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Seizure journal homepage: www.elsevier.com/locate/yseiz
Review
Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features Dmitry Duplyakov a,b,*, Galina Golovina c, Natalia Lyukshina d, Elena Surkova b, Christian E. Elger e, Rainer Surges e,** a
Cardiology Department, Samara Regional Cardiology Dispensary, Samara, Russia Samara State Medical University, Samara, Russia Cardiology Department, VAZ Medical Center, Togliatti, Russia d Neurology Department, Children’s Multifield Hospital No. 1, Togliatti, Russia e Department of Epileptology, University Hospital Bonn, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 June 2013 Received in revised form 2 March 2014 Accepted 5 March 2014
Episodes of transient loss of consciousness (TLOC) are commonly due to syncope or epileptic seizures. The distinction between both entities on clinical grounds and eyewitness accounts can be challenging and is often hampered by similar clinical features. We briefly summarize syncoperelated symptoms and present the case of a female patient who suffered from TLOC episodes due to both reflex syncope and epileptic seizures. Seizure-induced syncope is a rare complication particularly of non-generalized temporal lobe seizures and may be suspected in people with epilepsy who report new semiological features with sudden onset of atonia, TLOC and seizure-related falls. We review epidemiological, clinical and electroencephalographic aspects of seizure-related asystole and syncope and discuss their clinical relevance. The implantation of a cardiac pacemaker appears to efficiently prevent seizure-related falls and consecutive injuries and is an important treatment option if full seizure-control cannot be achieved in these patients. We describe a second case of a patient with refractory temporal lobe epilepsy and seizure-related syncope which ceased after the implantation of a cardiac pacemaker. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Reflex syncope Temporal lobe epilepsy Ictal asystole SUDEP Sudden unexpected death in epilepsy
1. Transient loss of consciousness and syncope Episodes of transient loss of consciousness (TLOC) are commonly due to syncope or epileptic seizures, but a psychogenic origin and other rare causes and mimics may play a role in some patients.1 Syncope is defined as TLOC caused by a transitory global hypoperfusion of the brain. According to the underlying pathophysiology, syncope is classified as reflex syncope (also called neurally mediated syncope), cardiac syncope or syncope due to orthostatic hypotension.1 In general hospitals, reflex syncope accounts for about two third of TLOC cases, about 10% are due to orthostatic hypotension, another 15% are of cardiac origin and the remaining TLOC-cases have other
* Corresponding author at: 43, Aerodromnaja St., Samara, Russia. Tel.: +7 846 373 70 82; fax: +7 846 373 70 82. ** Corresponding author at: Department of Epileptology, University Hospital Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. Tel.: +49 228 28714778; fax: +49 228 28719351. E-mail addresses: [email protected] (D. Duplyakov), [email protected] (R. Surges).
causes including epilepsy.2 Overall, syncope accounts for up to 3% of emergency room visits and for 1–6% of hospital admissions, with many patients undergoing expensive or inadequate tests and inappropriate specialist referrals, partly due to confusing clinical signs linked to syncopal episodes. 3–5 Apart from TLOC, syncope can be associated with a variety of other symptoms, depending on the underlying pathophysiology, the time course and severity of cerebral hypoperfusion. Prodromal phenomena (also called warning signs or presyncope) are usually linked to autonomic activation (e.g. enhanced parasympathetic and sympathetic activity) or reflect cerebral and retinal hypoperfusion. Typical sensations comprise feelings of light-headedness, warmness or nausea (both may be epigastric and rising), dizziness or vertigo and others.6,7 Prior to loss of consciousness, patients commonly display unclear thinking, fixation of the eyes in the midline and a ‘‘frozen’’ appearance, followed by a narrowing of the visual field, loss of color vision and ultimately complete loss of vision, sometimes followed by loss of hearing.7 Eyes are commonly open with the eyeballs turning up during loss of consciousness. During the episode, most individuals exhibit a loss of muscle tone (atonia), possibly causing recurrent falls.
http://dx.doi.org/10.1016/j.seizure.2014.03.004 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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‘‘Positive’’ motor signs, however, do frequently occur and include in particular myoclonic jerks, and much rarer stiffening of arms, legs or the whole body (resembling an opisthotonus).1,7 These motor symptoms, along with some of the prodromal signs, can considerably hamper the correct diagnosis, as they can resemble to those occurring during epileptic seizures. The correct diagnosis is further complicated by incomplete and inaccurate eyewitness accounts of syncope or epileptic seizures. Interestingly, the most accurately reported feature of such episodes is the muscle tone.8
2. Seizure-related bradyarrhythmias and syncope Epileptic seizures are caused by hypersynchronous neuronal discharges and display a large spectrum of sensory, motor and behavioral symptoms with or without TLOC, depending on the localization and extent of abnormal brain activity. In most patients, seizures lead to transient alterations of autonomic cardiorespiratory function.9 These autonomic symptoms include especially tachycardia or tachypnea, but apnea and bradycardia do also occur, thereby possibly leading to secondary syncope. 2.1. Prevalence of periictal bradyarrhythmias Seizure-related bradyarrhythmias including sinus bradycardia (heart rate below 60 beats per min), atrioventriuclar conduction blocks (2nd or 3rd degree) and asystole (commonly defined as RR intervals longer than 3–5 s) were reported with high variability in different studies and case series. Ictal bradycardia was observed in up 6% of the seizures and up to 13% of the patients during prolonged video-EEG telemetry, whereas it occurred in 2% of the seizures and 37% of the patients during ambulatory long-term ECG recordings using an implantable loop recorder.10–15 Ictal asystole was detected in up to 1% and 16% of the patients during prolonged video-EEG telemetry and ambulatory long-term ECG recordings, respectively.10–16 2.2. Pathomechanisms of periictal bradyarrhythmias The exact pathomechanisms underlying the onset of periictal bradyarrhythmias are unclear. Human and animals studies have provided some evidence for an asymmetric representation of sympathetic and parasympathetic networks in the brain (e.g. in the thalamus, hypothalamus, insular cortex, amygdala, hippocampus and brain stem), suggesting that e.g. parasympathetic functions are localized in the left hemisphere.17,18 Furthermore, seizure-related bradyarrhythmias have been especially observed in people suffering from temporal lobe epilepsy, and seem to be rarer in seizures originating in the frontal lobes or other brain regions.10,13,14,16,19–22 Therefore, one could assume that seizureactivity in the left temporal lobe activates parasympathetic function, thereby preferentially leading to bradyarrhythmias. Several case series have, however, produced controversial data without showing a consistent association between side of seizureonset, modulation of heart rate and onset of bradyarrhythmias.13,16,22–25 Instead, onset of bradycardia and asystole appears to be linked to the spread of seizure-activity to the contralateral side and bilateral seizure-activity.13,19,26 An alternative pathomechanism (in contrast to ictal activation of parasympathetic networks or disruption of sympathetic function) may involve reflex pathways which aim at counteracting a prominent seizurerelated tachycardia by excessive activation of the vagal nerve. This assumption is at least partly supported by the observation that ictal bradyarrhythmias are frequently preceded by transitory tachycardia.27
2.3. ECG and EEG patterns during periictal bradyarrhythmias The time interval between seizure-onset (as assessed by EEG changes or clinical signs) and onset of bradycardia or asystole is in average between 10 and 42 s, the mean duration of bradycardia and asystole varies between 20–30 and 13–24 s, respectively.12,16,19,20,27 During ictal asystole, rhythmic EEG patterns may resolve and EEG traces exhibit signs of cerebral hypoperfusion (i.e. bilateral high amplitude delta-slowing or background suppression/generalized EEG attenuation) instead. Bilateral high amplitude delta-slowing (BDS) occurs in average about 10 s after the onset of asystole, is associated with the duration of asystole and atonia (see below) and is variably followed by generalized EEG attenuation.12,13,16,28 Cerebral reperfusion is often accompanied by BDS which re-occurs after generalized EEG attenuation. EEG patterns during ictal asystole are, however, variable. In some patients, the ictal EEG pattern continues during ictal asystole, whereas in others, a generalized EEG attenuation replaces the rhythmic seizure activity without preceding BDS.16 2.4. Semiology of seizure-induced syncope Seizure-induced syncope is mainly caused by longer lasting asystole, whereas periictal bradycardia is usually asymptomatic.16 They predominantly occur with non-generalized temporal lobe seizures, so that the symptoms of syncope are often preceded by typical semiological temporal features such as epigastric aura, staring and unresponsiveness as well as oroalimentary and manual automatisms.12–14,16,19,20 Basically, two types of asystole-related clinical signs can be observed, those related to cerebral hypoperfusion (skin pallor; loss of muscle tone = atonia; TLOC; early myoclonic jerks; tonic motor symptoms, mostly generalized tonic posturing resembling opisthotonus; falls secondary to atonia or tonic motor symptoms) and those associated with cerebral reperfusion (skin flushing; late myoclonic jerks).12,13,16 About 10–12 s after the onset of asystole, the habitual ictal symptoms are interrupted by asystole-related motor features.13,16 Occurrence of atonia, tonic motor symptoms and late myoclonic jerks is linked to the duration of the asystole.13,16 Postictal re-orientation time seems to be similar in seizures with or without associated syncope.12 2.5. Clinical significance of seizure-related asystole There is an ongoing debate whether periictal asystole is a serious complication of epileptic seizures and whether it requires a specific treatment. In most cases, seizure-related asystole appears to be a rather benign condition which does not need cardiopulmonary reanimation measures.14,16,21,27 In the case of nongeneralized ‘‘uncomplicated’’ seizures, ictal asystole is likely to be a self-limiting event that is triggered by a seizure-induced predominant vagal effect on the heart and terminated by subsequent cerebral hypoperfusion and anoxia.27 This assumption is also supported by the observation that seizures with ictal asystole are shorter than those without asystole.28,29 Recurrent seizure-related syncope with falls, however, may lead to various, possibly serious injuries including fractures and traumatic hemorrhages.14,30 In the case of generalized tonic–clonic seizures, the significance of periictal asystole might be very different. A recent study has investigated monitored cases of sudden unexpected death in epilepsy (SUDEP) and near-SUDEP cases. A principal finding of this study was that apnea and asystole occurred in all SUDEP cases in the early postictal phase after generalized tonic–clonic seizures.15,31 In this context, it would be important to know whether periictal bradyarrhythmias in association with non-generalized seizures predict an increased
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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risk of later SUDEP. This is, however, not known to date and subject of future studies. 2.6. Treatment options of seizure-induced syncope Prevention of seizure-induced syncope can be achieved by successful seizure control. In newly diagnosed epilepsies, administration of anticonvulsant drugs may be sufficient to prevent seizures and associated syncope.14,20,30 In people with refractory focal epilepsy, however, epilepsy surgery should be considered to reach seizure-freedom.14 If sufficient seizure control cannot be achieved, the implantation of a cardiac pacemaker should be considered and recommended especially in those patients who suffer from seizure-related falls likely due to syncope and who display periictal asystole during combined EEG/ECG recordings. Fortunately, previous case series of patients with documented ictal asystole have reported successful prevention of seizure-related falls and injuries after the implantation of a cardiac pacemaker.13,14,30 The effects of a cardiac pacemaker on the risk of SUDEP are unclear to date. 3. Case reports 3.1. Case 1 A 49-year-old female patient was admitted to the Cardiology Department at the Samara Regional Cardiology Dispensary (Samara, Russia) after TLOC. It was known that while aged between 12 and 16 years, this patient was very intolerant of hot weather and experienced rare episodes of syncope in crowded and warm rooms or during long periods of standing in the upright position. On one occasion she suffered from syncope during an intravenous puncture. Between the age of 16 and 47, she was apparently free of syncope and only three years prior to admission to our hospital, episodes with TLOC re-occurred. Over the last 3 years, the patient experienced six episodes of fainting, with three of them occurring in the 6 months before admission. The fainting spells in adulthood were the same as they were in her adolescence. Most episodes also happened in warm rooms, with the patient being in an upright position. Once, the patient fainted while quickly turning her head, and once she experienced sudden loss of consciousness for no obvious reason. With these exceptions, all other syncopal attacks started with blurred vision and skin pallor, and occurred slowly. After the end of each attack, nausea and weakness persisted for about 2 h. The patient had no family history of fainting or other diseases causing TLOC. The patient’s clinical examination was, apart from some premature contractions, unremarkable (baseline heart rate 74 beats per minute, blood pressure 120/80 mmHg). Examination of other organs and systems revealed no abnormalities. Laboratory blood and urine tests were normal. Echocardiography also revealed no pathological findings: dimensions, global and local contractility, valves, pulmonary artery pressure were all normal. On February 1, 2008, a head-up tilt-test according to the Westminster protocol was performed and revealed a vasovagal response type 1 (development of bradycardia and hypotension: decrease of HR from 90 to 50 beats per minute and systolic blood pressure to 70 mmHg) with signs of presyncope. A carotid sinus massage was performed on the patient according to standard protocols. During left sinus massage with the patient in the upright position, a weak orthostatic hypotension occurred with a systolic blood pressure dropping from 120 to 80 mmHg accompanied by a slight dizziness. As the patient complained of heart palpitations, Holter ECG monitoring was performed (February 19, 2008). The average heart rate was 62 beats per minute (min 34, max 118). At 11:44 a.m. that day, while the patient was climbing the stairs, a
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typical presyncope developed, after which the patient fainted. During this episode, the ECG recordings exhibited an asystole of 34 s (Fig. 1). In view of the typical features of a reflex syncope (history, vasovagal response during tilt-test) and of the 34-s asystole episode registered during ECG-monitoring, the patient was referred to the hospital for permanent pacemaker implantation. A two-chamber pacemaker with Sudden Rate response function (Guidant, Insignia Ultra AVT Dr) was successfully implanted on March 25, 2008. Over the next two months, the patient experienced no episodes of syncope or TLOC, although she did suffer from some presyncopal attacks, which even tended to increase. However, not all of her episodes could be considered to be typical reflex syncope. For example, during some episodes, the patient complained of seeing a ‘‘bright light,’’ followed by loss of consciousness and oroalimentary automatisms. Each of these attacks lasted about 1 min. We decided to repeat the tilt test on this patient according to the Italian protocol with simultaneous registration of EEG (May 6, 2008). No significant hemodynamic changes or any complaints were revealed during the drug-free phase. After the patient took nitroglycerin, vasovagal response type 1 developed (development of relative bradycardia: heart rate dropped from 118 to 75 beats per minute, followed by a rhythm of pacemaker and arterial hypotension with a systolic blood pressure of 70 mmHg). However, most significant data were revealed on the EEG which displayed sharp-slow-wave complexes over the left temporal region (not shown). This interictal epileptiform activity was registered both before tilt test and during the entire period of orthostasis. On June 9, 2008, an episode with oroalimentary automatisms occurred during the patient’s sleep which subsequently developed into a secondarily generalized tonic clonic seizure lasting about 2 min. Cerebral MRI revealed hippocampal sclerosis on the left side (not shown). The patient was put on 600 mg carbamazepine per day. In late August 2008, tilt test was performed using the Westminster protocol with a negative response. Since then, the patient experienced no further episodes of loss of consciousness. In conclusion, this patient most probably presented TLOC episodes due to both reflex syncope and temporal lobe seizures (without a clearly proven link between seizures and syncope). 3.2. Case 2 A 56-year-old female patient was admitted to the Department of Epileptology at the University Hospital Bonn (Bonn, Germany) because of recurrent TLOC of unknown origin. Episodes of TLOC have started 10 years ago, occurred while lying, sitting or standing and have led to recurrent falls with multiple injuries. Episodes usually began with a rising epigastric sensation or an odd feeling in the head and were followed by staring without other symptoms. Because of suspected epilepsy, she was already put on valproic acid, lamotrigine and levetiracetam with a partial reduction of the frequency especially upon levetiracetam. Cardiological examinations (12-lead ECG, transthoracic echocardiography, Holter recordings) were unremarkable. Interictal EEG exhibited a sharp-slow wave focus over the left temporal anterior region, cerebral MRI showed a discrete hyperintensity of the left-sided mesiotemporal structures (not shown). Antibodies typically associated with limbic encephalitis were not detected in complementary blood examinations.32 During an ambulatory EEG-recording for 48 h, an unobserved epileptic seizure with left temporal lobe onset was detected during the night while lying on the bed which was accompanied by a progressive bradycardia starting 13 s after EEG seizure-onset and developing into an asystole of 16 s (Fig. 2A). In view of the refractory epilepsy, the patient was referred to cardiologists who implanted a DDD-pacemaker (evaluation for epilepsy surgery was denied by the patient). She was re-admitted 18 months later for
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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Fig. 1. Progressive prolongation of RR intervals with a subsequent 34-s asystole (A) and end of the syncopal attack with restoration of sinus rhythm (B).
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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Fig. 2. (A) Ambulatory EEG-recordings with simultaneous 1 channel-ECG registration display seizure-onset over the left temporal region (arrow 1), accompanied by a progressive bradycardia starting 13 s after EEG seizure-onset (arrow 2) and developing into an asystole of 16 s. Seizure cessation is indicated by arrow 3. (B) A recording 18 months later shows a similar seizure with onset over the left temporal region (arrow 1) and early activation of the cardiac pacemaker (arrow 2). Seizure cessation is indicated by arrow 3, cessation of cardiac stimulation by the pacemaker is indicated by arrow 4.
recurrent auras with or without subsequent unresponsiveness. Seizure-related falls have not occurred since the implantation of the cardiac pacemaker. Instead, we have captured several habitual left temporal lobe seizures during prolonged video-EEG telemetry which exhibited activation of the pacemaker during the epileptic seizures, suggesting that recurrence of seizure-related syncope was efficiently prevented by the implantation of the cardiac pacemaker (Fig. 2B).
UCB; is part of PRISM – the Prevention and Risk Identification of SUDEP Mortality Consortium which is funded by the NIH (NBIH/ NINDS – 1P20NS076965-01). Prof. Dr. C.E. Elger is consultant for Desitin and Novartis and received honoraria for talks from Pfizer and EISAI. The funding sources had no role in the design of this review, interpretation, or in the writing of the manuscript.
References 4. Conclusions Syncope and epileptic seizures are frequent causes of TLOC. The distinction between both entities on clinical grounds and eyewitness accounts can be challenging and is often hampered by similar clinical features such as epigastric sensations and clonic or tonic motor symptoms. Seizure-induced syncope is a rare complication especially of non-generalized temporal lobe seizures. People with epilepsy who report the onset of new semiological features such as atonia and seizure-related falls should undergo further investigations including 12-lead ECG and prolonged videoEEG telemetry or ambulatory EEG recordings with simultaneous ECG recordings. If full seizure-control cannot be achieved in these patients, the implantation of a cardiac pacemaker appears to efficiently prevent seizure-related falls and consecutive injuries. Disclosure Dr. R. Surges has received support for congress participation and speaker fees from EISAI; had a consultancy agreement with
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21. 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. 22. 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. 23. Kirchner A, Pauli E, Hilz MJ, Neundo¨rfer B, Stefan H. Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2002;73:73–5. 24. Opherk C, Coromilas J, Hirsch LJ. Heart rate and EKG changes in 102 seizures: analysis of influencing factors. Epilepsy Res 2002;52:117–27. 25. Surges R, Jordan A, Elger CE. Ictal modulation of cardiac repolarization, but not of heart rate, is lateralized in mesial temporal lobe epilepsy. PLoS ONE 2013;8:e64765. 26. Rossetti AO, Dworetzky BA, Madsen JR, Golub O, Beckman JA, Bromfield EB. Ictal asystole with convulsive syncope mimicking secondary generalisation: a depth electrode study. J Neurol Neurosurg Psychiatry 2005;76:885–7. 27. Schuele SU, Bermeo AC, Locatelli E, Burgess RC, Lu¨ders HO. Ictal asystole: a benign condition? Epilepsia 2008;49:168–71. 28. Schuele SU, Bermeo AC, Alexopoulos AV, Burgess RC. Anoxia-ischemia: a mechanism of seizure termination in ictal asystole. Epilepsia 2010;51:170–3. 29. Moseley BD, Ghearing GR, Benarroch EE, Britton JW. Early seizure termination in ictal asystole. Epilepsy Res 2011;97:220–4. 30. Moseley BD, Ghearing GR, Munger TM, Britton JW. The treatment of ictal asystole with cardiac pacing. Epilepsia 2011;52:e16–9. 31. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–77. 32. Malter MP, Elger CE, Surges R. Diagnostic value of CSF findings in antibodyassociated limbic and anti-NMDAR-encephalitis. Seizure 2013;22:136–40.
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Seizure journal homepage: www.elsevier.com/locate/yseiz
Review
Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features Dmitry Duplyakov a,b,*, Galina Golovina c, Natalia Lyukshina d, Elena Surkova b, Christian E. Elger e, Rainer Surges e,** a
Cardiology Department, Samara Regional Cardiology Dispensary, Samara, Russia Samara State Medical University, Samara, Russia Cardiology Department, VAZ Medical Center, Togliatti, Russia d Neurology Department, Children’s Multifield Hospital No. 1, Togliatti, Russia e Department of Epileptology, University Hospital Bonn, Germany b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 June 2013 Received in revised form 2 March 2014 Accepted 5 March 2014
Episodes of transient loss of consciousness (TLOC) are commonly due to syncope or epileptic seizures. The distinction between both entities on clinical grounds and eyewitness accounts can be challenging and is often hampered by similar clinical features. We briefly summarize syncoperelated symptoms and present the case of a female patient who suffered from TLOC episodes due to both reflex syncope and epileptic seizures. Seizure-induced syncope is a rare complication particularly of non-generalized temporal lobe seizures and may be suspected in people with epilepsy who report new semiological features with sudden onset of atonia, TLOC and seizure-related falls. We review epidemiological, clinical and electroencephalographic aspects of seizure-related asystole and syncope and discuss their clinical relevance. The implantation of a cardiac pacemaker appears to efficiently prevent seizure-related falls and consecutive injuries and is an important treatment option if full seizure-control cannot be achieved in these patients. We describe a second case of a patient with refractory temporal lobe epilepsy and seizure-related syncope which ceased after the implantation of a cardiac pacemaker. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Reflex syncope Temporal lobe epilepsy Ictal asystole SUDEP Sudden unexpected death in epilepsy
1. Transient loss of consciousness and syncope Episodes of transient loss of consciousness (TLOC) are commonly due to syncope or epileptic seizures, but a psychogenic origin and other rare causes and mimics may play a role in some patients.1 Syncope is defined as TLOC caused by a transitory global hypoperfusion of the brain. According to the underlying pathophysiology, syncope is classified as reflex syncope (also called neurally mediated syncope), cardiac syncope or syncope due to orthostatic hypotension.1 In general hospitals, reflex syncope accounts for about two third of TLOC cases, about 10% are due to orthostatic hypotension, another 15% are of cardiac origin and the remaining TLOC-cases have other
* Corresponding author at: 43, Aerodromnaja St., Samara, Russia. Tel.: +7 846 373 70 82; fax: +7 846 373 70 82. ** Corresponding author at: Department of Epileptology, University Hospital Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany. Tel.: +49 228 28714778; fax: +49 228 28719351. E-mail addresses: [email protected] (D. Duplyakov), [email protected] (R. Surges).
causes including epilepsy.2 Overall, syncope accounts for up to 3% of emergency room visits and for 1–6% of hospital admissions, with many patients undergoing expensive or inadequate tests and inappropriate specialist referrals, partly due to confusing clinical signs linked to syncopal episodes. 3–5 Apart from TLOC, syncope can be associated with a variety of other symptoms, depending on the underlying pathophysiology, the time course and severity of cerebral hypoperfusion. Prodromal phenomena (also called warning signs or presyncope) are usually linked to autonomic activation (e.g. enhanced parasympathetic and sympathetic activity) or reflect cerebral and retinal hypoperfusion. Typical sensations comprise feelings of light-headedness, warmness or nausea (both may be epigastric and rising), dizziness or vertigo and others.6,7 Prior to loss of consciousness, patients commonly display unclear thinking, fixation of the eyes in the midline and a ‘‘frozen’’ appearance, followed by a narrowing of the visual field, loss of color vision and ultimately complete loss of vision, sometimes followed by loss of hearing.7 Eyes are commonly open with the eyeballs turning up during loss of consciousness. During the episode, most individuals exhibit a loss of muscle tone (atonia), possibly causing recurrent falls.
http://dx.doi.org/10.1016/j.seizure.2014.03.004 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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‘‘Positive’’ motor signs, however, do frequently occur and include in particular myoclonic jerks, and much rarer stiffening of arms, legs or the whole body (resembling an opisthotonus).1,7 These motor symptoms, along with some of the prodromal signs, can considerably hamper the correct diagnosis, as they can resemble to those occurring during epileptic seizures. The correct diagnosis is further complicated by incomplete and inaccurate eyewitness accounts of syncope or epileptic seizures. Interestingly, the most accurately reported feature of such episodes is the muscle tone.8
2. Seizure-related bradyarrhythmias and syncope Epileptic seizures are caused by hypersynchronous neuronal discharges and display a large spectrum of sensory, motor and behavioral symptoms with or without TLOC, depending on the localization and extent of abnormal brain activity. In most patients, seizures lead to transient alterations of autonomic cardiorespiratory function.9 These autonomic symptoms include especially tachycardia or tachypnea, but apnea and bradycardia do also occur, thereby possibly leading to secondary syncope. 2.1. Prevalence of periictal bradyarrhythmias Seizure-related bradyarrhythmias including sinus bradycardia (heart rate below 60 beats per min), atrioventriuclar conduction blocks (2nd or 3rd degree) and asystole (commonly defined as RR intervals longer than 3–5 s) were reported with high variability in different studies and case series. Ictal bradycardia was observed in up 6% of the seizures and up to 13% of the patients during prolonged video-EEG telemetry, whereas it occurred in 2% of the seizures and 37% of the patients during ambulatory long-term ECG recordings using an implantable loop recorder.10–15 Ictal asystole was detected in up to 1% and 16% of the patients during prolonged video-EEG telemetry and ambulatory long-term ECG recordings, respectively.10–16 2.2. Pathomechanisms of periictal bradyarrhythmias The exact pathomechanisms underlying the onset of periictal bradyarrhythmias are unclear. Human and animals studies have provided some evidence for an asymmetric representation of sympathetic and parasympathetic networks in the brain (e.g. in the thalamus, hypothalamus, insular cortex, amygdala, hippocampus and brain stem), suggesting that e.g. parasympathetic functions are localized in the left hemisphere.17,18 Furthermore, seizure-related bradyarrhythmias have been especially observed in people suffering from temporal lobe epilepsy, and seem to be rarer in seizures originating in the frontal lobes or other brain regions.10,13,14,16,19–22 Therefore, one could assume that seizureactivity in the left temporal lobe activates parasympathetic function, thereby preferentially leading to bradyarrhythmias. Several case series have, however, produced controversial data without showing a consistent association between side of seizureonset, modulation of heart rate and onset of bradyarrhythmias.13,16,22–25 Instead, onset of bradycardia and asystole appears to be linked to the spread of seizure-activity to the contralateral side and bilateral seizure-activity.13,19,26 An alternative pathomechanism (in contrast to ictal activation of parasympathetic networks or disruption of sympathetic function) may involve reflex pathways which aim at counteracting a prominent seizurerelated tachycardia by excessive activation of the vagal nerve. This assumption is at least partly supported by the observation that ictal bradyarrhythmias are frequently preceded by transitory tachycardia.27
2.3. ECG and EEG patterns during periictal bradyarrhythmias The time interval between seizure-onset (as assessed by EEG changes or clinical signs) and onset of bradycardia or asystole is in average between 10 and 42 s, the mean duration of bradycardia and asystole varies between 20–30 and 13–24 s, respectively.12,16,19,20,27 During ictal asystole, rhythmic EEG patterns may resolve and EEG traces exhibit signs of cerebral hypoperfusion (i.e. bilateral high amplitude delta-slowing or background suppression/generalized EEG attenuation) instead. Bilateral high amplitude delta-slowing (BDS) occurs in average about 10 s after the onset of asystole, is associated with the duration of asystole and atonia (see below) and is variably followed by generalized EEG attenuation.12,13,16,28 Cerebral reperfusion is often accompanied by BDS which re-occurs after generalized EEG attenuation. EEG patterns during ictal asystole are, however, variable. In some patients, the ictal EEG pattern continues during ictal asystole, whereas in others, a generalized EEG attenuation replaces the rhythmic seizure activity without preceding BDS.16 2.4. Semiology of seizure-induced syncope Seizure-induced syncope is mainly caused by longer lasting asystole, whereas periictal bradycardia is usually asymptomatic.16 They predominantly occur with non-generalized temporal lobe seizures, so that the symptoms of syncope are often preceded by typical semiological temporal features such as epigastric aura, staring and unresponsiveness as well as oroalimentary and manual automatisms.12–14,16,19,20 Basically, two types of asystole-related clinical signs can be observed, those related to cerebral hypoperfusion (skin pallor; loss of muscle tone = atonia; TLOC; early myoclonic jerks; tonic motor symptoms, mostly generalized tonic posturing resembling opisthotonus; falls secondary to atonia or tonic motor symptoms) and those associated with cerebral reperfusion (skin flushing; late myoclonic jerks).12,13,16 About 10–12 s after the onset of asystole, the habitual ictal symptoms are interrupted by asystole-related motor features.13,16 Occurrence of atonia, tonic motor symptoms and late myoclonic jerks is linked to the duration of the asystole.13,16 Postictal re-orientation time seems to be similar in seizures with or without associated syncope.12 2.5. Clinical significance of seizure-related asystole There is an ongoing debate whether periictal asystole is a serious complication of epileptic seizures and whether it requires a specific treatment. In most cases, seizure-related asystole appears to be a rather benign condition which does not need cardiopulmonary reanimation measures.14,16,21,27 In the case of nongeneralized ‘‘uncomplicated’’ seizures, ictal asystole is likely to be a self-limiting event that is triggered by a seizure-induced predominant vagal effect on the heart and terminated by subsequent cerebral hypoperfusion and anoxia.27 This assumption is also supported by the observation that seizures with ictal asystole are shorter than those without asystole.28,29 Recurrent seizure-related syncope with falls, however, may lead to various, possibly serious injuries including fractures and traumatic hemorrhages.14,30 In the case of generalized tonic–clonic seizures, the significance of periictal asystole might be very different. A recent study has investigated monitored cases of sudden unexpected death in epilepsy (SUDEP) and near-SUDEP cases. A principal finding of this study was that apnea and asystole occurred in all SUDEP cases in the early postictal phase after generalized tonic–clonic seizures.15,31 In this context, it would be important to know whether periictal bradyarrhythmias in association with non-generalized seizures predict an increased
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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risk of later SUDEP. This is, however, not known to date and subject of future studies. 2.6. Treatment options of seizure-induced syncope Prevention of seizure-induced syncope can be achieved by successful seizure control. In newly diagnosed epilepsies, administration of anticonvulsant drugs may be sufficient to prevent seizures and associated syncope.14,20,30 In people with refractory focal epilepsy, however, epilepsy surgery should be considered to reach seizure-freedom.14 If sufficient seizure control cannot be achieved, the implantation of a cardiac pacemaker should be considered and recommended especially in those patients who suffer from seizure-related falls likely due to syncope and who display periictal asystole during combined EEG/ECG recordings. Fortunately, previous case series of patients with documented ictal asystole have reported successful prevention of seizure-related falls and injuries after the implantation of a cardiac pacemaker.13,14,30 The effects of a cardiac pacemaker on the risk of SUDEP are unclear to date. 3. Case reports 3.1. Case 1 A 49-year-old female patient was admitted to the Cardiology Department at the Samara Regional Cardiology Dispensary (Samara, Russia) after TLOC. It was known that while aged between 12 and 16 years, this patient was very intolerant of hot weather and experienced rare episodes of syncope in crowded and warm rooms or during long periods of standing in the upright position. On one occasion she suffered from syncope during an intravenous puncture. Between the age of 16 and 47, she was apparently free of syncope and only three years prior to admission to our hospital, episodes with TLOC re-occurred. Over the last 3 years, the patient experienced six episodes of fainting, with three of them occurring in the 6 months before admission. The fainting spells in adulthood were the same as they were in her adolescence. Most episodes also happened in warm rooms, with the patient being in an upright position. Once, the patient fainted while quickly turning her head, and once she experienced sudden loss of consciousness for no obvious reason. With these exceptions, all other syncopal attacks started with blurred vision and skin pallor, and occurred slowly. After the end of each attack, nausea and weakness persisted for about 2 h. The patient had no family history of fainting or other diseases causing TLOC. The patient’s clinical examination was, apart from some premature contractions, unremarkable (baseline heart rate 74 beats per minute, blood pressure 120/80 mmHg). Examination of other organs and systems revealed no abnormalities. Laboratory blood and urine tests were normal. Echocardiography also revealed no pathological findings: dimensions, global and local contractility, valves, pulmonary artery pressure were all normal. On February 1, 2008, a head-up tilt-test according to the Westminster protocol was performed and revealed a vasovagal response type 1 (development of bradycardia and hypotension: decrease of HR from 90 to 50 beats per minute and systolic blood pressure to 70 mmHg) with signs of presyncope. A carotid sinus massage was performed on the patient according to standard protocols. During left sinus massage with the patient in the upright position, a weak orthostatic hypotension occurred with a systolic blood pressure dropping from 120 to 80 mmHg accompanied by a slight dizziness. As the patient complained of heart palpitations, Holter ECG monitoring was performed (February 19, 2008). The average heart rate was 62 beats per minute (min 34, max 118). At 11:44 a.m. that day, while the patient was climbing the stairs, a
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typical presyncope developed, after which the patient fainted. During this episode, the ECG recordings exhibited an asystole of 34 s (Fig. 1). In view of the typical features of a reflex syncope (history, vasovagal response during tilt-test) and of the 34-s asystole episode registered during ECG-monitoring, the patient was referred to the hospital for permanent pacemaker implantation. A two-chamber pacemaker with Sudden Rate response function (Guidant, Insignia Ultra AVT Dr) was successfully implanted on March 25, 2008. Over the next two months, the patient experienced no episodes of syncope or TLOC, although she did suffer from some presyncopal attacks, which even tended to increase. However, not all of her episodes could be considered to be typical reflex syncope. For example, during some episodes, the patient complained of seeing a ‘‘bright light,’’ followed by loss of consciousness and oroalimentary automatisms. Each of these attacks lasted about 1 min. We decided to repeat the tilt test on this patient according to the Italian protocol with simultaneous registration of EEG (May 6, 2008). No significant hemodynamic changes or any complaints were revealed during the drug-free phase. After the patient took nitroglycerin, vasovagal response type 1 developed (development of relative bradycardia: heart rate dropped from 118 to 75 beats per minute, followed by a rhythm of pacemaker and arterial hypotension with a systolic blood pressure of 70 mmHg). However, most significant data were revealed on the EEG which displayed sharp-slow-wave complexes over the left temporal region (not shown). This interictal epileptiform activity was registered both before tilt test and during the entire period of orthostasis. On June 9, 2008, an episode with oroalimentary automatisms occurred during the patient’s sleep which subsequently developed into a secondarily generalized tonic clonic seizure lasting about 2 min. Cerebral MRI revealed hippocampal sclerosis on the left side (not shown). The patient was put on 600 mg carbamazepine per day. In late August 2008, tilt test was performed using the Westminster protocol with a negative response. Since then, the patient experienced no further episodes of loss of consciousness. In conclusion, this patient most probably presented TLOC episodes due to both reflex syncope and temporal lobe seizures (without a clearly proven link between seizures and syncope). 3.2. Case 2 A 56-year-old female patient was admitted to the Department of Epileptology at the University Hospital Bonn (Bonn, Germany) because of recurrent TLOC of unknown origin. Episodes of TLOC have started 10 years ago, occurred while lying, sitting or standing and have led to recurrent falls with multiple injuries. Episodes usually began with a rising epigastric sensation or an odd feeling in the head and were followed by staring without other symptoms. Because of suspected epilepsy, she was already put on valproic acid, lamotrigine and levetiracetam with a partial reduction of the frequency especially upon levetiracetam. Cardiological examinations (12-lead ECG, transthoracic echocardiography, Holter recordings) were unremarkable. Interictal EEG exhibited a sharp-slow wave focus over the left temporal anterior region, cerebral MRI showed a discrete hyperintensity of the left-sided mesiotemporal structures (not shown). Antibodies typically associated with limbic encephalitis were not detected in complementary blood examinations.32 During an ambulatory EEG-recording for 48 h, an unobserved epileptic seizure with left temporal lobe onset was detected during the night while lying on the bed which was accompanied by a progressive bradycardia starting 13 s after EEG seizure-onset and developing into an asystole of 16 s (Fig. 2A). In view of the refractory epilepsy, the patient was referred to cardiologists who implanted a DDD-pacemaker (evaluation for epilepsy surgery was denied by the patient). She was re-admitted 18 months later for
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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Fig. 1. Progressive prolongation of RR intervals with a subsequent 34-s asystole (A) and end of the syncopal attack with restoration of sinus rhythm (B).
Please cite this article in press as: Duplyakov D, et al. Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.03.004
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Fig. 2. (A) Ambulatory EEG-recordings with simultaneous 1 channel-ECG registration display seizure-onset over the left temporal region (arrow 1), accompanied by a progressive bradycardia starting 13 s after EEG seizure-onset (arrow 2) and developing into an asystole of 16 s. Seizure cessation is indicated by arrow 3. (B) A recording 18 months later shows a similar seizure with onset over the left temporal region (arrow 1) and early activation of the cardiac pacemaker (arrow 2). Seizure cessation is indicated by arrow 3, cessation of cardiac stimulation by the pacemaker is indicated by arrow 4.
recurrent auras with or without subsequent unresponsiveness. Seizure-related falls have not occurred since the implantation of the cardiac pacemaker. Instead, we have captured several habitual left temporal lobe seizures during prolonged video-EEG telemetry which exhibited activation of the pacemaker during the epileptic seizures, suggesting that recurrence of seizure-related syncope was efficiently prevented by the implantation of the cardiac pacemaker (Fig. 2B).
UCB; is part of PRISM – the Prevention and Risk Identification of SUDEP Mortality Consortium which is funded by the NIH (NBIH/ NINDS – 1P20NS076965-01). Prof. Dr. C.E. Elger is consultant for Desitin and Novartis and received honoraria for talks from Pfizer and EISAI. The funding sources had no role in the design of this review, interpretation, or in the writing of the manuscript.
References 4. Conclusions Syncope and epileptic seizures are frequent causes of TLOC. The distinction between both entities on clinical grounds and eyewitness accounts can be challenging and is often hampered by similar clinical features such as epigastric sensations and clonic or tonic motor symptoms. Seizure-induced syncope is a rare complication especially of non-generalized temporal lobe seizures. People with epilepsy who report the onset of new semiological features such as atonia and seizure-related falls should undergo further investigations including 12-lead ECG and prolonged videoEEG telemetry or ambulatory EEG recordings with simultaneous ECG recordings. If full seizure-control cannot be achieved in these patients, the implantation of a cardiac pacemaker appears to efficiently prevent seizure-related falls and consecutive injuries. Disclosure Dr. R. Surges has received support for congress participation and speaker fees from EISAI; had a consultancy agreement with
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