients with partial onset temporal lobe seizures,6,9,11-13,15-19,22,25,30-32,34,35 with an additional seven articles including both temporal and extratemporal epilepsies.20,23,24,27,28,37,38 Seven others noted their data was analyzed from patients with partial onset seizures with no specification of origin.7,10,21,26,29,33,39 Consistent with the type of epilepsies evaluated, 22 articles included partial onset seizures7,9-11,13,15-19,21,22,25,26,29-35,39 and

11 included generalized onset seizures.8,12,14,20,23,24,33,36-39

3.3. Defining ictal tachycardia

Of the 34 articles reviewed, 16 formally defined ictal tachycardia.6,7,11,14-16,19-21,23,25,29,30,35,37,39 The most frequent definition was a heart rate that exceeds 100 beats per minute (bpm); 5 of the 16 articles used this definition. A threshold of 100 bpm corresponds to the threshold for maximum normal heart rate for patients >15 years old, consistent with the populations under study in most articles. Other definitions utilized in more than one study included heart rate >120 bpm (n = 3), and heart rate >10 bpm above baseline heart rate (n = 3). Two articles utilized a definition of tachycardia that varied by age of study partici-pants.19,20 Four other articles defined significant changes in heart rate (not specified as tachycardia) relative to baseline measure-ments.24,28,31,36

3.4. Prevalence of ictal tachycardia by patient

Understanding the prevalence of this phenomenon is important to assessing its utility as a diagnostic. Estimates of the proportion of patients in whom ictal tachycardia was observed during at least one clinical seizure was derived from 20 articles (Table 2). In cases where 100% of seizures were reported to have the associated heart rate change, it was inferred that 100% of patients experienced the change. Two articles investigated only subclinical events and found that tachycardia was associated with between 7.7%6 and

Table 2

Percent of patients with ictal heart rate change/tachycardia during at least one seizure.

Definition of ictal tachycardia References Percent of patients

Heart rate change/tachycardia, Weil et al.28 38%a

not otherwise specified

Massetani et al.18 67%

Van Elmpt36 80%

Smith et al.26 84%

Kerem and Geva32 100%

Isik et al.12 100%

Marshall et al.17 100%

Jeppesen et al.13 100%

de Oliveira et al.22 100%

Epstein et al.10 100%

Increase in 10 bpm above baseline Wilder-Smith and Lim29 43%

Mayer et al.19 100%

Increase in 15 bpm above baseline Vaughn et al.37 83%

> 98 Percentile for age Moseley et al.20 76%

>100 bpm Adjei et al.6 7.7%a

Nei et al.21 53%

Zijlmans et al.39 93%

>120 bpm Britton et al.7 23%b

Blumhardt et al.30 92%

>140 bpm Rugg-Gunn et al.35 100%

Weighted average 82%c

a Subclinical seizures only.

b Patients with a previous diagnosis of ictal bradycardia. c Excludes data for articles evaluating subclinical seizures only and patients with a previous diagnosis of ictal bradycardia.

38%28 of patients. One study investigated only patients with a history of ictal bradycardia7 and reported that 23%(n = 13)of these patients also exhibited ictal tachycardia (>120 bpm). In ten articles that evaluated heart rate changes or ictal tachycardia not otherwise specified,10,12,13,17,18,22,26,28,32,36 the percent of patients with significant heart rate changes during at least one of their recorded seizures ranged from 38% to 100%. Across all articles evaluating clinical seizures (articles evaluating subclinical and bradycardia patients only not included), the weighted average percentage of patients with associated heart rate changes was 82%. The variance in outcomes reported may be due to factors including lobe of onset and the extent and speed of ictal spread; WilderSmith et al. proposed that their comparatively low rate of ictal tachycardia (43% of patients) may be due to a differential proportion of seizures originating from the frontal vs. temporal

lobe.29

Several articles evaluated intra-individual consistency in heart rate changes from seizure to seizure.15,21,26,30-32,36 Blumhardt et al. reported that when multiple seizures were recorded per patient, the pattern of R-R interval changes was similar for all ictal episodes.30 Kerem and Geva also noted that the pattern of ictal tachycardia was more predictable within seizures of the same patient but varied across patients.32 Five articles reported similar patterns in most but not all seizures within the same pa-tient.15,21,26,31,36 Leutmezer et al. analyzed peri-ictal heart rate patterns and found that each seizure followed one of two distinct patterns: continuous and steady increase in heart rate, or abrupt discontinuous increase in heart rate followed by a continuous steady increase. For patients with more than one seizure, 67.7% had one peri-ictal heart rate pattern, 17.6% had two, and 14.7% had three different patterns which included no change or decrease in heart rate.15 Both Smith et al. and Galimberti et al. reported that half of all patients who had more than one seizure recorded had variable heart rate changes from seizure to seizure.26,31 In addition to heart rate responses during seizures, it has been documented that refractory temporal lobe epilepsy is associated with dysfunction of inter-ictal autonomic responses including heart rate.40 These results indicate that some intra-individual variability is likely with respect to heart rate changes during ictal events, yet consistent patterns within patients may exist.

3.5. Prevalence of ictal tachycardia by seizure type

The literature cites the occurrence of ictal tachycardia across several different seizure types. This section summarizes the prevalence in each. The prevalence of ictal tachycardia and/or significant increases in heart rate reported in the literature by seizure type is summarized in Table 3.

3.5.1. Subclinical seizures

The articles reviewed here investigated both subclinical seizures and those with clinical manifestations; two articles exclusively investigated subclinical events and reported that tachycardia was associated with between 4%6 and 41%28 of subclinical seizures. One study evaluated subclinical seizures in addition to other seizures types and reported that of 13 subclinical seizures, only 1 (7.7%) showed tachycardia.10

3.5.2. Partial seizures

Sixteen articles reported either the percent of partial onset seizures with ictal tachycardia or the percent of patients exemplifying at least one instance of ictal tachycardia.10-12,15-20,23-26,29,30,38 The percent of partial seizures (with or without secondary generalization) associated with tachycardia ranged from 32.9% 11 to 100%. 10,12,17 Four additional articles reported significant heart rate increases (not specified as tachycardia) in

ВВИДЗЕ^И ARTICLE IN PRESS

Table 3

Percent of seizures with ictal heart rate change/tachycardia, by seizure type.

Definition of ictal tachycardia Author Subclinical Partial seizures Generalized seizures Mixed seizure types

Heart rate change/tachycardia, not de Oliveira et al.22 - 100% - -

otherwise specified Di Gennaro et al.9 92%

Epstein et al.10 8% 100% - -

Isiket al.12 - 100% 100% -

Galimberti et al.31 - 49% - -

Jeppesen et al.13 - - - 100%

Marshall et al.17 - 100% - -

Massetani et al.18 - 67% - -

Nilsen et al.33 - 74% 73% -

O'Regan and Brown24 - 35% 57% -

Smith et al.26 - 74% - -

van Elmpt et al.36 - - 48% -

Walker and Fish38 - 64% 89% -

Weil et al.28 41% - - -

Increase in 10bpm above baseline Mayer et al.19 Wilder-Smith and Lim29 Schernthaner et al.25 - 98% 33% 84% - -

Increase in 15 bpm above baseline Vaughn et al.37 - - - 52%

HR > 107.06 bpm Garcia et al.11 - 32.9% - -

Ictal HR increase >1 SD of the mean Leutmezer et al.15 - 86.9% - -

pre-ictal HR

>98 Percentile for age Moseley et al.20 - 55% 66% -

>100 bpm Adjei et al.6 Zijlmans et al.39 4% - - 73%

Keilson et al.14 - - - 93%

Opherk et al.23 - 73% 100% -

>120bpm Li and Roche et al.16 Blumhardt et al.30 - 39% 61% - -

Britton et al.7 - 13% - -

Weighted average 12% 71%a 64% 76%

a Excludes data from Britton et al.7 as this article included only patients with a previous diagnosis of ictal bradycardia.

49%-100% of partial seizures.9,22,31,33 The weighted average of study results presented here gives an estimate of 71% of partial seizures with ictal tachycardia and/or significant heart rate changes.

Additional variability was found within partial onset seizures; de Oliveira et al. reported that although 100% of complex partial seizures were associated with an increase during ictal events, no heart rate changes were observed in simple partial seizures.22 Similarly, Epstein et al. reported an additional increase in mean heart rate when seizures spread from regional limbic to bilateral cortical areas; heart rate increased from a baseline of 80-124 bpm (55%) when ipsilateral spread was complete, and increased another 17% when seizures spread bilaterally.10 Finally, while Leutmezer et al. reported no significant difference in heart rate around ictal onset for seizures that eventually secondarily generalized;15 three other articles reported that secondarily generalized seizures were more likely to be associated with tachycardia than those that

remain localized.20,21,33

3.5.3. Generalized seizures

In addition to partial onset seizures, 11 articles evaluated heart rate changes associated with generalized sei-zures.8,12,14,20,23,24,33,36-39 Seven articles reported the percent of generalized seizures associated with tachycardia and/or significant increases in heart rate; results ranged from 48% to 100% with a weighted average of 64%.12,2a23,24,33,3638 van Elmpt et al. noted the absence of heart rate changes during several myoclonic seizures leading to the lower percentage of seizures associated with heart rate changes (48%).36 Absence seizures were typically excluded from articles; however, one article reported no significant change in heart rate during absence seizures.24 Four articles included generalized seizures in the respective analyses but did not report results separately; the percentage of all seizures associated with tachycardia in these articles ranged from 52% to

100%.13,14,37,39 Finally, two articles reported a significantly higher proportion of generalized seizures were associated with tachycardia when compared to non-generalized complex partial seizures in the same analysis (p < 0.01),20,23 while Blumhardt et al. noted that heart rate changes and initial acceleration tended to be greater with bilateral EEG discharges than with unilateral discharges.30

3.6. Lobe of onset

Lobe of onset was consistently evaluated as a potential influencing factor with respect to heart rate changes occurring during seizures. Considering articles that evaluated seizures with a clinical manifestation, the vast majority of studies reviewed here report significant increase in heart rate during seizures originating

from the temporal lobe.9-12,15-19,22,25,26,28,30-35,38 Of these, nine

studies evaluated differences in lobe of onset including temporal

vs. extratemporal and/or mesial vs. lateral origins within the temporal lobe.9,11,12,15,19,25,28,31,33

Three articles indicated that seizures of temporal lobe onset were more likely to have heart rate changes when compared to extratemporal epilepsies.11,15,28 Garcia et al. reported that 78% and Weil et al. reported that 62% of seizures of temporal lobe onset were associated with changes in heart rate compared to 22% and 11% of extratemporal seizures, respectively.11,28 Conversely, Isik et al. reported no difference in heart rate changes for temporal or extratemporal seizures,12 while Galimberti et al. reported that 80% of seizures showing early heart rate decrease were of temporal origin.31 Schernthaner et al. reported similar rates of ictal tachycardia for temporal lobe (92.9%) and frontal lobe onset seizures (83.3%); however ictal heart rate variability was significantly higher in frontal lobe onset seizures when compared to temporal lobe.25 Finally, Nilsen et al. reported that patients with frontal lobe seizures had higher interictal heart rate and a trend

toward lower pre-ictal heart rate compared to patients with temporal lobe seizures.33

When considering differences between seizures originating from mesial or lateral structures, Schernthaner et al25 reported no significant difference in the degree of heart rate increase between mesial and lateral temporal lobe origin, yet heart rate changes preceded EEG changes more frequently in lateral than mesial temporal lobe seizures (p = 0.03). Similarly, Di Gennaro et al.9 and Mayer et al.19 reported that the onset of ictal heart rate increases occurred earlier in the mesial than in the lateral temporal seizures in both adult and pediatric populations, respectively.

When evaluating subclinical seizures, Epstein et al. reported that activity in the temporal lobe did not affect heart rate, yet increases were seen when additional areas were recruited.10 In contrast, Weil et al. reports a change in heart rate in subclinical seizures from the temporal lobe but not from the frontal lobe.28

3.7. Lateralization

Several articles evaluated lateralization as a potential influencing factor on the occurrence of and/or degree of heart rate changes associated with seizures. In stimulation studies, electrical stimulation of right insula tends to produce tachycardia; whereas, stimulation of left insula more often produced bradycardia.3 Although it has been hypothesized that the right sections of the autonomic system exert greater control on cardiac functions than the left,3 the majority of articles reviewed here reported no

differences regarding lateralization.10,11,16,21,23,25,31,35 Five articles

did indicate a potential differential effect for seizures originating from the left or right side,6,9,15,18,19 with the majority of these indicating more influence from the right side. Leutmezer et al. reported that ictal tachycardia was seen more often in seizures originating from the right vs. left side.15 Similarly, Di Gennaro et al. reported in a sub-group analysis that males with right temporal lobe seizures had a significantly greater increase in heart rate compared with left-sided mesial temporal lobe seizures within the first 10 s after seizure onset.9 Although not statistically significant, Schernthaner et al. reported a higher heart rate increase for seizures with right temporal onset compared to those with left temporal onset.25

Mayer et al. reported two distinct and specific heart rate patterns for temporal lobe seizures originating from the right including an initial high increase followed by a fast decrease or a low but sustained increase; seizures originating from the left temporal lobe presented with primarily moderate heart rate dynamics.19 Finally, Massetani et al.18 reported greater relative risk variability associated with seizures with a right sided focus, while Adjei et al.6 reported that left temporal lobe epilepsy patients had higher mean heart rate and reduced heart rate variability before, during, and after subclinical patterns.

3.8. Magnitude of heart rate change

Of those articles defining ictal tachycardia, six report a mean absolute change in heart rate during an ictal event (bpm).11,12,15,19,23,25 By taking a weighted average of the absolute change, the average change in heart rate was an increase of 34.23 bpm per seizure and 33.51 bpm per patient. One additional study reported an average increase in heart rate (not specified as tachycardia) from 73 ± 2.5 bpm at baseline to 109 ± 3.2 bpm during the ictal phase of complex partial seizures.22 Keilson et al. reported an average increase in heart rate of 60% (range 0%-160%) during ictal events, with a 64% increase in heart rate for generalized seizures compared to 56% of right and 50% of seizures lateralized from the left side.14 Similarly, Leutmezer et al. reported the relative heart rate increase for temporal lobe seizures was 64.8%.15

Five articles reported the percentage of seizures at variable levels of tachycardia.12,14,29,30,39 Blumhardt et al. reported that tachycardia exceeded 120 bpm in 67%, 140 bpm in 30%, and 160 bpm in 12% of partial seizures.30 Keilson et al. reported tachycardia >120 bpm in 76% and >150 bpm in 48% of electro-graphic seizures.14 Isik et al. reported the increase in mean heart rate was <10 bpm in 42.6% of seizures, 10-19 bpm in 12.8% of all seizure types, and 70 bpm in one patient.12 Zijlmans et al. reported an increase in heart rate of more than 10 bpm in 73% of seizures and in increase of more than 20 bpm in 55% of seizures.39 Finally, Wilder-Smith et al. reported that 22% of partial seizures were associated with moderate tachycardia (20-50% increase), and 11% were associated with severe tachycardia (>50% increase).29 Small to moderate increases were consistently more frequent than severe levels of tachycardia.

3.9. Timing of change

Several articles report the occurrence of heart rate changes prior to seizure onset. Zijlmans et al. reported 23% and Mayer et al. reported 28% of all seizures had an associated pre-ictal tachycar-dia.19,39 Additional articles reported variable increases in heart rate that preceded ictal onset. Blumhardt et al. reported that in 57.3% of seizures with heart rate changes, the increase preceded rhythmic seizure activity by a mean of 10.2 s (range 3 -20).30 Data from Schernthaner et al. indicated that heart rate changes preceded ictal onset in 76% of seizures measured non-invasively, and 45.7% of seizures monitored using depth electrodes.25 Similarly, Leutmezer et al. reported 75.9% of all seizures had heart rate changes that preceded ictal onset, with heart rate changes preceding EEG seizure onset by 14 s in the temporal lobe and by 8 s preceding EEG seizure onset in extratemporal origins of seizures.15 Di Gennaro et al. reported that in 98% of the total mesial seizures included in the study, the heart rate increase occurred 5 s before the ictal EEG discharge whereas in 95% of the total lateral seizures, ictal heart rate increases coincided with the onset of the ictal EEG discharge.9 Finally, Nilsen et al. reported that the heart rate in the pre-ictal period was higher in patients with secondarily generalized tonic clonic seizures compare to patients with complex partial seizures.33 All studies of timing of heart rate increase in relation to seizure onset are subject to potential sampling error involving capture of true seizure onset.

A study utilizing power spectrum analysis of heart rate variability reported that 100% of seizures (n = 3 patients; 6 seizures) showed reciprocal high frequency power peaks between 10 s pre seizure-onset and 24 s post seizure-onset.13 Furthermore, the reciprocal HF-power amplitude exceeded non-seizure maximum for all seizures between 30 s pre seizure-onset and seizure onset time. These high reciprocal HF power peaks suggest suppressed parasympathetic activity at seizure onset which opens the possibility to predict seizures using heart rate variability seconds before seizure onset. Several articles reported significant increase in heart rate at seizure onset or within the first 30 s of seizure onset11,14,17,27,29,31 with maximal heart rate achieved for a majority of seizures within the first 60 s.17,19,30 Calandra-Buonaura et al. evaluated heart rate variability and showed a shift of sympathetic/parasympathetic cardiac control toward a dominant sympathetic expression in the 10 s before seizure onset; however heart rate changes were only evident 1 s before onset.8

4. Discussion

Scientific literature supports the occurrence of significant increases in heart rate associated with ictal events in a large proportion of patients with epilepsy using concurrent electroencephalogram (EEG) and electrocardiogram (ECG); a weighted

^ ARTICLE IN PRESS

K.S. Eggleston et al./Seizure xxx (2014) xxx-xxx

average of 82% of patients had at least one seizure associated with a significant increase in heart rate across studies evaluated here. Intra-individual variability was noted in several articles;15,21,26,30-32,36 thus, although a patient may have a history of ictal tachycardia, not every seizure may be associated with increased heart rate. The average percentage of seizures associated with significant heart rate changes including tachycardia was similar for generalized (64%) and partial onset seizures (71%), however it is likely the magnitude of change is increased when seizures move from focal to generalized and additional brain centers are recruited. Using data reported in the literature reviewed here, on average, the change in heart rate during seizures was >30 bpm and consistent with a relative change >50% when compared to baseline heart rates. The majority of articles reviewed evaluated seizures of temporal lobe origin; when multiple lobes of onset were considered, results indicated that seizures of temporal lobe origin were more likely to have an associated tachycardia compared to seizures of extratemporal lobe ori-

gins.1

8 The evidence to support an effect of seizure lateralization

on heart rate in the literature was inconclusive, but suggests that events with increase in heart rate are more highly influenced by the right anatomic structures.6,9,15,18,19 Finally, the timing of the change in heart rate has been documented to occur in the pre-ictal state, raising a possibility for intervention. The majority of studies indicated a significant rise in heart rate within first 30 s of seizure onset.

Observational data is subject to selection bias; however, most studies took measures to control bias by selecting random or consecutive patients and/or using a control group. Additionally, this phenomenon may be susceptible to publication bias in that it is likely results were published upon retrospective identification of an association between increase in heart rate and seizure onset; this is consistent with the fact that the majority of studies reviewed here were based on observational data collected during retrospective review of case series. The most significant limitation of the articles presented here is the range of definitions of ictal tachycardia, thus making the comparison of results across articles difficult. The heart rate at which tachycardia is present may vary by age; thus, when defining and determining the presence of ictal tachycardia, a definition which incorporates patient demographics such as age should be considered. Studies do not yet define a false-positive rate for heart-rate increases in people with epilepsy, but not associated with seizures. We similarly do not know whether the magnitude and time course of heart rate increases associated with seizures differs systematically from heart rate increases due to other causes.

5. Conclusion

Significant changes in heart rate associated with ictal onset provide a promising and non-invasive biomarker for seizure detection and perhaps even prediction. Many of the patients evaluated in the articles reviewed here were presenting for EEG evaluation due to the refractory nature of their seizures. Together with the high prevalence of tachycardia in this population, we hypothesize that ictal tachycardia is likely to be associated with drug-resistant epilepsy. Moseley et al. conducted a linear regression analysis and found that ictal tachycardia was significantly associated with >3 failed anti-epileptic drugs (p < 0.001) and seizure generalization (p = 0.001).20 Thus, these characteristics may be indicators of increased likelihood of ictal tachycardia.

A limitation to seizure detection based on heart rate includes heart rate increases associated with normal autonomic nervous system activity; however, it has been suggested that the magnitude of mean increases in heart rate during epileptic seizures is sufficiently large when compared to non-strenuous exercises which may allow for distinction and subsequent

detection of seizures.41 Nevertheless, accurate detection of seizures is likely to require an adjustable threshold given the variability in the magnitude of heart rate changes associated with seizures within and across patients.

Conflict of interest statement

K. Eggleston and B. Olin are employees and stock holders of Cyberonics, Inc., which is developing technology that uses ictal tachycardia as a biomarker of seizure activity. Additionally, Dr. Fisher has been a paid consultant for Cyberonics, although no financial support was provided for contributing to this article.

Acknowledgements

Cyberonics, Inc., would like to acknowledge Shaun Comfort MD, MBA; former Employee of Cyberonics, for participating in original research, and Caroline Ross; Employee of Cyberonics, for editorial support. Dr. Fisher is supported by the Maslah Saul MD, James & Carrie Anderson Chair and the Susan Horngren and Littlefield Funds.

References

1. Devinsky O. Diagnosis and treatment of temporal lobe epilepsy. Rev Neurol Dis 2004; 1(2-9.

2. Jansen K, Lagae L. Cardiac changes in epilepsy. Seizure: J Brit Epilepsy Assoc 2010;19:455-60. http://dx.doi.org/10.1016Zj.seizure.2010.07.008. pii:S1059-1311(10)00157-3.

3. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727-32.

4. Custer JW, Rau RE. Johns hopkins: the harriet lane handbook. 18th ed. Mosby Elsevier Inc; 2008.

5. MEDDEV. 2.7.1 Rev.3. European Commission Enterprise and Industry Directorate General; 2009.

6. Adjei P, et al. Do subclinical electrographic seizure patterns affect heart rate and its variability? Epilepsy Res 2009;87:281-5. http://dx.doi.org/10.1016/j.eplep-syres.2009.08.011. pii:S0920-1211(09)00239-3.

7. Britton JW, Ghearing GR, Benarroch EE, Cascino GD. The ictal bradycardia syndrome: localization and lateralization. Epilepsia 2006;47:737-44. http:// dx.doi.org/10.1111/j. 1528-1167.2006.00509.x.

8. Calandra-Buonaura G, et al. Physiologic autonomic arousal heralds motor manifestations of seizures in nocturnal frontal lobe epilepsy: implications for pathophysiology. Sleep Med 2012;13:252-62. http://dx.doi.org/10.1016/ j.sleep.2011.11.007.

9. Di Gennaro G, et al. Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures. Clin Neurophysiol 2004;115:1169-77. http://dx.doi.org/10.1016/j.clinph.2003.12.016. pii:S1388245703004851.

10. Epstein MA, Sperling MR, O'Connor MJ. Cardiac rhythm during temporal lobe seizures. Neurology 1992;42:50-3.

11. Garcia M, D'Giano C, Estelles S, Leiguarda R, Rabinowicz A. Ictal tachycardia: its discriminating potential between temporal and extratemporal seizure foci. Seizure: J Brit Epilepsy AssocV 10 2001:415-9. http://dx.doi.org/10.1053/ seiz.2000.0529.

12. Isik U, Ayabakan C, Tokel K, Ozek MM. Ictal electrocardiographic changes in children presenting with seizures. Pediatr Int: Off J Japan Pediatr Soc 2012;54:27-31. http://dx.doi.org/10.1111/j.1442-200X.2011.03453.x.

13. Jeppesen J, Beniczky S, Fuglsang-Frederiksen A, Sidenius P, Jasemian Y. Detection of epileptic-seizures by means of power spectrum analysis of heart rate variability: a pilot study. Technol Health Care 2010;18:417-26. http:// dx.doi.org/10.3233/THC-2010-0606.

14. Keilson MJ, Hauser WA, Magrill JP. Electrocardiographic changes during electrographic seizures. Arch Neurol 1989;46:1169-70.

15. Leutmezer F, Schernthaner C, Lurger S, Potzelberger K, Baumgartner C. Elec-trocardiographic changes at the onset of epileptic seizures. Epilepsia 2003;44:348-54.

16. Li LM, Roche J, Sander JW. Ictal ECG changes in temporal lobe epilepsy. Arq Neuropsiquiatr 1995;53:619-24.

17. Marshall DW, Westmoreland BF, Sharbrough FW. Ictal tachycardia during temporal lobe seizuresJT Mayo Clinic Proc. 1983;58:443-6.

18. Massetani R, Strata G, Galli R, Gori S, Gneri C, Limbruno U, et al. Alteration of cardiac function in patients with temporal lobe epilepsy: different roles of EEG-ECG monitoring and spectral analysis of RR variability. Epilepsia 1997;38:363-9.

19. Mayer H, et al. EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy. Neurology 2004;63:324-8. pii:63/2/324.

20. Moseley BD, Nickels K, Britton J, Wirrell E. How common is ictal hypoxemia and bradycardia in children with partial complex and generalized convulsive seizures? Epilepsia 2010;51:1219-24. http://dx.doi.org/10.1111/j. 1528-1167.2009.02490.x. pii:EPI2490.

21. Nei M, Ho RT, Sperling MR. EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia 2000;41:542-8.

22. Oliveira GR, Gondim FeA, Hogan RE, Rola FH. Heart rate analysis differentiates dialeptic complex partial temporal lobe seizures from auras and non-epileptic seizures. Arq Neuropsiquiatr 2007;65:565-8.

23. Opherk C, Coromilas J, Hirsch LJ. Heart rate and EKG changes in 102 seizures: analysis of influencing factors. Epilepsy Res 2002;52:117-27. pii:S0920121102002152.

24. O'Regan ME, Brown JK. Abnormalities in cardiac and respiratory function observed during seizures in childhood. Dev Med Child Neurol 2005;47:4-9.

25. Schernthaner C, Lindinger G, Potzelberger K, Zeiler K, Baumgartner C. Auto-nomic epilepsy - the influence ofepileptic discharges on heart rate and rhythm. Wien Klin Wochenschr 1999;111:392-401.

26. Smith PE, Howell SJ, Owen L, Blumhardt LD. Profiles of instant heart rate during partial seizures. Electroencephalogr Clin Neurophysiol 1989;72:207-17.

27. Toth V, et al. Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy. Eur J Neurol: OffJ EurFed of Neurol Soc 2010;17:780-7. http://dx.doi.org/10.1111/j. 1468-1331.2009.02939.x. pii:ENE2939.

28. Weil S, Arnold S, Eisensehr I, Noachtar S. Heart rate increase in otherwise subclinical seizures is different in temporal versus extratemporal seizure onset: support for temporal lobe autonomic influence. Epileptic Disord: Int Epilepsy J Videotape 2005;7:199-204.

29. Wilder-Smith E, Lim SH. Heart rate changes during partial seizures: a study amongst Singaporean patients. BMC Neurol 2001;1:5.

30. Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986;1:1051-6. pii:S0140-6736(86)91328-0.

31. Galimberti CA, Marchioni E, Barzizza F, Manni R, Sartori I, Tartara A. Partial epileptic seizures of different origin variably affect cardiac rhythm. Epilepsia 1996;37:742-7.

32. Kerem DH, Geva AB. Forecasting epilepsy from the heart rate signal. Med Biol Eng Comput 2005;43:230-9.

33. Nilsen kB, Haram M, Tangedal S, Sand T, Brodtkorb E. Is elevated pre-ictal heart rate associated with secondary generalization in partial epilepsy? Seizure: J Brit Epilesy AssocV 19 2010:291-5. http://dx.doi.org/10.1016/j.seizure.2010.03.003. pii:S1059-1311(10)00057-9.

34. Novak V, Reeves LA, Novak P, Low AP, Sharbrough WF. Time-frequency mapping of R-R interval during complex partial seizures of temporal lobe origin. J Auton Nerv Syst 1999;77:195-202.

35. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet 2004;364:2212-9. http://dx.doi.org/10.1016/S0140-6736(04)17594-6. pii:S0140673604175946.

36. van Elmpt WJ, Nijsen TM, Griep PA, Arends JB. A model of heart rate changes to detect seizures in severe epilepsy. Seizure: J Brit Epilepsy Assoc 2006;15:366-75. http://dx.doi.org/10.1016Zj.seizure.2006.03.005. pii:S1059-1311(06)00059-8.

37. Vaughn BV, Quint SR, Tennison MB, Messenheimer JA. Monitoring heart period variability changes during seizures II. Diversity and trends. J Epilepsy 1996;9:27-34.

38. Walker F, Fish DR. Recording respiratory parameters in patients with epilepsy. Epilepsia 1997;38:S41-2. http://dx.doi.org/10.1111/j.1528-1157.1997.tb06126.x. pii:EPIS41.

39. Zijlmans M, Flanagan D, Gotman J. Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition ofan objective clinical sign. Epilepsia 2002;43:847-54. pii:epi37801.

40. Ansakorpi H, Korpelainen JT, Suominen K, Tolonen U, Myllyla VV, Isojarvi JI. Interictal cardiovascular autonomic responses in patients with temporal lobe epilepsy. Epilepsia 2000;41:42-7.

41. Osorio I, Schachter S. Extracerebral detection of seizures: a new era in epilep-tology? Epilepsy Behav 2011;22(Suppl 1):S82-7. http://dx.doi.org/10.1016/ j.yebeh.2011.09.012.