Review
Cardiac changes in epilepsy
K. Jansen, L. Lagae
*
University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
Contents
1. Introduction . . . 455
2. Acute cardiac changes and epilepsy . . . 456
2.1. Tachycardia . . . 456
2.2. Bradycardia and asystole . . . 457
2.3. Conduction disorders . . . 457
2.4. SUDEP . . . 457
2.5. Syncope . . . 458
2.6. Cardiac ischemia . . . 458
3. Chronic cardiac changes in epilepsy . . . 458
3.1. Heart rate variability (HRV) . . . 458
3.2. AED and HRV . . . 458
3.3. Chronic and refractory epilepsy and HRV . . . 458
3.4. Vagal nerve stimulation (VNS) and HRV . . . 459
4. Conclusion . . . 459
References . . . 459
1. Introduction
It has been shown that epilepsy and seizures can have a profound effect on cardiac function. Subtle cardiac rhythm changes in the preictal and ictal period are potential biomarkers and can be used in algorithms to anticipate and detect seizures. The phenomenon of SUDEP is closely linked to ictal cardiac changes.
In this short review, we describe the most frequent autonomic cardiac changes seen during seizures and in epilepsy. Emphasis will be put on the recent insights into the links between different seizure types and cardiac changes.
In general, the autonomic nervous system is fundamental for maintaining homeostasis in the body through regulation of heart rate, respiration, micturition, digestion and reproduction. The output from the autonomic nervous system is determined by a balance of medullary reflexes and influences of the cerebral cortex. The medulla integrates information from the respiratory, cardi-ovagal and vasomotor reflex centers where a distinction can be made between parasympathetic and sympathetic reflex centers.
A R T I C L E I N F O Article history:
Received 5 January 2010
Received in revised form 5 July 2010 Accepted 9 July 2010 Keywords: Autonomic Heart Childhood epilepsy SUDEP Nervus vagus A B S T R A C T
Epilepsy and seizures can have a dramatic effect on the autonomic nervous system by involvement of the central autonomic control centers. The peri-ictal changes can lead to short-term alteration of cardiac functions in patients with seizures, and are partially hemispheric specific. Changes in heart rhythm, conduction and even subtle signs of ischemia have been reported. Ictal asystole and the lock-step phenomenon during seizures play an important role in the pathophysiology of SUDEP. In patients with longlasting epilepsy and multiple seizures, there are now convincing arguments for a chronic dysfunction of the autonomic nervous system. In this sense, heart rate variability can be considered as a biomarker of autonomic dysfunction in epilepsy. Early recognition of these short- and long-term cardiac effects will become useful in predicting seizures and in guiding more individualized treatment in the near future.
ß2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author at: University Hospitals Leuven, Paediatric Neurology, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16343845; fax: +32 16343842.
E-mail address:[email protected](L. Lagae).
Contents lists available atScienceDirect
Seizure
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y s e i z
1059-1311/$ – see front matter ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2010.07.008
In cardiac control the parasympathetic output to the heart is mediated by the vagus nerve. The vagus nerve starts in the medulla oblongata, where it originates from two separate nuclei, the dorsal motor nucleus (DMN) and the more ventrally located nucleus ambiguous (NA). These two brainstem centers are thought to have a distinct evolutionary origin. In the ‘‘polyvagal theory’’, the DMN is considered the most primitive part of the vagus with a tonic output on heart rate. The NA is the more recently developed or ‘‘smart vagus’’, responsible for phasic vagal output to the heart, as reflected by respiratory sinus arrhythmia or RSA.1
Increase in vagal efferent activity results in decrease of heart rate, atrio-ventricular conduction and ventricular excitability. There is a close coupling between the respiratory centers and the cardiovascular system. The vagal efferents receive direct input from the respiratory centers in the brainstem. The respiratory centers get information from aortic receptors and lung stretch receptors. Excitation exists during expiration by stimulation of the chemo and baroreceptors in the lungs and aorta. Inhibition is caused by lung inflation through information from the lung stretch receptors.
The sympathetic output to the heart is mediated by neurons from the rostral ventrolateral medulla resulting in an increased automatism of the sinus node, increase in atrio-ventricular conduction and ventricular excitability and contractility.
Higher brain systems have a descending control on autonomic outflow from the brainstem to the heart. The output of the medullary reflexes is influenced by the insular cortex, orbito-frontal cortex, cingulate, amygdala, hypothalamus and peri-aqueductal gray matter. The insula and prefrontal cortex are thought to represent the autonomic nervous system at the cortical level. During fetal development, the insula is the first cortical center of maturation and vascularisation, with a right sided predominance.2–4Input from the insula can give rise to an excitatory ‘‘pressor’’ or inhibitory ‘‘depressor’’ response at the cardiac level.5,6 There is evidence of a hemispheric specific organisation of this response as shown in the depth electrode studies by Oppenheimer et al.,7 with the pressor response lateralized to the right and depressor response to the left hemisphere.
2. Acute cardiac changes and epilepsy
Changes in cardiac function in epilepsy imply an activation of the central autonomic network. In patients with seizures, epileptic discharges are thought to propagate to the central autonomic network and change or disturb normal autonomic control of vital cardiac functions. This activation of central autonomic nervous system is thought to be responsible for the peri-ictal autonomic cardiac symptoms observed in epilepsy patients. The importance of these autonomic features in the pathophysiology of epilepsy and its complications has become more clear in the last years.8–11Due to the hemispheric specific organisation of the central autonomic nervous system, autonomic symptoms in epileptic seizures can provide lateralizing and localizing information. In return, better recognition of clinical autonomic signs in epilepsy can provide more information on the organisation of the central autonomic nervous system (Fig. 1).
2.1. Tachycardia
Ictal tachycardia has been reported in up to 100% of seizures. Tachycardia can precede, coincide or follow ictal discharges.12–14 As tachycardia may also precede the clinical and EEG onset of the seizure it is not always considered secondary to the clonic phase. The time lag between tachycardia and seizure onset varies between 0.7 and 49.3 s. A possible mechanism is the propagation of epileptic discharges to the right insular cortex.7A predominance for tachycardia in right sided temporal seizures can be expected and is in some13,15but not all16,17studies confirmed, suggesting influence of other factors to explain the tachycardia. Ictal onset tachycardia seems more prominent in TLE as compared with extratemporal seizures (XTLE),18,19supporting the hypothesis that involvement of insular cortex is a key part of ictal tachycardia. The duration of the tachycardia is also longer in patients with mesial temporal lobe epilepsy compared to XTLE. It is possible that epileptic discharges propagate towards the insular cortex more easily and for a longer duration in TLE as compared to XTLE.
Tachycardia and development of tachyarrhythmia during seizures is one of the possible causes of sudden unexplained
death in epilepsy patients (SUDEP). Tachycardia leading to malig-nant ventricular tachycardia and ventricular fibrillation has been illustrated to be the cause of near SUDEP in a patient with TLE.20 2.2. Bradycardia and asystole
Bradycardia and bradyarrhythmia are much less frequent and are seen in seizures of various origins. A severe slowing of the heart rate leading to asystole and syncope is referred to as the ictal bradycardia syndrome.21
actors predisposing patients to ictal bradyarrhythmia remain difficult to define. The pathophysiology of bradyarrhythmia is probably mediated through a complex cortical network. Cortical stimulation of the left insular cortex and amygdalae have been noted to elicit bradycardia.22,23The left hemisphere appears to be the more common site of origin, again supporting the hypothesis of hemispheric specific organisation of cortical cardiac control.24,25 An atrio-ventricular block was noted in one patient during cortical stimulation of the left temporal basal area.26These results suggest a higher risk of bradyarrythmia in epileptic seizures with seizure spreading to the left insular cortex and amygdalae. The onset zone of epileptic discharges in patients with ictal bradycardia is most frequent temporal and less frontal, supporting the hypothesis of an insular influence.
Ictal bradycardia up to ictal asystole has been reported in patients with refractory partial seizures and could be another important link with SUDEP.27
2.3. Conduction disorders
Conduction disorders seem to be common during seizures in intractable epilepsy. Nei et al.28could demonstrate the presence of arrhythmias or conduction disorders in seizures, particularly if these are prolonged or generalized. They include atrial fibrillation, supraventricular tachycardia and atrial and ventricular premature depolarisation.
EKG changes, including T-wave inversion and ST-depression, were more frequent and potentially more dangerous in patients with generalized seizures.29
2.4. SUDEP
It is well known that people with epilepsy have an increased risk for sudden unexpected death or SUDEP. SUDEP is defined as the sudden unexpected non-traumatic and non-drowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom post-mortem examination does not reveal a structural or toxicological cause for death.30Opeskin and Berkovic looked at demographics and risk factors among epilepsy patients. Their profile of patients at risk for SUDEP are young persons with epilepsy. They are most likely to die during sleep and seizure-related. Obstructive apnea could be one explanation for sleep related death, but is not supported by coroners’ findings. The position of the patient, together with lack of supervision of recovery from the seizure is more likely.31,32They found no correlation with seizure frequency or particular epilepsy or number of AEDs.33They did not find a difference in duration of epilepsy between SUDEP and control groups. However, previous studies have shown that SUDEP patients have earlier onset, longer duration of epilepsy and more frequent seizures. There is evidence for an increase of cardiac autonomic stimulation in patients with SUDEP, more pronounced in epileptic seizures during sleep,34compatible with the demo-graphic findings.
The exact mechanism of SUDEP remains an open question but is probably multifactorial. An interaction between the central and
peripheral autonomic nervous system and cardiopulmonary system is assumed. There are three well recognized main pathophysiologic mechanisms already known to trigger SUDEP35–37:
1. cardiovascular: ictal arrhythmias including ictal asytole and the lock-step phenomenon;
2. neurogenic: neurogenic pulmonary edema;
3. respiratory: ictal respiratory suppression, central or obstructive apnea.
The first possible mechanism underlying SUDEP are seizure related cardiac arrhythmias with tachyarrhytmias, bradycardia and ictal asystole as explained above. Tachyarrhythmias can evolve to ventricular tachycardia and ultimately ventricular fibrillation. In bradyarrhythmias, evolution to ictal asystole is observed in patients with focal epilepsy. Both a sudden increase of vagal tone or the effect of post-ganglionic epileptic discharges on the heart as described below can be considered as an explanation for the disturbed cardiac rhythm in epileptic seizures. Schuele reported a series of 10 patients with focal epilepsy and ictal asystole, 8 with TLE and 2 with XTLE.38,39The loss of consciousness was observed during video-electroencephalographic observation and occurred late during the clinical event. Loss of postural tone was preceded by 8 s of asystole. In these patients activation leading to ictal asystole is most likely mediated through an increased vagal tone. The pattern of ictal asystole and the slowing EEG pattern of cerebral hypoperfusion closely resembled the pattern seen in vasovagal asystole. The underlying mechanism is most likely similar in both conditions and assumes involvement of medullary reflex centers during epileptic discharges, responsible for the increase of vagal tone. In the two patients with XTLE asystole could have been triggered by hypoxia due to prolonged tonic muscle contraction and respiratory arrest, and are not due to seizure propagation to the medullary reflex centers.
Another important neurophysiological phenomenon was de-scribed by Hilz et al.40Seizure induced activation of the central autonomic nervous system can cause a direct effect on post-ganglionic discharges on the heart. This results in a synchronisa-tion of cardiac autonomic discharges with epileptogenic activity, called the lock-step phenomenon and induces a lethal bradyar-rythmia or asystole. Electrical stimulation of the insular cortex results in a time-locked response on heart rhythm and can produce different types of arrhythmia. In animal models electrical microstimulation synchronised to the T wave of the ECG resulted in increasing degrees of heart block and lead to escape rhythms and ultimately asystole and dead.7Secondary neurogenic pulmonary edema is known as a rare life-threatening complication of central nervous system injuries and epilepsy. Experimental studies have postulated severe sympathetic discharge as the base of neurogenic pulmonary edema. The cerebral sites regarded as trigger zones of the sympathetic discharge are found in the posterior part of the hypothalamus and in the ventral and dorsal medulla, comprising the medial reticulated nucleus, dorsal motor vagus nucleus and solitary tract.41 The sympathetic discharge causes systemic and pulmonary vasoconstriction, resulting in increase in pulmonary capillary hydrostatic pressure and shift of fluid into the alveoli and interstitium.42A third possible mechanism in SUDEP is respiratory suppression. Central respiratory depression can be the result of epileptic discharges. Apnea is a rare clinical feature of seizures, but laryngeal spasm and apnea have been reported as isolated epileptic features or in complex partial seizures.43 The focal seizures associated with apnea seem to originate mostly from the temporal lobe.44This observation together with the results of invasive EEG monitoring in adults points to involvement of the limbic system in seizures complicated by respiratory depression.45 Obstructive
apnea and respiratory arrest have already been observed due to tonic muscle contraction during seizures. This can lead to severe hypoxia and trigger asystole.
Besides these three important triggers in the pathophysiology of SUDEP, the evidence for individual predisposing risk factors is growing. In some cases, these predisposing factors might be genetic. Patients with an epilepsy syndrome caused by a mutation in the sodium channel gene as in generalized epilepsy with febrile seizures plus or severe myoclonic epilepsy of infancy seem to have a higher risk for SUDEP.46Chronic and refractory epilepsy and treatment of epilepsy with anti-epileptic drugs have an influence on the autonomic balance, also predisposing patients for cardiovascular complications. The latter will be discussed further in the text. 2.5. Syncope
The difference between syncope due to cardiac arrhythmia and seizures in patients with established epilepsy remains clinically challenging. In patients with epilepsy a distinction has to be made between a cardiovascular or epileptic cause of loss of conscious-ness and syncope. Cardiovascular autonomic balance is deter-mined by medullary reflexes triggered by activation of baroreceptors, cardiac receptors and chemoreceptors and influ-ences from the cerebral cortex, hypothalamus, amygdalae and peri-aqueductal gray. As we mentioned earlier, patients with epileptic seizures can develop various cardiovascular problems, arrhythmias, ictal bradycardia and prolonged asystole caused by epileptic discharges in higher autonomic control centers. These cardiovascular problems can lead to ictal syncope as a result of cerebral hypoperfusion. On the other hand, the sudden loss of tone in patients with ictal asystole may be the result of ictal activation of specific areas in the brain leading to loss of consciousness. Rapid spread of ictal epileptic discharges with involvement of the pontine reticular formation can lead to loss of consciousness and a clinical syncope.5
2.6. Cardiac ischemia
As earlier mentioned, excessive autonomic stimulation may result in cardiac arrhythmias. But repetitive autonomic stimula-tion can also lead to structural damage to the heart. This increases the susceptibility to cardiac arrhythmias or ischemia. Myocardial fibrosis has already been found in patients with SUDEP.47Patients with uncomplicated seizures do not seem to have postictal troponin elevation, but signs of ischemia on EKG and elevated cardiac enzymes in epileptic patients suggest secondary cardiac damage.48,49Alehan et al. could show presence of elevated BNP and CK-MB in patients with seizures, the first evidence of subtle cardiac dysfunction in epilepsy patients.50
3. Chronic cardiac changes in epilepsy 3.1. Heart rate variability (HRV)
Heart rate variability can be used as a tool to show information on the functional state of the autonomic nervous system. HRV is a mirror of neuronal influences on the cardiac pacemaker as one of the important functions of the autonomic nervous system. Reduced HRV has been established to be an increased risk of death in acute myocardial infarction and in patients with diabetic neuropathy. But various diseases are accompanied by a loss of ANS functionality and therefore HRV can be used in health risk stratification.51
The physiologic fluctuations of the heart rate are defined by intrinsic oscillators at three different frequencies. These three main frequency components in HRV reflect the sympatho-vagal balance.52
1. Respiratory sinus arrhythmia (RSA) is the most important high frequency oscillator at 0.25 Hz. RSA is defined as the high frequency (HF) spectral component and considered as a marker of vagal modulation. RSA is heart rate variability in synchrony with respiration. The R–R interval is shortened during inspira-tion and prolonged during expirainspira-tion. This is a biologic phenomenon that is thought to have a positive influence on gas exchange by optimal ventilation/perfusion matching with low energy expenditure.
2. In the medium frequency 0.1 Hz the Mayer waves are most important. The rhythm corresponding to Mayer waves is defined as the low frequency (LF) component and considered as an indicator of sympathetic activation. This rhythm originates from the baroreceptor loop.
3. The very low frequency (VLF) component at 0.05 Hz is defined by thermoregulation, combined with humoral factors and other slow components.
Heart rate variability was found to be lower in patients with chronic refractory epilepsy, possibly resulting from parasympa-thetic or vagal reduction. This can make patients more susceptible to tachycardia and fibrillation and possibly SUDEP.53,54
Impaired baroreflex function was observed in a study of Du¨tsch et al. in patients with temporal lobe epilepsy.55 The impaired function can be another sign of autonomic instability in these epileptic patients and a contributing factor in cardiac arrhythmias. Serious heart rate oscillations in the postictal phase were noted in a few patients.56Although, they occur in a minority of patients, they could be a potential risk factor for SUDEP.
3.2. AED and HRV
Heart rate variability seems to be different in treated patients compared to untreated. It is possible that treatment of seizures prevents detrimental effects on autonomic cardiac control. Hallioglu et al. found a significant difference in children treated with valproic acid, oxcarbazepine or phenobarbital and children without treatment. In the treated group better HRV was found. These results indicate that patients without anti-epileptic drug treatment have suppressed parasympathetic activity.57 But treatment can also have a negative effect on HRV. A suppressive effect of carbamazepine on both parasympathetic and sympathetic cardiac functions was found in newly diagnosed epileptic patients.58 Lossius et al. looked at autonomic parameters after discontinuation of monotherapy, they found an increase of both parasympathetic and sympathetic functions, demonstrated by spectral analysis of HRV.59
3.3. Chronic and refractory epilepsy and HRV
Patients with longlasting and multiple seizures seem to be prone to chronic dysfunction of autonomic cardiac control. In patients with newly diagnosed (median time 27 months) and untreated epilepsy, no difference was found in heart rate variability.60
Mukherjee et al.61studied a cohort of well controlled and a cohort of refractory patients and could show with a series of autonomic tests that higher vasomotor tone, higher sympathetic tone, lower parasympathetic tone and reactivity was found in the group of refractory epilepsy patients. The observed dysautonomia could be a predisposing factor to SUDEP. Chroni et al.62 could demonstrate altered cardiovagal control in patients with chronic epilepsy. They used simple neurophysiologic tests of the auto-nomic nervous system, Valsalva, Tilt-test, RR interval in normal and deep breathing and sural nerve conductance to show a chronic effect of epilepsy on the autonomous nervous system. Sathya-prabha et al.63used heart rate and blood pressure measurements in
rest, after Valsalva and postural change. Autonomic dysfunction was found in 56.3% of the patients with chronic refractory epilepsy, compared to a control group. In their study the dysfunction of the autonomic system was more severe if the epilepsy was longer lasting.
Ansakorpi et al.64,65 looked at refractory TLE patients to demonstrate interictal autonomic dysfunction in response to certain stimuli. He used newer analysis methods to demonstrate altered complexity of heart rate in refractory epilepsy patients. Ronkainen et al.66 found loss of HRV and suppressed circadian dynamics in TLE, as well in controlled as in refractory patients.
In children with refractory epilepsy, the same arguments for a chronic autonomic dysfunction are found. Heart rate abnormalities were noted in children and adolescents with complex partial seizures. The abnormalities were much more frequent compared to adults and occurred in 98% of the complex partial seizures. Heart rate variability also seems to be lower in children with chronic refractory epilepsy, possibly resulting from parasympathetic or vagal reduction. This can make patients more susceptible to tachycardia and fibrillation54(Harnod).
3.4. Vagal nerve stimulation (VNS) and HRV
The vagal nerve consists for 80% out of afferents and 20% of efferents. Vagal efferents originate in the nucleus ambiguus and DMN of the vagus. Cell bodies in the nucleus ambiguus send special visceral efferent fibers to the striated muscle fibers of palate, pharynx, larynx and esophagus. Cell bodies in the DMN send general efferents to the heart, lungs and gastro-intestinal tract. Afferent fibers originate in the end organs: heart, lungs and gastro-intestinal tract. These cells project axons to the nucleus tractus solitaries (NTS), which then project to hypothalamus, amygdale, dorsal raphe and thalamus. Vagal nerve stimulation produces evoked potentials recorded from the cerebral cortex, the hippo-campus, the thalamus, and the cerebellum. Most of the cardiovagal fibers run through the right vagus nerve, so stimulation of the left vagus in the treatment of epilepsy is preferred to avoid potential detrimental effects on heart rhythm.67These structures in turn synapse throughout the cerebral cortex and seem to have an overall inhibitory effect. This was supported by the study of Ben-Menachem et al.68who showed an increase of GABA in the CSF in patients with VNS and a decrease of the excitatory aspartate.
For a long time, stimulation of the vagal nerve with VNS was thought to have no effect on cardiac action. In contrast, Frei and Osorio69 showed that left vagal nerve stimulation has complex effects on instantaneous heart rate and heart rate variability with large interindividual variability. They found different cardiac chronotropic effects, either bradycardia or tachycardia, immedi-ately followed by bradycardia during stimulation. HRV was found to be increased or decreased.
The recent work of Stemper and Devinsky70showed that VNS influences both sympathetic and parasympathetic cardiac regula-tions. The variability of the observed responses in patients treated with VNS illustrates the interplay of divers afferent information and central influences.
4. Conclusion
There is growing evidence for the importance of the involve-ment of the central autonomic nervous system in epilepsy patients. Short-term alteration of cardiac functions in patients with seizures is caused by involvement of the central autonomic control centers in seizure activity. Due to a hemispheric specific localization of these control centers, the effect can give information on lateralisation of the seizure. In return, autonomic symptoms in seizure semeiology can give information on the localisation and
lateralisation of important autonomic centers in the central nervous system as shown in the figure. Acute changes in cardiac function during seizures include tachycardia, bradycardia up to ictal asystole and more subtle conduction disorders. The patho-physiology of syncope in patients with epilepsy remains difficult. Loss of consciousness can be due to cardiovascular complications or involvement of the pontine reticular formation in seizure propagation. Repetitive autonomic stimulation can lead to structural damage of the heart. Cardiac ischemia as well as myocardial fibrosis is already demonstrated in epilepsy patients. The mechanism of SUDEP is multifactorial. We can identify three different pathophysiologic triggers: acute cardiovascular changes during seizures, tachyarrhythmias, bradyarrhythmias and ictal asystole, neurogenic pulmonary edema and respiratory complica-tions with central and obstructive apnea. Besides these triggers, chronic epilepsy, drugs and genetics seem to be important predisposing factors in patients with epilepsy.
In patients with longlasting epilepsy and multiple seizures, there are arguments for a chronic dysfunction of the autonomic nervous system. Heart rate variability is one of the markers used to show information on the functional state of the autonomic nervous system and is impaired in patients with longlasting epilepsy and refractory seizures. Treatment of epilepsy with AED, not only VNS can improve but also suppress heart rate variability. Early recognition and possible prevention of these short- and long-term effects can prove to be of vital importance in the future.
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