Scholarly article on topic 'Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review'

Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review Academic research paper on "Clinical medicine"

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{"Ictal asystole" / "Ictal bradycardia syndrome" / Syncope / Epilepsy / SUDEP}

Abstract of research paper on Clinical medicine, author of scientific article — Giada Giovannini, Stefano Meletti

Abstract We report the case of a 69-year-old woman who presented with recurring episodes of mental confusion/dizziness followed by loss of consciousness, intense pallor, and sweating. Cardiologic investigations were unremarkable. The electroencephalogram recorded during one typical episode allowed the demonstration of a right frontotemporal seizure with progressive bradycardia leading to a 9-second asystole. Following levetiracetam treatment up to 2500mg/day, seizures with ictal asystole (IA) recurred. An MRI compatible pacemaker was then implanted. At 26-month follow-up, the patient has not had further episodes of loss of consciousness. A systematic review (1950–Apr 2014) searching for cases in which IA was an early manifestation of epilepsy led to the observation of 31 cases. The time lag between the first seizures and the correct diagnosis of IA was long (average: 27months; median: 12months). Clinical history alone was not sufficient to prompt a correct diagnosis of IA, and only 11 out of 31 cases presented with symptoms suggestive of a seizure disorder. The majority of patients had a frontotemporal epilepsy with a slight prevalence of left-side involvement (19 out of 31). Ictal bradycardia–asystole is an important condition that should be recognized by epileptologists, neurologists, as well as emergency department physicians. It is important to underscore that IA not only can occur in patients with drug-resistant epilepsy but also may be the first manifestation of the patient's epilepsy.

Academic research paper on topic "Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review"

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Epilepsy & Behavior Case Reports

journal homepage: www.elsevier.com/locate/ebcr

Case Report

Ictal asystole as the first presentation of epilepsy: A case report and

systematic literature review

CrossMark

Giada Giovannini, Stefano Meletti *

Department of Biomedical, Metabolic, and Neural Science, University of Modem and Reggio Emilia, NOCSAE Hospital, Modena, Italy

ARTICLE INFO

Article history:

Received 16 June 2014

Received in revised form 27 June 2014

Accepted 29 June 2014

Available online xxxx

Keywords: Ictal asystole

Ictal bradycardia syndrome

Syncope

Epilepsy

ABSTRACT

We report the case of a 69-year-old woman who presented with recurring episodes of mental confusion/ dizziness followed by loss of consciousness, intense pallor, and sweating. Cardiologic investigations were unremarkable. The electroencephalogram recorded during one typical episode allowed the demonstration of a right frontotemporal seizure with progressive bradycardia leading to a 9-second asystole. Following levetiracetam treatment up to 2500 mg/day, seizures with ictal asystole (IA) recurred. An MRI compatible pacemaker was then implanted. At 26-month follow-up, the patient has not had further episodes of loss of consciousness. A systematic review (1950-Apr 2014) searching for cases in which IA was an early manifestation of epilepsy led to the observation of 31 cases. The time lag between the first seizures and the correct diagnosis of IA was long (average: 27 months; median: 12 months). Clinical history alone was not sufficient to prompt a correct diagnosis of IA, and only 11 out of 31 cases presented with symptoms suggestive of a seizure disorder. The majority of patients had a frontotemporal epilepsy with a slight prevalence of left-side involvement (19 out of 31).

Ictal bradycardia-asystole is an important condition that should be recognized by epileptologists, neurologists, as well as emergency department physicians. It is important to underscore that IA not only can occur in patients with drug-resistant epilepsy but also may be the first manifestation of the patient's epilepsy.

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

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

1. Introduction

Epileptic seizures can influence the heart, and in particular, they frequently generate changes in heart rate (HR) [1]. Sinus ictal tachycardia (IT), defined as an increase in HR higher than the baseline plus one-third

[2], is the most frequently found arrhythmia (accounting for 80-100% of all seizures). It has generally no cardiac consequences, and it can anticipate the beginning of the seizure or occur simultaneously with it

A less frequently observed arrhythmia is sinus ictal bradycardia (IB); defined as an R-Rinterval is greater than 2 s [4]. Ictal bradycardia

☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Corresponding author at: Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSAE Hospital, via Giardini 1355,41126 Modena, Italy.Tel.: +39 0593961676; fax: +39 0593961336.

E-mail addresses: giovannini.giada@gmail.com (G. Giovannini), stefano.meletti@unimore.it (S. Meletti).

can be found in < 6% of seizures. A severe slowing of the HR leading to asystole is called "ictal bradycardia syndrome". Ictal asystole (IA) is defined as the absence of ventricular complexes for > 4 s accompanied by electrographic seizure onset [5]. Ictal asystole is a rare condition that can be found in 0.27-0.4% of patients undergoing video-EEG monitoring [6,7]. The asystole usually follows changes in the scalp-recorded EEG even if, in some cases, cardiac rhythm changes precede an obvious EEG discharge. Ictal asystole always goes along with a diffuse slowing and flattening of the electrical brain activity seen on the EEG that possibly causes the interruption of the ictal activity itself by an anoxic-ischemic mechanism [8,9]. Clinically, the IA corresponds to a loss of consciousness and a loss of muscle tone that sometimes may be accompanied by myoclonic components. This kind of autonomic dysregulation is generally found in focal chronic epilepsies: 80% of IA cases are associated with temporal lobe epilepsy (TLE) [10,11], while the remaining 20% are linked to extra-TLE (mainly frontal lobe epilepsy) [12].

To obtain relevant clinical information on IA when it occurs as an early (or as first) clinical symptom in the patient's epilepsy history, we present a personal experience in a single case and a systematic review (without meta-analysis, narrative) on this topic.

http://dx.doi.org/10.1016/j.ebcr.2014.06.001

2213-3232/© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

2. Methods

2.1. Case report

We, hereby, present a case of IA in a patient with new-onset epilepsy observed in our neurology ward.

2.2. Systematic literature search

We conducted a systematic review of the literature available in PubMed (1950-Apr 2014), searching for cases in which ictal asystole was documented (EEG with ECG registration) as an early manifestation in a new-onset epilepsy or in a newly diagnosed epilepsy [13]. We, therefore, included cases in which IA was a clinical symptom that prompted the diagnosis of epilepsy. We also included cases with an already established epilepsy diagnosis whose seizures had not already failed to respond to adequate trials of two tolerated, appropriately chosen antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. As a consequence, we excluded all the cases in which ictal asystole was observed in the context of drug-resistant epilepsy (as defined by the authors themselves).

The search keywords used, according to the MeSH terms, were the following: "Epilepsy AND Asystole OR Ictal Asystole OR Ictal bradycardia syndrome OR Ictal Bradycardia".

The initial search identified 829 citations. After data analysis and extraction, we identified 29 reports of suspected ictal asystole in new-onset/newly diagnosed epilepsy, but eight articles were finally excluded because they lacked a clear EEG/ECG coregistration of the phenomenon (see flowchart, Fig. 1).

The primary outcomes of the review were to evaluate the time lag between the first episode of loss of consciousness and the diagnosis of ictal asystole and to define the ictal clinical symptoms associated with or preceding loss of consciousness. We also evaluated the following: lobar involvement, etiology, hemispheric lateralization of the seizure, and therapy (AEDs chosen and pacemaker implantation).

3. Case presentation

A 69-year-old woman came to the emergency department for recurring episodes over the previous month characterized by mental confusion, light-headedness, and dizziness followed by loss of consciousness, with intense pallor and sweating. Recovery was quite rapid (20-40 s), and no postictal aphasia or other deficits were reported. Interictal neurological examination was normal.

In her past medical history, the relevant elements were as follows: a thyroid papillary tumor treated with thyroidectomy (16 years before), a catamenial migraine (since her youth), a meningioma of the left cavernous sinus treated with surgery (11 years before) followed by gamma-knife radiosurgery (5 years before), and a right frontal meningioma treated with gamma-knife radiosurgery (the year before).

The carotid sinus massage and the tilt-table test were both negative for vasovagal syncope and orthostatic hypotension. The cardiologic investigations performed (transthoracic echocardiography and Holter ECG) were also unremarkable.

Even if the semiology of the events was not suggestive of seizures/ epilepsy, this possibility was considered (multiple meningiomas). Indeed, a prolonged EEG monitoring allowed the recording of one typical episode demonstrating a right frontotemporal epileptic seizure with progressive bradycardia leading to a 9-second asystole (Fig. 2A). The brain MRI confirmed the presence of multiple meningiomas together with postactinic gliosis of the right temporal lobe (Fig. 2B).

Since there were no modifications from the previous MRI, a neuro-surgical intervention to remove the right frontotemporal meningioma was not considered a priority, also taking into account the previous neurosurgical history of the patient and the presence of postradiotherapy white matter changes in the right temporal lobe that could have had,

iNITIAL SEARCH: 829 articles

> -a» 110 not in English

articles in English: 719

> -^ 525 excluded after title analysis

194 articles

> -^ 74 excluded after abstract analysis

120 articles

> -^ 11 not available

109 articles

> -^ 23 were reviews

86 articles

> ->i 6 with primitive cardiac cause for loss of consciousness

80 articles

N 10 with arrhythmias other than asystole

70 articles

> -àk 5 with not detailed clinical history of patients

65 articles

> -^ 36 with IA in drug-resistant epilepsy

29 articles

\ -ât 8 with no co-EEG/EKG documentation [20-27]

FINAL SELECTION: 21 articles

Fig. 1. Flowchart illustrating the literature review process.

per se, a role in the ictogenesis of the patient's seizures. An appropriate antiepileptic drug (AED) therapy was then started with levetiracetam progressively titrated to 1500 mg/day. The patient remained seizurefree for a month, after which, a seizure with IA and falls recurred. Firstly, the AED therapy was increased to 2500 mg/day; however, since the patient presented with two IA events in the following month, she was readmitted to the hospital, and a dual-chamber MRI-compatible pacemaker was implanted.

Fig. 2. A. During hyperventilation, rhythmic theta activity and spikes started from the right frontotemporal regions. The ECG trace showed a baseline HR of approximately 80 bpm. 27 s after the beginning of the seizure, the HR dropped; after 47 s, an asystole lasting for 9 s appeared, then the baseline cardiac rhythm returned. During the asystole, the EEG showed hypersynchronous slowing and amplitude increasing of the background electrical activity. Then the brain electrical activity flattened, and the patient presented with loss of consciousness. B. Coronal IR sequence (left panel) with gadolinium showing a meningioma of the left cavernous sinus (white arrow) and a meningioma of the right frontotemporal convexity (red arrow). Coronal FLAIR image (right panel) showing postactinic white matter hyperintensity of the right temporal lobe.

At 26-month follow-up, the patient has had no further episodes of loss of consciousness, and no arrhythmia was recorded by the pacemaker.

4. Discussion

The relations between seizures and the heart are very complex. The pathogenesis of these events is not completely and clearly understood. These arrhythmic events could easily occur in patients without any cardiac alterations. The mainstream theory is that the seizures may lead to the involvement and the stimulation of a circuit comprising the insula, the cingulate cortex, the amygdala, and the hypothalamus. This circuit regulates the cardiac functions through the connections to the brainstem and the spinal cord nuclei [14]. The ictal bradycardia syndrome could be found in patients with a long-lasting history of epilepsy, in particular of refractory epilepsy caused by a continuing impairment of the neurocardiac regulatory system as a result of repeated

seizures and, maybe, AED treatment. The impairment of the neurocardiac regulatory system is well demonstrated by the lower heart rate variability (HRV) in patients with TLE [15]. This can make patients more susceptible also to fibrillation and tachyarrhythmias [16-18]. In these cases, IA should be particularly suspected if the usual semiology of seizures occur together with syncopal episodes [19-21]. On the contrary, the presented case demonstrates clearly that IA can be the only and the first ictal manifestation of new-onset epilepsy, and for this reason, it could be easily overlooked.

4.1. Treatment choices in the presented case

As there are no guidelines to address the management of ictal arrhythmias, we focused on the decision-making process of implanting a pacemaker [22]. Even if these events are generally benign and self-limited, it is theorized that they could contribute to SUDEP, although a link of the IA with SUDEP is still missing [23]. When an IA is detected,

Table 1

Reviewed studies.

Ref. Age (years) Sex Baseline EKG Duration before diagnosis Lobe MRI/etiology Side Asystole duration AED before diagnosis AED after diagnosis Pacemaker implantation

Fincham R.W. et al. [27] 68 M UNK Some w O Posttraumatic R 33 - PHT Yes

Reeves A.L. et al. [28] 60 M Run of SVT 3y T Normal R 6 - CBZ No

Fuhr and Leppert [4] 69 M Normal First episode FT Not performed R 5 UNK UNK UNK

Rugg-Gunn et al. [7] 34 M Normal 1y Bil Normal Bil 25-30 PHT, CBZ PHT, CBZ Yes

Dubois-Teklali F. et al. [29] 2 M Normal 9m T Normal L 20 - VPA, OXCBZ Yes

CarinciV. etal. [30] 78 M UNK 2d FT Previous clipping of intracranial aneurysm L 10 - - Yes

Ghearing G. et al. [31] 72 F Normal 3y T Normal L 4 - UNK UNK

Bae E.K. et al. [32] 61 F 2nd degree AV block 7m T Normal L UNK - LEV Yes

DinanA. etal. [33] 59 M Normal 4d T Ischemic changes in insular region L 4 - LEV Yes

Enkiri S. et al. [34] 38 M Normal Some d F Normal L 22.5; 8.5; 24.5 - OXCBZ No

Schuele S.U. et al. [35] 14 F Normal <1 y T Normal L 33 LEV LEV Yes

13 F Normal 1y Vertex Normal - 5 LEV LEV Yes

Kouakam C. et al. [36] 37 F Normal 4y T Normal L 30 - VGB, CBZ No

77 F 1st degree AV block 5y T Posttraumatic R 10 - CBZ No

47 F Normal 2y T Normal R 30 - VGB Yes

54 F Normal 8y T Normal L 15 - OXCBZ, CLB No

52 M Normal 1y T Normal L 30 - CBZ No

21 F Normal 2y T Normal L 27 - CBZ, TPM Yes

29 F Normal 18 y T Normal L 12 - LTG No

83 F Normal 3y T Normal R 20 - OXCBZ No

34 F Normal m T HS L 40 - CBZ, LEV No

NovyJ. et al. [37] 46 M Normal 5y T Normal L 7 - VPA Yes

Lanz A. et al. [38] 41 M Normal 1y T Normal R 25 CBZ, PRI CBZ Yes

63 F Left bundle brunch block 14 m FT DNET L 34 TPM - Yes

Lee et al. [39] 41 F Normal Some w T Anti-NMDAR encephalitis L 15 - Steroids, TPM, LEV Yes

Marynissen T. et al. [40] 48 M Atrial fibrillation 2y T Normal UNK 15 - YES (Not spec) Yes

Millichap J.J. et al. [41] 15 F Normal 1m T Anti-NMDAR encephalitis L 22 - IVG, PHT, LEV, PB, Steroids Yes

Strzelczyk A. et al. [42] 66 F Normal 5y T Normal R 21 - VPA Yes

Kang D.Y. et al. [43] 54 M UNK 2y T Normal L 40 CBZ CBZ Yes

Wittekind S.G. et al. [25] 32 M Normal 16 m FT Normal R 18.5 - LEV Yes

Heerey et al. [44] 24 F Normal 1y T Normal L 30 LEV, LCS LEV, LCS Yes

Present study 69 F Normal Some m T Meningiomas and gliosis R 9 - LEV Yes

F, female; M, male; d, days; m, months; y, years; T, temporal; FT, frontotemporal; L, left; R right; Bil, bilateral; SVT, supraventricular tachycardia; HS, hippocampal sclerosis; CBZ, carbamazepine; CLB, clobazam; GBP, gabapentin; LEV, levetiracetam; LCS, lacosamide; LTG, lamotrigine; OXCBZ, oxcarbazepine; PHT, phenytoin; PRI, primidone; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid; IVG, intravenous globulin; UNK, unknown.

to avoid ictal traumatic falls and to reduce the correlated morbidity, a pacemaker is often implanted [5,24]. However, the benefit of cardiac pacing in patients with IA has not been confirmed. In a clinical series of patients with IA, the benefits of the pacemaker implantation during long-term follow-up were not clear since the recurrence rate of IA was lower than expected, and, therefore, there was no need for the pacemaker activation [2]. Since, in our case, the patient did not have refractory epilepsy (it was a new epilepsy diagnosis), we first tried to achieve seizure control (preventing asystole too) with an effective medical therapy. Indeed, it has been suggested that if one achieves, medically or surgically, seizure freedom, there is no risk of further asystole, so the pacemaker's implantation could be avoided [25]. Contrarily, if seizure freedom could not be achieved and there is persistence of IA, a pacemaker implantation shall be taken into account, as it was in our patient [26].

42. Literature review

There are relatively few reported cases of ictal asystole in the context of a new-onset/newly diagnosed epilepsy. Twenty-one articles in 31 patients (18 females) were fully analyzed [4,7,25,27-44] (see Table 1). The asystole was self-limiting in every case and lasted 20 s on average (ranging from 4 to 40 s).

Notably, the time between the first presentation of epilepsy and the diagnosis of ictal asystole was, on average, 27 months (median: 12 months), ranging from 1 day to 18 years.

Interestingly, subjective symptomatology suggestive of a focal seizure preceding loss of consciousness was reported in only seven out of 31 cases: visual illusion [27], hallucinations [36], jamais vu [43], fear [37], psychic aura [35], and epigastric auras [28,42]. Ictal motor behaviors suggestive of a seizure disorder (tonic and clonic contractions and automatisms) were described in four patients [31,34-36]. Finally, postictal confusion or focal neurological deficit was described in seven cases [4,25,29,30,36,40,43]. Overall, in the majority of cases, as in the described patient, seizure-related auras or ictal seizure-related semiology was lacking: blurred vision, dizziness, nausea, and light-headedness were the most commonly reported symptoms.

The average age at presentation was 46 years (ranging from 2 to 83 years, median: 47 years). In five cases, interictal alterations of the basal ECG were described, and this could be identified as a further risk factor. The majority of patients had a frontotemporal epilepsy with a slight prevalence of left side involvement (19 out of 31 cases), supporting the idea that there is not a strict side effect [45,46], even if previous findings suggested a "lateralization hypothesis" where the right-sided seizures would result in tachycardia and the left-sided seizures in bradycardia [47-50]. Interestingly, in two patients, the IA was observed in the context of an anti-NMDA receptor encephalitis [39,41], a condition that involves a more generalized autonomic dysregulation.

The majority of patients had no AED therapy at the time of ictal asystole diagnosis (24/31). In the majority of cases (21 patients out of 31), a pacemaker was implanted. Antiepileptic drug therapy was begun after the diagnosis of IA in all but two patients. Interestingly, only four out of31 patients had sodium channel blocker drugs before diagnosis. Therefore, a major causal mechanism of these drugs in inducing IA can be ruled out in this context.

We would like to highlight the importance of ECG-EEG monitoring in diagnosing the real cause of a recurrent unexplained loss of consciousness [21]. In fact, the time elapsed between first seizures and IA diagnosis was, on average, more than two years. This delay in correct diagnosis can potentially expose the patient to risks of traumatic falls and, theoretically, to sudden unexplained death in epilepsy (SUDEP) [51-55]. Notably, the absence in the clinical patient's history of symptoms or signs suggesting the diagnosis of a seizure disorder is insufficient to exclude IA. Indeed, only a minority of patients with IA presented with signs/symptoms suggestive of seizures/epilepsy. Therefore, an EEG with ECG monitoring is mandatory in these cases.

5. Conclusions

Ictal asystole is an important condition that should be recognized by epileptologists, neurologists, as well as emergency department physicians as the nonrecognition of this entity leads to a misdiagnosis (syncope) with consequences that can be dangerous for the patient. In particular, it is important to know that IA not only can occur in patients with a diagnosis of epilepsy already known but also may be the first manifestation of the patient's epilepsy.

Disclosure of conflicts of interest

None of the authors has any conflict of interest to disclose. No financial or material support was received by any of the authors in conducting this research or in preparing this manuscript. We also confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

Nei M, Ho RT, Sperling MR. EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia 2000;41 (5):542-8.

Schuele S, Bermeo AC, Locatelli E, Burgess RC, Lüders HO. Ictal asystole: a benign condition? Epilepsia2008;49(1):168-71.

Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia 2010;51(5):725-37.

Fuhr P, Leppert D. Cardiac arrest during partial seizure. Neurology 2000;54:2026. Moseley BD, Ghearing GR, Munger TM, Britton JW. The treatment of ictal asystole with cardiac pacing. Epilepsia 2011;52(4):e16-9.

Rocamora R, Kurthen M, Lickfett L, von Oertzen J, Elger CE. Cardiac asystole in epilepsy: clinical and neurophysiology features. Epilepsia 2003;44(2):179-85. Rugg-Gunn FJ, Duncan JS, Smith SJM. Epileptic cardiac asystole. J Neurol Neurosurg Psychiatry 2000;68:100-26.

Nguyen-Michel V-H, Adam C, Dinkelacker V, Pichit P, Boudali Y, Dupont S, et al. Characterization of seizure-induced syncopes: EEG, ECG and clinical features. Epilepsia 2014;55(1):146-55.

Schuele SU, Bermeo AC, Alexopoulos AV, Burgess RC. Anoxia-ischemia: a mechanism of seizure termination in ictal asystole. Epilepsia 2010;51(1):170-3. Carvalho KS, Salanova V, Markand ON. Cardiac asystole during a temporal lobe seizure. Seizure 2004;13:595-9.

Duplyakov D, Golovina G, Lyukshina N, Surkova E, Elger CE, Surges R. Syncope, seizure-induced bradycardia and asystole: two cases ofclinical and pathophysiolog-ical features. Seizure 2014 Mar;S1059-1311(14)00070-3.

Mascia A, Quarato PP, Sparano A, Esposito V, Sebastiano F, Occhiogrosso G, et al. Cardiac asystole during right frontal lobe seizures: a case report. Neurol Sci 2005; 26:340-3.

Thurman David J, Beghi Ettore, Begley Charles E, Berg Anne T, Buchhalter Jeffrey R, Ding Ding, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011;52(S7):2-26.

Zubair S, Arshad AB, Saeed B, Luqman S, Oommen KJ. Ictal asystole — late manifestation of partial epilepsy and importance of cardiac pacemaker. Seizure 2009; 18:457-61.

Jansen K, Lagae L. Cardiac changes in epilepsy. Seizure 2010;19:455-60. Espinosa PS, Lee JW, Tedrow UB, Bromfield Eb, Dworetzky BA. Sudden unexpected near death in epilepsy: malignant arrhythmia from a partial seizure. Neurology 2009, May 12;72:1702.

Ferlisi M, Tomei R, Carletti M, Moretto G, Zanoni T. Seizure induced ventricular fibrillation: a case of near-SUDEP. Seizure 2013;22:249-51.

Vedovello M, Baldacci F, Nuti A, Cipriani G, Ulivi M, Vergallo A, et al. Peri-ictal prolonged atrial fibrillation after generalized seizures: description of a case and etiopathological considerations. Epilepsy Behav 2012;23:377-8. Beal JC, Sogawa Y, Ceresnak SR, Mahgerefteh J, Moshe SL. Late onset ictal asystole in refractory epilepsy. Paediatr Neurol 2011;45:253-5.

Varade P, Rayes M, Basha M, Watson C. Ictal syncope in a patient with temporal lobe epilepsy. Neurology 2013;80:e172-4.

Rubboli G, Bisulli F, Michelucci R, Meletti S, Ribani MA, Cortelli P, et al. Sudden falls due to seizure-induced cardiac asystole in drug-resistant focal epilepsy. Neurology 2008 May 13;70:1933-5.

Lim ECH, Lim SH, Wilder-Smith E. Brain seizes, heart ceases: a case of ictal

asystole. J Neurol Neurosurg Psychiatry 2000;69:557-9.

Leung H, Kwan P, Elger CE. Finding the missing link between ictal bradyarhythmia,

ictal asystole and sudden unexpected death in epilepsy. Epilepsy Behav 2006;

9:19-30.

Akbar U, Rincon F, Carran M, Campellone J, Milcarek B, Burakgazi E. Increased prevalence of temporary cardiac pacing in people with epilepsy. Seizure 2012; 21:518-21.

Wittekind SG, Lie O, Hubbard S, Viswanathan MN. Ictal asystole: an indication for pacemaker implantation and emerging cause of sudden death. PACE 2012 July;35: e193-6.

[26] Rugg-Gunn FJ, SimisterRJ, Squirrel M, Holdright DR Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet 2004;364:2212-9.

[27] Fincham RW, Shivapour ET, Leis AA, Martins JB. Ictal bradycardia with syncope: a case report. Neurology 1992 Nov;42(11):2222-3.

[28] Reeves AL, Nollet KE, Klass DW, Sharbrough FW, So EL. The ictal bradycardia syndrome. Epilepsia 1996;37(10):983-7.

[29] Dubois-Teklali F, Nguyen-Morel MA, Douchin S, Defaye P, Vercueil L. Clustering syncope in a young male with temporal lobe seizures. Dev Med Child Neurol 2006; 48:687-9.

[30] Carinci V, Barbato G, Baldrati A, Di Pasquale G. Asystole induced by partial seizures: a rare cause of syncope. PACE 2007 November;30:1416-9.

[31] GhearingGR, MungerTM,Jaffe AS, Benarroch EE, BrittonJW. Clinical cues for detecting ictal asystole. Clin Auton Res 2007;17:221-6.

[32] Bae EK, Park K, Kim H, Jung KH, Lee ST, Chu K, et al. Ictal asystole and eating reflex seizures with temporal lobe epilepsy. Epilepsy Behav 2011 ;20:404-6.

[33] Dinan A, de Toffol B, Pallix M, Breard G, Babuty D. Cardiac arrest: it's all in the head. Lancet 2008;371:1476.

[34] Enkiri SA, Ghavami F, Anyanwu C, Eldadah Z, Morrissey R, Motamedi GK New onset left frontal lobe seizure presenting with ictal asystole. Seizure 2011;20:817-9.

[35] Schuele SU, Bermeo AC, Alexopoulos AV, Burgess RC, Dinner DS, Foldvary-Schaefer N. Video-electrographic and clinical features in patients with ictal asystole. Neurology 2007;69:434-41.

[36] Kouakam C, Daems C, Guedon-Moreau L, Delval A, Lacroix D, Derambure F, et al. Recurrent unexplained syncope may have a cerebral origin: report of 10 cases of arrhythmogenic epilepsy. Arch Cardiovasc Dis 2009;102:397-407.

[37] Novy J, Carruzzo A, Pascale P, Maeder-Ingvar M, Genne D, Pruvot E, et al. Ictal brady-cardia and asystole: an uncommon cause of syncope. Int J Cardiol 2009;133:e90-3.

[38] Lanz M, Oehl B, Brandt A, Schulze-Bonhage A. Seizure induced cardiac asystole in epilepsy patients undergoing long term video-EEG monitoring. Seizure 2011; 20:167-72.

[39] Lee M, Lawn N, Prentice D, Chan J. Anti-NMDA receptor encephalitis associated with ictal asystole. J Clin Neurosci 2011;18:1716-8.

[40] Marynissen T, Govers N, Vydt T. Ictal asystole: case report with review of literature. Acta Cardiol 2012 Aug;67(4):461-4.

[41] Millichap JJ, Goldstein JL, Laux LC, Nordli DR, Stack CV, Wainwright MS. Ictal asystole and anti-N-methyl-D-aspartate receptor antibody encephalitis. Pediatrics 2011;127: e781.

[42] Strzelczyk A, Cenusa M, Bauer S, Hamer HM, Mothersill IW, Grunwald T, et al. Management and long-term outcome in patients presenting with ictal asystole or bradycardia. Epilepsia 2011;52(6):1160-7.

[43] Kang DY, Oh IY, Lee SR Choe WS, Yoon JH, Lee SK, et al. Recurrent syncope triggered by temporal lobe epilepsy: ictal bradycardia syndrome. Korean Circ J 2012; 42:349-51.

[44] Heerey A, Nash P, Hennessey M. The ictal bradycardia syndrome: persistence of seizures despite cardiac pacemaker implantation. Ir Med J 2014, Mar;107(3):80-1.

[45] BrittonJW, Ghearing GR Benarroch EE, Cascino GD. The ictal bradycardia syndrome: localization and lateralization. Epilepsia 2006;47(4):737-44.

[46] 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(8):847-54.

[47] Leutmezer F, Schernthaner C, Lurger S, Potzelberger K, Baumgartner C. Electrocardiographic changes at the onset of epileptic seizures. Epilepsia 2003;44(3):348-54.

[48] Mayer H, Benninger F, Urak L, Plattner B, Geldner J, Feucht M. EKG abnormalities in children and adolescent with symptomatic temporal lobe epilepsy. Neurology 2004; 63:324-8.

[49] Oppenheimer SM, Wilson JX, Guiraudon G, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death? Brain Res 1991;550(1):115-21.

[50] Tinuper P, Bisulli F, Cerullo A, Carcangiu R Marini C, Pierangeli G, et al. Ictal bradycardia in partial epileptic seizures: autonomic investigation in three cases and literature review. Brain 2001;124:2361-71.

[51] Jeppesen J, Fuglsang-Frederiksen A, Brugada R Pedersen B, Rubboli G, Johansen P, et al. Heart rate variability analysis indicates preictal parasympathetic overdrive preceding seizure-induced cardiac dysrhythmias leading to sudden unexpected death in a patient with epilepsy. Epilepsia 2014 Apr;4:1-5.

[52] NashefL, Walker F, Allen P, Sander JWAS, Shorvon SD, Fish DR. Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. J Neurol Neurosurg Psychiatry 1996;60:297-300.

[53] Ryvlin P, Montavont A, Kahane P. Sudden unexpected death in epilepsy: from mechanisms to prevention. Curr Opin Neurol 2006;19:194-9.

[54] So EL. What is known about the mechanisms underlying SUDEP? Epilepsia 2008; 49(Suppl.9):93-8.

[55] Velagapudi P, Turagam M, Laurence T, Kocheril A. Cardiac arrhythmias and sudden unexpected death in epilepsy (SUDEP). PACE 2012 March;35:363-70.