Ictal Modulation of Cardiac Repolarization, but Not of Heart Rate, Is Lateralized in Mesial Temporal Lobe Epilepsy

<div><p>Objectives</p><p>Human and animal studies provided controversial data on asymmetric cortical representation of cardiac function, which may partially be due to different study designs and inter-individual variability. Here, we investigated whether seizure-related changes in heart rate (HR) and cardiac repolarization depend on the side of seizure-activity in people with mesial temporal lobe epilepsy (mTLE).</p><p>Methods</p><p>To account for inter-individual variability, EEG and ECG data were reviewed from patients with medically refractory mTLE undergoing pre-surgical video-EEG telemetry with at least 2 seizures arising from each hippocampus as assessed by bilateral hippocampal depths electrodes. RR and QT intervals were determined at different timepoints using a one-lead ECG. QT intervals were corrected for HR (QTc) using 4 established formulas.</p><p>Results</p><p>Eighty-two seizures of 15 patients were analyzed. HR increased by ∼30% during hippocampal activity irrespective of the side (p = 0.411). QTc intervals were lengthened to a significantly greater extent during left hippocampal seizures (e.g. difference of QT intervals between preictal and ictal state using Bazett’s formula; left side 32.0±5.3 ms, right side 15.6±7.7 ms; p = 0.016). Abnormal QTc prolongation occurred in 7 of 41 left hippocampal seizures of 4 patients, and only in 2 of 37 right hippocampal seizures of 2 patients.</p><p>Conclusions</p><p>Seizure-related modulation of cardiac repolarization, but not of HR, appears to depend on the side of ictal activity, strengthening the hypothesis of asymmetric cerebral representation of cardiac function. The clinical relevance of this is unclear, but may indicate an increased risk of abnormal ictal QT prolongation in people with left mTLE.</p></div

Clinical characteristics of patients.

*<p>At telemetry.</p>§<p>follow-up in months.</p>#<p>according to Engel classification.</p><p>c, electrode contacts; ExHipp, extrahippocampal; Hipp, hippocampal; HS, hipppocampal sclerosis; L, left; n.a., not applicable; R, right; SAHE, selective amygdala-hippocampectomie; TL, temporal lobe.</p

Implantation scheme and flowchart of patient selection.

<p>(A) Scheme of implantation of intracranial electrodes to assess hippocampal activity and (B) flowchart of selection and inclusion of patients.</p

Summary of seizure-related QT alterations.

*<p>Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol. 2004;37 Suppl: 81–90 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064765#pone.0064765.s003" target="_blank">table S1</a>). In 5 of the 82 included seizures, ictal QT intervals could not been reliably analyzed.</p

Plot of HR and QTc changes per patient.

<p>(A) Relative ictal HR changes and (B) absolute QTc differences using Bazett’s formula were plotted separately for each patient and side of seizure activity. Corresponding data pairs from each patient were connected with a line. Note that only in two patients, QTc increased by more than 10 ms during right hippocampal seizures as compared to left hippocampal seizures (B, highlighted in red). (C) Individual QTc values (Bazett) did not correlate with corresponding absolute ictal heart rates (linear regression, p = 0.67). Examples were illustrated using Bazett’s formula, as this correction formula is known to overestimate corrected QT values, so that a potential artificial bias, if present, should be clearly visible.</p

Example of original EEG- and ECG-traces during a focal seizure with right-sided hippocampal onset.

<p>(A) Implantation scheme of intracranial electrodes (patient no. 119). (B–E) EEG-traces in bipolar montage (localization as given in panel A, the lower numbers apply to the contacts opposite to the cable outlet of the respective strip or depths electrodes) and ECG-traces (last trace, labeled as EKG1-EKG2, represents derivation Einthoven II with inverted polarity). The time period of the recordings is indicated in panel F. (B) Arrow indicates seizure-onset in the right hippocampus. (C) The arrow indicates onset of ictal activity in the left hippocampus. (D) Note the compromised ECG trace due to movement artifacts of the patient. (E) The arrow indicates the abrupt termination of seizure activity. (F) Time course of HR during this focal seizure with impaired responsiveness and complex automatisms. The arrows indicate the time periods from which example panels B–E have been selected. Note the missing values after propagation of ictal activity to the left hemisphere (time period between arrows “C” and “E”).</p

HR and QTc increase with ictal activity, whereupon modulation of QTc, but not of HR, is asymmetrically lateralized.

<p>(A) Absolute HR at different timepoints from all patients was averaged (based on a mean HR per timepoint and side of seizure-onset per patient). Paired data for right- (white bars) and left-hippocampal onset (grey bars) were available from all 15 patients at all timepoints. (B) Relative HR changes from all patients were averaged with no significant difference of ictal modulation of HR between left- and right-onset seizures. (C) QT intervals corrected with all four formulas (grey bars, left-hippocampal seizures; white bars, right-hippocampal seizures) were plotted versus three timepoints (1, preictal; 2, unilateral ictal activity; 3, postictal). (D) The absolute ictal changes of QT intervals using all four correction formulas (Ba, Bazett; Fri, Fridericia; Ho, Hodges; Fra, Framingham) were separately plotted for left- (grey bars) and right-hippocampal seizures (white bars). QT lengthening was significantly greater during left-hippocampal activity as assessed with all 4 correction formulas, suggesting an asymmetric ictal modulation of cardiac repolarization. All data expressed as mean±S.E.M.</p

Gene-disrupting microdeletions found only in patients with genetic generalised epilepsy.

<p>GGE, genetic generalised epilepsy; CTR: population control; Chr: chromosome, start/end: genomic start and end point of the deleted segment, hg19; ^<i>P</i>-value: type-1 error rate for a χ2-test with df = 1; OR, 95%-CI, odds ratio with 95% confidence interval. Disease phenotype: ASD: autism spectrum disorder, ADHD: attention deficit hyperactivity disorder, AN: anorexia nervosa, AUT: autism, BPD: bipolar disorder, EE: epileptic encephalopathy, EPI: epilepsy, ID: intellectual disability, MCP: microcephaly, SCZ: schizophrenia; GGE syndromes: CAE: childhood absence epilepsy, JAE: juvenile absence epilepsy, JME: juvenile myoclonic epilepsy, EGMA: epilepsy with generalised tonic-clonic seizures alone predominantly on awakening, EGTCS: epilepsy with generalised tonic-clonic seizures alone, gsw: generalised spike and wave discharges on the electroencephalogram, number/: age-at-onset of afebrile generalised seizures. # previously published in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005226#pgen.1005226.ref026" target="_blank">26</a>] and * [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005226#pgen.1005226.ref027" target="_blank">27</a>]. Bold gene symbols indicate genes previously implicated in epileptogenesis.</p><p>Gene-disrupting microdeletions found only in patients with genetic generalised epilepsy.</p

Functional gene enrichment and network analysis.

<p>Significant gene-set enrichments on 329 genes deleted in GGE patients revealed an enrichment of GRIN2B interacting proteins, genes of the MGI abnormal emotion/affect behaviour annotation and of the GO cognition annotation. Segmental clusters of genes belonging to a gene family were removed. Positional clustering of genes physically linked on a microdeletion is indicated by a slash between the gene symbols.</p><p>Functional gene enrichment and network analysis.</p