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The relationship between seizure onset zone and ictal tachycardia: An intracranial EEG study
Clinical Neurophysiology 126 (2015) 2255–2260
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
The relationship between seizure onset zone and ictal tachycardia: An intracranial EEG study Maria Stefanidou a,⇑, Chad Carlson b, Daniel Friedman c a
Boston University School of Medicine, Dept. of Neurology, Boston, MA, USA Medical College of Wisconsin, Dept. of Neurology, Milwaukee, WI, USA c New York University, Comprehensive Epilepsy Center, New York, NY, USA b
a r t i c l e
i n f o
Article history: Accepted 21 January 2015 Available online 14 February 2015 Keywords: Refractory epilepsy Tachycardia Intracranial EEG SUDEP
h i g h l i g h t s There is not a strict hemispheric lateralization on the cortical control of sympathetic function during
seizures. Evolution of seizures over larger areas of brain and in particular spread to the contralateral hemi-
sphere, define the degree and rate at which ictal tachycardia occurs. Development of ictal tachycardia early in a seizure is a common and reproducible occurrence in the
same individual and may be used as a biomarker in the development of automatic seizure detection systems.
a b s t r a c t Objectives: Seizures are often accompanied by ictal tachycardia, which, when pronounced, is one of the cardiac arrhythmias associated with sudden unexpected death in epilepsy (SUDEP). We examined the relationship between the lateralization and localization of seizure onset and development of ictal tachycardia. Methods: We identified patients who underwent bi-hemispheric intracranial EEG recording over a period of 18 months. Two to four consecutive seizures were reviewed for each patient. Results: Fifty-seizures from 19 consecutive patients were analyzed. Forty seizures (80%) developed tachycardia (>20% increase from baseline), but laterality at seizure onset did not predict its occurrence (p = 0.168). Bi-laterality at ictal onset was associated with early ictal tachycardia (<10 s) (p = 0.0208). Seizures out of sleep developed tachycardia faster (mean 19.7 s vs. 68.2 s, p = 0.0067), but the state of alertness was not predictive of the development of tachycardia within 10 s of seizure onset. Temporal and/or orbito-frontal lobe involvement was associated with tachycardia when compared to any other lobar combinations at ictal onset (p = 0.0073). Conclusion: Laterality at seizure onset does not predict the occurrence of ictal tachycardia. Involvement of the temporal and orbito-frontal cortex, spread to the contralateral hemisphere and state of alertness, may define the degree and rate of autonomic changes. Significance: Our results help clarify the autonomic control during seizures and offer potential use for future studies in SUDEP risk and automatic seizure detection. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction ⇑ Corresponding author at: Boston University School of Medicine, 72 East Concord Street, Neurology C-3, Boston, MA 02118, USA. Tel.: +1 617 638 8456; fax: +1 617 638 5354. E-mail address: [email protected] (M. Stefanidou).
Autonomic discharges observed during seizures may lead to both cardiac and respiratory changes. Ictal sinus tachycardia is the most commonly observed electrocardiographic change and
http://dx.doi.org/10.1016/j.clinph.2015.01.020 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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maximal ictal heart rate has been shown to be significantly higher in those who later died of sudden unexpected death in epilepsy (SUDEP) (Nei et al., 2004), a significant cause of death that may account for up to 17% of deaths among patients with epilepsy (Jehi and Najm, 2008; Nei and Hays, 2010). Prior studies have evaluated the influence of hemispheric laterality and/or lobar involvement at seizure onset on the degree and direction of these changes with conflicting results. Stimulation studies (Oppenheimer et al., 1992) and analysis of spontaneously occurring seizures have suggested an association between right hemispheric onset and development of marked ictal tachycardia (Leutmezer et al., 2003; Mayer et al., 2004) versus left hemispheric onsets associated with ictal bradycardia (Almansori et al., 2006). Other studies have demonstrated that the hemisphere involved at seizure onset does not reliably predict the development of ictal tachycardia (Garcia et al., 2001; Moseley et al., 2011; Opherk et al., 2002; Rugg-Gunn et al., 2004; Wilder-Smith and Lim, 2001). Cerebral regions regarded responsible for autonomic control include the insula, the anterior cingulate and the ventromedial prefrontal cortex (Jehi and Najm, 2008; Shorvon and Tomson, 2011). There is evidence that ictal tachycardia occurs more frequently in temporal lobe epilepsy (TLE) (Moseley et al., 2011) and some investigators have argued that among temporal lobe seizures, those originating in the mesial temporal structures are more likely to manifest with ictal tachycardia (Garcia et al., 2001; Leutmezer et al., 2003). On the other hand, a study by Opherk showed that the region of onset did not influence the ictal HR significantly (Opherk et al., 2002). The type of seizure (simple partial seizures (SPS), complex partial seizures (CPS), generalized and tonic seizures) has also been evaluated in the development of ictal tachycardia with some studies supporting no significant association (Keilson et al., 1989; Rugg-Gunn et al., 2004) and others demonstrating a higher prevalence of tachycardia among generalized seizures (Moseley et al., 2011; Nei et al., 2000; Opherk et al., 2002). Ictal tachycardia tends to occur early after seizure onset and often precedes the clinical and even the electrographic changes observed on scalp EEG (Blumhardt et al., 1986; Sevcencu and Struijk, 2010; Zijlmans et al., 2002). It also frequently occurs in a stereotypical pattern within an individual, making tracking of HR activity a potential non-invasive marker to be included in seizure warning systems or even in ‘‘on demand’’ electrical stimulation therapies (Sevcencu and Struijk, 2010). In this retrospective study, we used bi-hemispheric intracranial EEG (ICEEG) recording that allows for precise spatial and temporal localization of seizure onset and spread to examine the development of ictal tachycardia in patients with refractory epilepsy. We defined ictal tachycardia as a 20% increase in heart rate (HR) from baseline.
(baseline) were reviewed for each patient. For two patients only two seizures met criteria for inclusion. For patients with fewer than three similar seizures, seizures of an additional seizure type were included, if available; this allowed for three or four seizures per patient analyzed. Following identification of the included seizures, the ICEEG and EKG data were extracted and analyzed separately. Instantaneous HR was automatically calculated using the R-R interval derived by NicOne (Natus, Madison, WI) software. The raw EKG tracing was visually reviewed to verify accuracy of the calculated HR. We defined significant tachycardia as a 20% increase in HR compared to baseline HR. Early ictal tachycardia was defined as development of significant tachycardia within 10 s from seizure onset (Galimberti et al., 1996). The baseline was calculated as the mean HR over the 90 s preceding the electrographic seizure onset. Upon review of the electrographic seizures on the ICEEG recording, the ictal localization was categorized as frontal (F), orbitofrontal (O-F), temporal (T; including mesial temporal when depth electrodes were available), parietal (P) and occipital (O) regions for each second of each seizure. For the included seizures, the video recording was also reviewed in order to determine the type of seizure (SPS, CPS +/ secondary generalization, tonic, subclinical) and onset out of the awake or asleep state. Age, gender, magnetic resonance imaging (MRI) findings, and results of the pathologic analysis of resected tissue when available were also collected (Table 1). Correlations were examined using Pearson’s chi-square and Fischer’s exact test for categorical data and unpaired t-test and Kruskal–Wallis one-way analysis of variance for continuous data. P values < 0.05 were considered statistically significant. This study was approved by the Internal Review Board of New York University School of Medicine. 3. Results Nineteen consecutive patients (6 men and 13 women – mean age 29.7, range 15–51) were identified. All eligible patients had focal onset treatment resistant epilepsy (documented failure of at least 3 anti-epileptic drugs (AEDs)). On admission patients were on a varying number of AEDs (range 1–5, median 3) that were gradually tapered to capture seizures. Fifty-nine seizures were reviewed. Nine seizures were excluded from analysis because the EKG was not interpretable throughout the electrographic seizure and no tachycardia developed during the interpretable portion of the EKG tracing. It was, therefore, impossible to determine if tachycardia developed later in those seizures (Supplementary Table S1). 3.1. Hemispheric lateralization at ictal onset
2. Methods The New York University Comprehensive Epilepsy Center electroencephalography (EEG) reports were reviewed to identify patients who had undergone bi-hemispheric intracranial EEG recordings for epilepsy surgery over an 18-month period. Children below 12 years of age, patients with prior brain resection, patients experiencing status epilepticus, and those who had previous cerebral radiation therapy, were excluded. All patients underwent 128-channel ICEEG recordings. A standard pre-cordial single-channel electrocardiogram (ECG) was recorded continuously on the EEG in all cases. Three consecutive, electrographically similar seizures with interpretable EKG at seizure onset and over the preceding 90 s
Laterality at ictal onset did not predict the occurrence of ictal tachycardia (Chi-square 3.568, 2, p = 0.168) (Fig. 1). Forty seizures (80%) were associated with significant (>20% increase in HR) tachycardia. Twelve seizures had bilateral and 28 seizures had unilateral ictal onset. Among those with unilateral ictal onset, 13 (46%) developed tachycardia only upon spread to the contralateral hemisphere. Ten seizures (6 patients) had interpretable EKG throughout the electrographic seizure and did not develop a significant increase in HR. Time to development of significant tachycardia varied between 3 and 243 s (mean 37.8 s, median 16.5 s) and did not depend on laterality at seizure onset (Kruskal Wallis p = 0.248). Bilateral ictal activity at seizure onset was associated with early ictal tachycardia (<10 s) (Chi-square 7.747, 2, p = 0.0208) (Fig. 2).
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M. Stefanidou et al. / Clinical Neurophysiology 126 (2015) 2255–2260 Table 1 Clinical characteristics. Pt
Age
Gender
MRI findings
Type of resection
Pathology
1
32
M
Lesionectomy
Low grade neuroepithelial tumor
2 3
24 51
M F
L sphenoethmoidal basal encephalocele TSC R MTS
No resection R AMTL
4 5 6 7
26 20 28 26
M F F M
No resection No resection No resection L frontal lobe
8 9
47 35
F F
Non-lesional Non-lesional TSC L frontal cortical signal abnormality Non-lesional R MTS
No resection T: GMH H: MTS Biopsy: R frontal WMNH No resection No resection Ganglioglioma
10
46
M
Possible R MTS
R AMTL
11
32
M
R temporal, parietal occipital lobe
12 13 14
26 49 28
F F F
B/L temporal GMH R occipital GMH R temporal cortical dysplasia. Non-lesional Non-lesional Non-lesional
15 16 17
15 27 21
F F F
Non-lesional Non-lesional TSC
No resection L insula L AMTL
18 19
16 17
F F
Non-lesional L temporal cortical dysplasia
R occipital lobe L AMTL
No resection R AMTL
No resection No resection L AMTL
No resection T: Cortical dysplasia H: MTS T: Cortical dysplasia, WMNH H: MTS, dysplasia T: GMH H: GMH, cortical dysplasia
No resection No resection T: Cortical dysplasia, WMNH H: Neuronal loss, dysplasia, WMNH No resection Cortical dysplasia, WMNH T: Cortical tubers H: Neuronal loss Cortical dysplasia T: Cortical dysplasia, WMNH H: MTS
M: Male, F: Female, R: Right, L: Left, TSC: Tuberous Sclerosis Complex, MTS: Mesial Temporal Sclerosis, AMTL: Anterior Mesial Temporal Lobectomy, T: Temporal Lobe, H: Hippocampus, GMH: Grey Matter Heterotopia, WMNH: White Matter Neuronal Heterotopia.
Fig. 1. Percentage of seizures that develop ictal tachycardia vs. laterality of seizure onset.
Fig. 3. Percentage of seizures with T/OF lobe involvement at seizure onset vs. any other lobar combination between seizures with and without development of ictal tachycardia.
Fig. 2. Percentage of seizures that develop early (<10 s) ictal tachycardia between groups of bilateral, left and right hemispheric onset. Seizures that did not develop tachycardia are not included in the graph.
Fig. 4. Time to tachycardia over stage of alertness.
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Fig. 5. HR changes of two seizures from the same patient is shown in (A) The electrographic EEG involvement of the temporal and orbitofrontal regions over time is also shown. The dotted line marks the time of tachycardia onset (17 s for both seizures). The raw data is seen in (B) with the purple marker at the electrographic onset of the seizure and the red arrow at onset of tachycardia. LMF: left mesial frontal, LAF: left anterior frontal, LFP: left frontal posterior, LTP: left temporal parietal, LAT: left anterior temporal, LPT: left posterior temporal, RLF: right lateral frontal, RAF, right anterior frontal, RAT: right anterior temporal, RTA: right temporo-parietal, RMT: right midtemporal, RPT: right posterior temporal, RTPO: right temporo-occipital, LDMF: left depth mesial frontal (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
3.2. Lobar localization at ictal onset Twenty-nine seizures had an ictal onset limited to one lobar region (F, OF, T, P or O). In the remaining 19 seizures, synchronous ictal activity could be seen over 2–5 regions. There was no individual lobar involvement at seizure onset that could predict the development of ictal tachycardia, Given the very
small number of extra-temporal onset seizures, further analysis was performed after we categorized ictal onsets into two groups; one group to involve either the temporal, orbito-frontal, or a combination of these two regions, versus any other lobar combination at seizure onset. Involvement of T and/or OF lobe at seizure onset was more likely to be linked to ictal tachycardia (Fisher’s exact test p = 0.007) (Fig. 3).
M. Stefanidou et al. / Clinical Neurophysiology 126 (2015) 2255–2260
3.3. Other clinical characteristics Among seizures that developed ictal tachycardia, those arising out of sleep did so faster than those that occurred in awake patients (mean 23.4 s vs. 68.2 s, t = 2.347, p = 0.0246) (Fig. 4). Complex partial seizures with or without secondary generalization and tonic seizures were more likely to develop ictal tachycardia (39/44) when compared to subclinical and simple partial seizures (1/6) (Fisher’s exact test p = 0.0006).
4. Discussion This study presents the largest series of patients undergoing bilateral intracranial EEG analyzed for increase in ictal HR changes. We were able to show that significant sinus tachycardia is a common phenomenon, but laterality at seizure onset does not predict its occurrence. Involvement of the temporal and orbito-frontal cortex may correlate with increased sympathetic drive. Spread to the contralateral hemisphere, as well as the state of alertness, may further define the degree and rate at which autonomic changes occur. There is evidence in the literature of an alteration of the autonomic –sympatho/parasympathetic – balance among patients with epilepsy that is present both interictally (altered heart rate variability, faster HR) and during seizures (cardiac arrhythmias, ictal apnea) and seems to evolve in time along with the epileptic process (Sevcencu and Struijk, 2010). In particular, ictal sinus tachycardia is the most common electrocardiographic change and in our cohort it was seen in 80% of seizures and 17/19 patients. Though it is often a benign phenomenon (Britton et al., 2006), Nei et al. showed that among patients who died of SUDEP the maximal ictal HR was significantly higher, compared to controls, with greater increases with seizures arising out of sleep (Nei et al., 2004). In our cohort, tachycardia occurred early into a seizure (median 16.5 s) and significantly faster in those seizures arising out of the asleep state. Its early occurrence and the observation that recurrent seizures in the same patient are often accompanied by similar features (Smith et al., 1989) (Fig. 5) suggest that tracking of HR activity may be used as a potential non-invasive surrogate marker in seizure warning systems or even in ‘‘on demand’’ electrical stimulation therapies. Of note, the latency observed in our study may be underestimated as seizures that were accompanied by marked movement leading to obscured HR data were excluded; thus it is possible that some patients with later onset ictal HR increases were not identified. In our study the hemispheric laterality of seizure onset did not predict the development of ictal tachycardia in accordance with previous studies (Garcia et al., 2001; Moseley et al., 2011; Opherk et al., 2002; Rugg-Gunn et al., 2004; Wilder-Smith and Lim, 2001). This offers further evidence favoring the lack of a strict lateralized hemispheric representation of cortical autonomic control. There was, however, a link between increased sympathetic drive and T and/or OF lobe involvement at seizure onset. The small number of extra-temporal onset focal seizures in our surgical cohort limited our ability, though, to assess the contribution of individual lobes to the development of ictal tachycardia. Interesting data come from the potential contribution of bihemispheric involvement in the control of autonomic function. Bilateral onset seizures were associated with early ictal tachycardia (<10 s) and out of those seizures that were unilateral at onset, 46% developed tachycardia only upon spread to the contralateral hemisphere, consistent with previous findings that generalization increases the magnitude and acceleration of IT (Epstein et al., 1992; Sevcencu and Struijk, 2010) and tachycardia is more often accompanied by bilateral discharges (Wilder-Smith and Lim, 2001).
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Moreover, studies looking into other ictal autonomic changes raise the question of bi-hemispheric involvement in their modulation. Ictal hypoxemia (Moseley et al., 2010), desaturations (Bateman et al., 2008), apnea (Seyal and Bateman, 2009), and bradycardia (Britton et al., 2006) occurred more frequently with bi-hemispheric involvement. In addition, the thalamus, which has been implicated in seizure generalization, appears to amplify the ictal cardiovascular effects (Sevcencu and Struijk, 2010). Our study was limited to the evaluation of ictal tachycardia and did not address other cardiac arrhythmias or concurrent respiratory changes, but raises the question of deeper subcortical structures participating in the autonomic response. A limiting factor in the interpretation of the various studies is the variety of definitions used for tachycardia with some looking at HR changes of 20–50% from baseline and others defining it based on normal HR for age (greater than 98th percentile or >100 bpm). Future studies will need to further define the association between the degree and rate of HR change, its potential link to SUDEP and its use as a surrogate marker for diagnosis of a seizure. 5. Conclusion The above findings support the hypothesis that there is not a strict hemispheric lateralization on the cortical control of autonomic functions during seizures. There is some evidence that involvement of the temporal and orbito-frontal cortex at seizure onset may correlate with increased sympathetic drive, but the small number of extra-temporal onset seizures in this series limits the interpretation of our findings. Evolution of the seizures over larger areas of brain (complex vs. simple partial and subclinical seizures) and in particular spread to the contralateral hemisphere, as well as the state of alertness at the time of seizure onset, may further define the degree and rate at which autonomic changes occur in ways that are not yet fully elucidated. Acknowledgements We thank Cerena Brunson for her assistance in retrieving the EEG records for review. Conflict of interest: None of the authors has any conflict of interest to disclose. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clinph.2015.01. 020. References Almansori M, Ijaz M, Ahmed SN. Cerebral arrhythmia influencing cardiac rhythm: a case of ictal bradycardia. Seizure 2006;15:459–61. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239–45. Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986;1:1051–6. Britton JW, Ghearing GR, Benarroch EE, Cascino GD. The ictal bradycardia syndrome: localization and lateralization. Epilepsia 2006;47:737–44. Epstein MA, Sperling MR, O’Connor MJ. Cardiac rhythm during temporal lobe seizures. Neurology 1992;42:50–3. 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. Garcia M, D’Giano C, Estelles S, Leiguarda R, Rabinowicz A. Ictal tachycardia: its discriminating potential between temporal and extratemporal seizure foci. Seizure 2001;10:415–9. Jehi L, Najm IM. Sudden unexpected death in epilepsy: impact, mechanisms, and prevention. Clevel Clin J Med 2008;75(Suppl. 2):S66–70. Keilson MJ, Hauser WA, Magrill JP. Electrocardiographic changes during electrographic seizures. Arch Neurol 1989;46:1169–70.
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Leutmezer F, Schernthaner C, Lurger S, Potzelberger K, Baumgartner C. Electrocardiographic changes at the onset of epileptic seizures. Epilepsia 2003;44:348–54. Mayer H, Benninger F, Urak L, Plattner B, Geldner J, Feucht M. EKG abnormalities in children and adolescents with symptomatic temporal lobe epilepsy. Neurology 2004;63:324–8. 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. Moseley BD, Wirrell EC, Nickels K, Johnson JN, Ackerman MJ, Britton J. Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res 2011;95:237–45. Nei M, Hays R. Sudden unexpected death in epilepsy. Curr Neurol Neurosci Rep 2010;10:319–26. Nei M, Ho RT, Abou-Khalil BW, Drislane FW, Liporace J, Romeo A, et al. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia 2004;45:338–45. Nei M, Ho RT, Sperling MR. EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia 2000;41:542–8. Opherk C, Coromilas J, Hirsch LJ. Heart rate and EKG changes in 102 seizures: analysis of influencing factors. Epilepsy Res 2002;52:117–27.
Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727–32. 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. Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia 2010;51:725–37. Seyal M, Bateman LM. Ictal apnea linked to contralateral spread of temporal lobe seizures: intracranial EEG recordings in refractory temporal lobe epilepsy. Epilepsia 2009;50:2557–62. Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;12:1–2. http://dx.doi.org/10.1016/S0140-6736(11)60176-1. Smith PE, Howell SJ, Owen L, Blumhardt LD. Profiles of instant heart rate during partial seizures. Electroencephalogr Clin Neurophysiol 1989;72:207–17. Wilder-Smith E, Lim SH. Heart rate changes during partial seizures: a study amongst Singaporean patients. BMC Neurol 2001;1:5. Zijlmans M, Flanagan D, Gotman J. Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign. Epilepsia 2002;43:847–54.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
The relationship between seizure onset zone and ictal tachycardia: An intracranial EEG study Maria Stefanidou a,⇑, Chad Carlson b, Daniel Friedman c a
Boston University School of Medicine, Dept. of Neurology, Boston, MA, USA Medical College of Wisconsin, Dept. of Neurology, Milwaukee, WI, USA c New York University, Comprehensive Epilepsy Center, New York, NY, USA b
a r t i c l e
i n f o
Article history: Accepted 21 January 2015 Available online 14 February 2015 Keywords: Refractory epilepsy Tachycardia Intracranial EEG SUDEP
h i g h l i g h t s There is not a strict hemispheric lateralization on the cortical control of sympathetic function during
seizures. Evolution of seizures over larger areas of brain and in particular spread to the contralateral hemi-
sphere, define the degree and rate at which ictal tachycardia occurs. Development of ictal tachycardia early in a seizure is a common and reproducible occurrence in the
same individual and may be used as a biomarker in the development of automatic seizure detection systems.
a b s t r a c t Objectives: Seizures are often accompanied by ictal tachycardia, which, when pronounced, is one of the cardiac arrhythmias associated with sudden unexpected death in epilepsy (SUDEP). We examined the relationship between the lateralization and localization of seizure onset and development of ictal tachycardia. Methods: We identified patients who underwent bi-hemispheric intracranial EEG recording over a period of 18 months. Two to four consecutive seizures were reviewed for each patient. Results: Fifty-seizures from 19 consecutive patients were analyzed. Forty seizures (80%) developed tachycardia (>20% increase from baseline), but laterality at seizure onset did not predict its occurrence (p = 0.168). Bi-laterality at ictal onset was associated with early ictal tachycardia (<10 s) (p = 0.0208). Seizures out of sleep developed tachycardia faster (mean 19.7 s vs. 68.2 s, p = 0.0067), but the state of alertness was not predictive of the development of tachycardia within 10 s of seizure onset. Temporal and/or orbito-frontal lobe involvement was associated with tachycardia when compared to any other lobar combinations at ictal onset (p = 0.0073). Conclusion: Laterality at seizure onset does not predict the occurrence of ictal tachycardia. Involvement of the temporal and orbito-frontal cortex, spread to the contralateral hemisphere and state of alertness, may define the degree and rate of autonomic changes. Significance: Our results help clarify the autonomic control during seizures and offer potential use for future studies in SUDEP risk and automatic seizure detection. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction ⇑ Corresponding author at: Boston University School of Medicine, 72 East Concord Street, Neurology C-3, Boston, MA 02118, USA. Tel.: +1 617 638 8456; fax: +1 617 638 5354. E-mail address: [email protected] (M. Stefanidou).
Autonomic discharges observed during seizures may lead to both cardiac and respiratory changes. Ictal sinus tachycardia is the most commonly observed electrocardiographic change and
http://dx.doi.org/10.1016/j.clinph.2015.01.020 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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maximal ictal heart rate has been shown to be significantly higher in those who later died of sudden unexpected death in epilepsy (SUDEP) (Nei et al., 2004), a significant cause of death that may account for up to 17% of deaths among patients with epilepsy (Jehi and Najm, 2008; Nei and Hays, 2010). Prior studies have evaluated the influence of hemispheric laterality and/or lobar involvement at seizure onset on the degree and direction of these changes with conflicting results. Stimulation studies (Oppenheimer et al., 1992) and analysis of spontaneously occurring seizures have suggested an association between right hemispheric onset and development of marked ictal tachycardia (Leutmezer et al., 2003; Mayer et al., 2004) versus left hemispheric onsets associated with ictal bradycardia (Almansori et al., 2006). Other studies have demonstrated that the hemisphere involved at seizure onset does not reliably predict the development of ictal tachycardia (Garcia et al., 2001; Moseley et al., 2011; Opherk et al., 2002; Rugg-Gunn et al., 2004; Wilder-Smith and Lim, 2001). Cerebral regions regarded responsible for autonomic control include the insula, the anterior cingulate and the ventromedial prefrontal cortex (Jehi and Najm, 2008; Shorvon and Tomson, 2011). There is evidence that ictal tachycardia occurs more frequently in temporal lobe epilepsy (TLE) (Moseley et al., 2011) and some investigators have argued that among temporal lobe seizures, those originating in the mesial temporal structures are more likely to manifest with ictal tachycardia (Garcia et al., 2001; Leutmezer et al., 2003). On the other hand, a study by Opherk showed that the region of onset did not influence the ictal HR significantly (Opherk et al., 2002). The type of seizure (simple partial seizures (SPS), complex partial seizures (CPS), generalized and tonic seizures) has also been evaluated in the development of ictal tachycardia with some studies supporting no significant association (Keilson et al., 1989; Rugg-Gunn et al., 2004) and others demonstrating a higher prevalence of tachycardia among generalized seizures (Moseley et al., 2011; Nei et al., 2000; Opherk et al., 2002). Ictal tachycardia tends to occur early after seizure onset and often precedes the clinical and even the electrographic changes observed on scalp EEG (Blumhardt et al., 1986; Sevcencu and Struijk, 2010; Zijlmans et al., 2002). It also frequently occurs in a stereotypical pattern within an individual, making tracking of HR activity a potential non-invasive marker to be included in seizure warning systems or even in ‘‘on demand’’ electrical stimulation therapies (Sevcencu and Struijk, 2010). In this retrospective study, we used bi-hemispheric intracranial EEG (ICEEG) recording that allows for precise spatial and temporal localization of seizure onset and spread to examine the development of ictal tachycardia in patients with refractory epilepsy. We defined ictal tachycardia as a 20% increase in heart rate (HR) from baseline.
(baseline) were reviewed for each patient. For two patients only two seizures met criteria for inclusion. For patients with fewer than three similar seizures, seizures of an additional seizure type were included, if available; this allowed for three or four seizures per patient analyzed. Following identification of the included seizures, the ICEEG and EKG data were extracted and analyzed separately. Instantaneous HR was automatically calculated using the R-R interval derived by NicOne (Natus, Madison, WI) software. The raw EKG tracing was visually reviewed to verify accuracy of the calculated HR. We defined significant tachycardia as a 20% increase in HR compared to baseline HR. Early ictal tachycardia was defined as development of significant tachycardia within 10 s from seizure onset (Galimberti et al., 1996). The baseline was calculated as the mean HR over the 90 s preceding the electrographic seizure onset. Upon review of the electrographic seizures on the ICEEG recording, the ictal localization was categorized as frontal (F), orbitofrontal (O-F), temporal (T; including mesial temporal when depth electrodes were available), parietal (P) and occipital (O) regions for each second of each seizure. For the included seizures, the video recording was also reviewed in order to determine the type of seizure (SPS, CPS +/ secondary generalization, tonic, subclinical) and onset out of the awake or asleep state. Age, gender, magnetic resonance imaging (MRI) findings, and results of the pathologic analysis of resected tissue when available were also collected (Table 1). Correlations were examined using Pearson’s chi-square and Fischer’s exact test for categorical data and unpaired t-test and Kruskal–Wallis one-way analysis of variance for continuous data. P values < 0.05 were considered statistically significant. This study was approved by the Internal Review Board of New York University School of Medicine. 3. Results Nineteen consecutive patients (6 men and 13 women – mean age 29.7, range 15–51) were identified. All eligible patients had focal onset treatment resistant epilepsy (documented failure of at least 3 anti-epileptic drugs (AEDs)). On admission patients were on a varying number of AEDs (range 1–5, median 3) that were gradually tapered to capture seizures. Fifty-nine seizures were reviewed. Nine seizures were excluded from analysis because the EKG was not interpretable throughout the electrographic seizure and no tachycardia developed during the interpretable portion of the EKG tracing. It was, therefore, impossible to determine if tachycardia developed later in those seizures (Supplementary Table S1). 3.1. Hemispheric lateralization at ictal onset
2. Methods The New York University Comprehensive Epilepsy Center electroencephalography (EEG) reports were reviewed to identify patients who had undergone bi-hemispheric intracranial EEG recordings for epilepsy surgery over an 18-month period. Children below 12 years of age, patients with prior brain resection, patients experiencing status epilepticus, and those who had previous cerebral radiation therapy, were excluded. All patients underwent 128-channel ICEEG recordings. A standard pre-cordial single-channel electrocardiogram (ECG) was recorded continuously on the EEG in all cases. Three consecutive, electrographically similar seizures with interpretable EKG at seizure onset and over the preceding 90 s
Laterality at ictal onset did not predict the occurrence of ictal tachycardia (Chi-square 3.568, 2, p = 0.168) (Fig. 1). Forty seizures (80%) were associated with significant (>20% increase in HR) tachycardia. Twelve seizures had bilateral and 28 seizures had unilateral ictal onset. Among those with unilateral ictal onset, 13 (46%) developed tachycardia only upon spread to the contralateral hemisphere. Ten seizures (6 patients) had interpretable EKG throughout the electrographic seizure and did not develop a significant increase in HR. Time to development of significant tachycardia varied between 3 and 243 s (mean 37.8 s, median 16.5 s) and did not depend on laterality at seizure onset (Kruskal Wallis p = 0.248). Bilateral ictal activity at seizure onset was associated with early ictal tachycardia (<10 s) (Chi-square 7.747, 2, p = 0.0208) (Fig. 2).
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M. Stefanidou et al. / Clinical Neurophysiology 126 (2015) 2255–2260 Table 1 Clinical characteristics. Pt
Age
Gender
MRI findings
Type of resection
Pathology
1
32
M
Lesionectomy
Low grade neuroepithelial tumor
2 3
24 51
M F
L sphenoethmoidal basal encephalocele TSC R MTS
No resection R AMTL
4 5 6 7
26 20 28 26
M F F M
No resection No resection No resection L frontal lobe
8 9
47 35
F F
Non-lesional Non-lesional TSC L frontal cortical signal abnormality Non-lesional R MTS
No resection T: GMH H: MTS Biopsy: R frontal WMNH No resection No resection Ganglioglioma
10
46
M
Possible R MTS
R AMTL
11
32
M
R temporal, parietal occipital lobe
12 13 14
26 49 28
F F F
B/L temporal GMH R occipital GMH R temporal cortical dysplasia. Non-lesional Non-lesional Non-lesional
15 16 17
15 27 21
F F F
Non-lesional Non-lesional TSC
No resection L insula L AMTL
18 19
16 17
F F
Non-lesional L temporal cortical dysplasia
R occipital lobe L AMTL
No resection R AMTL
No resection No resection L AMTL
No resection T: Cortical dysplasia H: MTS T: Cortical dysplasia, WMNH H: MTS, dysplasia T: GMH H: GMH, cortical dysplasia
No resection No resection T: Cortical dysplasia, WMNH H: Neuronal loss, dysplasia, WMNH No resection Cortical dysplasia, WMNH T: Cortical tubers H: Neuronal loss Cortical dysplasia T: Cortical dysplasia, WMNH H: MTS
M: Male, F: Female, R: Right, L: Left, TSC: Tuberous Sclerosis Complex, MTS: Mesial Temporal Sclerosis, AMTL: Anterior Mesial Temporal Lobectomy, T: Temporal Lobe, H: Hippocampus, GMH: Grey Matter Heterotopia, WMNH: White Matter Neuronal Heterotopia.
Fig. 1. Percentage of seizures that develop ictal tachycardia vs. laterality of seizure onset.
Fig. 3. Percentage of seizures with T/OF lobe involvement at seizure onset vs. any other lobar combination between seizures with and without development of ictal tachycardia.
Fig. 2. Percentage of seizures that develop early (<10 s) ictal tachycardia between groups of bilateral, left and right hemispheric onset. Seizures that did not develop tachycardia are not included in the graph.
Fig. 4. Time to tachycardia over stage of alertness.
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Fig. 5. HR changes of two seizures from the same patient is shown in (A) The electrographic EEG involvement of the temporal and orbitofrontal regions over time is also shown. The dotted line marks the time of tachycardia onset (17 s for both seizures). The raw data is seen in (B) with the purple marker at the electrographic onset of the seizure and the red arrow at onset of tachycardia. LMF: left mesial frontal, LAF: left anterior frontal, LFP: left frontal posterior, LTP: left temporal parietal, LAT: left anterior temporal, LPT: left posterior temporal, RLF: right lateral frontal, RAF, right anterior frontal, RAT: right anterior temporal, RTA: right temporo-parietal, RMT: right midtemporal, RPT: right posterior temporal, RTPO: right temporo-occipital, LDMF: left depth mesial frontal (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
3.2. Lobar localization at ictal onset Twenty-nine seizures had an ictal onset limited to one lobar region (F, OF, T, P or O). In the remaining 19 seizures, synchronous ictal activity could be seen over 2–5 regions. There was no individual lobar involvement at seizure onset that could predict the development of ictal tachycardia, Given the very
small number of extra-temporal onset seizures, further analysis was performed after we categorized ictal onsets into two groups; one group to involve either the temporal, orbito-frontal, or a combination of these two regions, versus any other lobar combination at seizure onset. Involvement of T and/or OF lobe at seizure onset was more likely to be linked to ictal tachycardia (Fisher’s exact test p = 0.007) (Fig. 3).
M. Stefanidou et al. / Clinical Neurophysiology 126 (2015) 2255–2260
3.3. Other clinical characteristics Among seizures that developed ictal tachycardia, those arising out of sleep did so faster than those that occurred in awake patients (mean 23.4 s vs. 68.2 s, t = 2.347, p = 0.0246) (Fig. 4). Complex partial seizures with or without secondary generalization and tonic seizures were more likely to develop ictal tachycardia (39/44) when compared to subclinical and simple partial seizures (1/6) (Fisher’s exact test p = 0.0006).
4. Discussion This study presents the largest series of patients undergoing bilateral intracranial EEG analyzed for increase in ictal HR changes. We were able to show that significant sinus tachycardia is a common phenomenon, but laterality at seizure onset does not predict its occurrence. Involvement of the temporal and orbito-frontal cortex may correlate with increased sympathetic drive. Spread to the contralateral hemisphere, as well as the state of alertness, may further define the degree and rate at which autonomic changes occur. There is evidence in the literature of an alteration of the autonomic –sympatho/parasympathetic – balance among patients with epilepsy that is present both interictally (altered heart rate variability, faster HR) and during seizures (cardiac arrhythmias, ictal apnea) and seems to evolve in time along with the epileptic process (Sevcencu and Struijk, 2010). In particular, ictal sinus tachycardia is the most common electrocardiographic change and in our cohort it was seen in 80% of seizures and 17/19 patients. Though it is often a benign phenomenon (Britton et al., 2006), Nei et al. showed that among patients who died of SUDEP the maximal ictal HR was significantly higher, compared to controls, with greater increases with seizures arising out of sleep (Nei et al., 2004). In our cohort, tachycardia occurred early into a seizure (median 16.5 s) and significantly faster in those seizures arising out of the asleep state. Its early occurrence and the observation that recurrent seizures in the same patient are often accompanied by similar features (Smith et al., 1989) (Fig. 5) suggest that tracking of HR activity may be used as a potential non-invasive surrogate marker in seizure warning systems or even in ‘‘on demand’’ electrical stimulation therapies. Of note, the latency observed in our study may be underestimated as seizures that were accompanied by marked movement leading to obscured HR data were excluded; thus it is possible that some patients with later onset ictal HR increases were not identified. In our study the hemispheric laterality of seizure onset did not predict the development of ictal tachycardia in accordance with previous studies (Garcia et al., 2001; Moseley et al., 2011; Opherk et al., 2002; Rugg-Gunn et al., 2004; Wilder-Smith and Lim, 2001). This offers further evidence favoring the lack of a strict lateralized hemispheric representation of cortical autonomic control. There was, however, a link between increased sympathetic drive and T and/or OF lobe involvement at seizure onset. The small number of extra-temporal onset focal seizures in our surgical cohort limited our ability, though, to assess the contribution of individual lobes to the development of ictal tachycardia. Interesting data come from the potential contribution of bihemispheric involvement in the control of autonomic function. Bilateral onset seizures were associated with early ictal tachycardia (<10 s) and out of those seizures that were unilateral at onset, 46% developed tachycardia only upon spread to the contralateral hemisphere, consistent with previous findings that generalization increases the magnitude and acceleration of IT (Epstein et al., 1992; Sevcencu and Struijk, 2010) and tachycardia is more often accompanied by bilateral discharges (Wilder-Smith and Lim, 2001).
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Moreover, studies looking into other ictal autonomic changes raise the question of bi-hemispheric involvement in their modulation. Ictal hypoxemia (Moseley et al., 2010), desaturations (Bateman et al., 2008), apnea (Seyal and Bateman, 2009), and bradycardia (Britton et al., 2006) occurred more frequently with bi-hemispheric involvement. In addition, the thalamus, which has been implicated in seizure generalization, appears to amplify the ictal cardiovascular effects (Sevcencu and Struijk, 2010). Our study was limited to the evaluation of ictal tachycardia and did not address other cardiac arrhythmias or concurrent respiratory changes, but raises the question of deeper subcortical structures participating in the autonomic response. A limiting factor in the interpretation of the various studies is the variety of definitions used for tachycardia with some looking at HR changes of 20–50% from baseline and others defining it based on normal HR for age (greater than 98th percentile or >100 bpm). Future studies will need to further define the association between the degree and rate of HR change, its potential link to SUDEP and its use as a surrogate marker for diagnosis of a seizure. 5. Conclusion The above findings support the hypothesis that there is not a strict hemispheric lateralization on the cortical control of autonomic functions during seizures. There is some evidence that involvement of the temporal and orbito-frontal cortex at seizure onset may correlate with increased sympathetic drive, but the small number of extra-temporal onset seizures in this series limits the interpretation of our findings. Evolution of the seizures over larger areas of brain (complex vs. simple partial and subclinical seizures) and in particular spread to the contralateral hemisphere, as well as the state of alertness at the time of seizure onset, may further define the degree and rate at which autonomic changes occur in ways that are not yet fully elucidated. Acknowledgements We thank Cerena Brunson for her assistance in retrieving the EEG records for review. Conflict of interest: None of the authors has any conflict of interest to disclose. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clinph.2015.01. 020. References Almansori M, Ijaz M, Ahmed SN. Cerebral arrhythmia influencing cardiac rhythm: a case of ictal bradycardia. Seizure 2006;15:459–61. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239–45. Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986;1:1051–6. Britton JW, Ghearing GR, Benarroch EE, Cascino GD. The ictal bradycardia syndrome: localization and lateralization. Epilepsia 2006;47:737–44. Epstein MA, Sperling MR, O’Connor MJ. Cardiac rhythm during temporal lobe seizures. Neurology 1992;42:50–3. 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. Garcia M, D’Giano C, Estelles S, Leiguarda R, Rabinowicz A. Ictal tachycardia: its discriminating potential between temporal and extratemporal seizure foci. Seizure 2001;10:415–9. Jehi L, Najm IM. Sudden unexpected death in epilepsy: impact, mechanisms, and prevention. Clevel Clin J Med 2008;75(Suppl. 2):S66–70. Keilson MJ, Hauser WA, Magrill JP. Electrocardiographic changes during electrographic seizures. Arch Neurol 1989;46:1169–70.
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