eMedicine Specialties > Neurology > Seizures and Epilepsy

Epilepsy and the Autonomic Nervous System

Author: Shahin Nouri, MD, Director, Comprehensive Epilepsy Center, Associate Chief, Division of Neurology, New York Methodist Hospital
Contributor Information and Disclosures

Updated: Nov 24, 2009

Introduction

The interaction between seizures and the autonomic nervous system (ANS) is very complex. Abnormal neuronal electrical activity corresponding to a seizure can involve central centers for the regulation of autonomic activity. A seizure can present with autonomic symptoms initially, during its propagation, or during the aftermath. In addition, patients with epilepsy experience long-lasting changes in the regulation of the ANS and their target organs (eg, the heart).

The probable paths of propagation of the epileptic electrical activity are as follows: The ictal impulse involves either or both temporal and frontal areas. The insular cortex is then involved in both temporal and frontal seizures, and the hippocampus is involved in temporal seizures. This activity is then spread through the limbic system with involvement of the amygdala, hypothalamus, and thalamus. These in turn stimulate the ANS nuclei in medulla, including the nucleus tractus solitarius (NTS) and ambiguous nuclei. Both sympathetic and parasympathetic efferent discharges are then generated. See Media file 1.

• Ictal Autonomic Changes
• Interictal (Baseline) Autonomic Changes
• Relationship of the Autonomic Functions and Sudden Unexpected Death in Epilepsy (SUDEP) (See eMedicine article Sudden Unexpected Death in Epilepsy.)
• Antiepileptic Medications and Autonomic Changes
• Differentiation Between Seizure and Syncope 

Ictal Autonomic Changes

Autonomic phenomena can constitute the initial seizure manifestation, or can result from propagation of the hypersynchronized electrical impulse to autonomic central nuclei. Simple partial seizures with autonomic manifestations have an ictal focus involving ANS centers without impairing awareness. The ANS centers can be involved secondarily in complex partial (CP), absence, generalized tonic, and generalized tonic-clonic (GTC) seizures. Autonomic symptoms accompany all GTC seizures and one third of simple partial seizures.

In a first comprehensive study, Van Buren et al investigated autonomic functions in 13 patients during 20 epileptic attacks of temporal lobe (TL) origin. Simultaneously with electroencephalography (EEG), they recorded autonomic phenomena as represented by changes in ECG, blood pressure, respiratory movements, skin temperature and resistance, esophageal pressure, and gastric pressure. They reported the occurrence in a majority of the patients of a fairly stereotyped pattern of initial decrease in skin resistance and swallowing, followed by cessation of respiration and gastric motility, and then tachycardia, hypotension, and decrease in pulse amplitude. They concluded that this pattern was indicative of propagation of the electrical activity through spatially separated autonomic centers.¹ Similar observations were reported in patients who had seizures induced by electroconvulsive therapy (ECT).²

Table 1 summarizes autonomic symptoms and signs accompanying seizures. These manifestations of ANS involvement will be discussed in detail in this section.

Table 1. Autonomic Symptoms and Signs Associated With Seizures

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Differential diagnosis of ictal autonomic phenomena includes organic diseases of the viscera (eg, carcinoid, pheochromocytoma), hypoglycemia, panic attacks, and primary autonomic system dysfunctions.

Cardiovascular

Alteration of the heart rate during a seizure is a well-known phenomenon. Jackson and his associates first described autonomic symptoms in seizures caused by mesial temporal lobe lesions. Early works of Gastaut, White et al, and Van Buren documented the correlation of temporal lobe partial epileptic activity with cardiovascular phenomena.^3,4,1 Many of the earlier studies were based on observations of autonomic phenomena during seizures induced by ECT or epileptogenic substances. Many anecdotal reports and case series evaluated autonomic phenomena in unprovoked seizures; however, only a limited number of studies have used simultaneous recordings of EEG and ECG. Table 2 reviews several studies of ictal cardiac manifestations with simultaneous EEG and ECG recordings in unprovoked seizures.

Table 2. Review of Selected Studies on Ictal Cardiac Manifestations in Unprovoked Seizures

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Abbreviations: SP indicates simple partial; CP, complex partial; GC, generalized clonic; GTC, generalized tonic-clonic; T, temporal; F, frontal; O, occipital lobe; ex-T, extratemporal.

ECG changes

The spectrum of ECG changes during epileptic activity is extensive. Erickson studied ictal ECG changes systematically for the first time.¹⁹ He reported ictal tachycardia and T-wave flattening. Initial bradycardia followed by tachycardia has been documented in as many as 64% of patients with petit mal and 100% of those with GTC seizure attacks.^20,21,22 Tachycardia is reported in 74-92% of patients with complex partial seizures.^7,6,23,16

Persistent bradycardia is less common and is documented in 3-7% of patients with complex partial seizures.^1,12 Ictal cardiac rhythm and conduction abnormalities are reported in 5-42% of patients with partial seizures. Rhythm abnormalities include atrial fibrillation, sinus arrhythmia, atrial and ventricular premature depolarizations, bundle-branch block, torsade de pointes, asystole, ST-segment and T-wave abnormalities, and QT prolongation.^24,25,12,13

Tachycardia and tachyarrhythmias

Most studies that have documented EEG and ECG recordings report tachycardia in 64-93% of complex partial seizures, mostly of temporal lobe origin.^1,5,12 Schernthaner et al assessed ECG recordings that were recorded simultaneously with EEG during 107 seizures. They reported ictal tachycardia (heart rate increase >10 bpm) in 83% of seizures. Heart rate changes usually occurred several seconds prior to seizure onset as recorded on scalp EEG. Tachycardia occurred significantly more often in seizures with onset in the temporal lobe. Few investigators have evaluated the cardioregulatory mechanisms in children with epilepsy. Mayer et al showed tachycardia in 98% of children suffering complex partial seizures of temporal lobe origin and as such more frequently than in adults.¹⁶

Bradycardia and cardiac arrest

Sustained cardiac bradyarrhythmias and asystole associated with seizures are reported less frequently in the literature than tachyarrhythmias and are most likely secondary to parasympathetic autonomic dysfunction. Cardiac bradyarrhythmias and arrest have been documented in both generalized and complex partial seizures.²⁶ Nashef et al reported bradycardia in most patients who experienced central apnea during seizure.¹⁰ In their study of 90 seizure attacks, Schernthaner et al reported ictal bradycardia (heart rate decrease >10 bpm) in 3% of seizures. In this study, bradycardia was observed only in seizures of frontal lobe (FL) origin. Similar findings have been documented in 3-11% of patients with complex partial seizures, mostly those of temporal lobe origin.^{1,27,6,28,12,15}

The localization of the epileptic focus with prominent bradycardia has been shown to be in the left temporal area in some studies.²⁹ This might need further studies to clarify, since there is also evidence supporting bilateral origin of ictal events.^30,31

Reeves et al documented the syndrome of ictal bradycardia in 27 patients with simultaneous EEG and ECG recordings. Diagnosis was made after documentation of bradycardia/asystole, syncope, and EEG evidence of preceding epileptic activity. Patients suffered prolonged decreases in heart rate that began during the seizure but persisted after the seizure stopped. Simultaneous EEG showed generalized slowing, possibly secondary to cerebral hypoperfusion as well as to postictal effects. Although this phenomenon could potentially have a fatal outcome, no cases of death by this mechanism have been documented. Eighty-seven percent of the seizures originated from temporal lobe foci, and the remainder from frontal and occipital lobes.¹¹ Complete atrioventricular block has been documented during partial epileptic attacks.

Ictal bradycardia is postulated to be the cause of loss of consciousness resembling syncope in some patients. This might impose a diagnostic challenge.^{25,32,9,33,34}

Rugg-Gun et al evaluated prolonged ECG recorded over a month in a small group of refractory patients. A loop recorder was implanted in 20 patients and the heart rate changes were evaluated in 327 seizures over 22,000 patient-hours. Ictal bradycardia (<40 bpm) was rare, occurring in 8 (2.1%) recorded events in 7 patients. Four patients (21%) had bradycardia or periods of asystole with subsequent permanent pacemaker insertion. Three of these 4 (16% of the total) had potentially fatal asystole. The type of antiepileptic medications was not significant. This study has delineated similarities between this patient population and the population at high risk for SUDEP.¹⁷

ECG could be interpreted during 377 seizures. The authors report only rare (0.24%) bradycardias with heart rate less than 40 bpm. However, these occurred in 4 of the 20 patients (21%). Three of the 4 patients (16% of the total) proved to require a permanent pacemaker placement. The seizure focus in patients with ictal bradycardias proved, as in most other studies, to be in the temporal areas (75%), and in temporal lobes (75%). The type of antiepileptic medications was not significant.

Heart rate variability

Heart rate variability (HRV) during a seizure can be calculated from ECG recorded simultaneously with EEG. HRV before, during, and after the seizure can be an indicator of the sum of sympathetic and parasympathetic input to the heart. Novak et al documented rapid parasympathetic withdrawal approximately 30 seconds before seizure onset and a sympathetic activation peak at seizure onset.³⁵

In a group of patients with secondarily generalized complex partial seizures, Delamont et al reported an increase in parasympathetic activity before the seizure to above normal values, and a significant fall to previously established normal values following the seizure.³⁶ They proposed that preictal elevation of cardiac parasympathetic activity may be a marker for secondary generalization of seizures. Al-Aweel et al evaluated HRV in frequency domain and demonstrated an increase in immediate postictal low-frequency oscillations.³⁷ This is yet another indicator of postictal autonomic instability. Increased sympathetic and decreased vagal HR modulation often precede the electroclinical onset and ictus of temporal lobe seizures. The postictal period is characterized by decreased vagal HR modulation that persists for considerably longer after secondarily generalized seizures.

Decreased HRV is known to increase the vulnerability of cardioregulatory centers, leading to an increase in ventricular automaticity, and potentially to arrhythmia (see Mechanism below).

Subjective sensations

Cardiac and thoracic sensations are another aspect of cardiovascular involvement. Patients may report palpitations or irregular heart beats during a seizure attack. Patients have reported subjective awareness of heart pounding in the absence of ECG changes.³⁸ An earlier study reported angina during a seizure attack.³⁹ Devinsky et al reported atypical angina as the primary epileptic manifestation in 5 patients.²⁷

Mechanism

In an animal model, Lathers et al investigated the "lockstep phenomenon."⁴⁰ They recorded cardiac autonomic neuronal discharges in anesthetized cats. Under EEG monitoring, seizures were induced by intravenous injection of pentylenetetrazol. Cardiac postganglionic sympathetic and vagal discharges were synchronized with both ictal and interictal discharges. Premature ventricular contractions, ST/T changes, and conduction blocks occurred during interictal spikes. They concluded that the lockstep phenomenon might explain propagation of the electrical impulse to central ANS regulatory centers, thus provoking arrhythmogenic potentials.

In a recent study, Goodman et al induced hypertension and bradycardia after temporal lobe seizures in kindled rats. Their results indicate that amygdaloid kindled seizures activate both branches of the ANS.⁴¹ Bradycardia was mediated by activation of the parasympathetic system, whereas the pressor response was caused by an increase in peripheral resistance due to alpha-adrenergic receptor activation. In a similar model of kindling in rats, bradycardia lasted up to a week postictally.⁴² Stimulation of the thalamus in rats can cause seizures and subsequently a variety of cardiac arrhythmias as well as hypotension in association with both ictal and interictal discharges.⁴³

Zaatreh et al recently evaluated the association between the baseline interictal epileptiform discharges and autonomic output in humans.⁴⁴ Their study showed brief bradycardia in the heartbeat after right hemispheric interictal discharges and brief tachycardia after left hemispheric interictal discharges. The time span between two heartbeats in the ECG (RR interval) was measured during interictal discharges in the EEG. These were compared with the RR interval immediately after the interictal activity. Two hundred right-sided and 200 left-sided interictal discharges were compared. With the activity on the right, 116 had an RR prolongation (brief bradycardia), while only 17 had RR shortening (brief tachycardia). However, on the left side, in 100 cases, an RR shortening was noted, and, in 31 cases, an RR prolongation was noted.

Most ictal cardiovascular events have been reported in temporal lobe complex partial seizures. frontal lobe seizures are known to cause bradyarrhythmias more often than temporal lobe seizures. Oppenheimer et al reported that stimulation of the left anterior insula causes bradycardia and depressor responses.²⁴ They documented tachycardia and pressor responses with right insular stimulation. These findings have been confirmed by other researchers.²⁸ Inactivation by injection of amobarbital caused reverse results, ie, heart rate increased after left hemisphere inactivation and decreased after right hemisphere inactivation.⁴⁵ In addition, the time lag between ictal spikes and the induced cardiac changes has been documented to be longer with frontal lobe than with temporal lobe seizures.¹²

Generally, tachycardia occurs before EEG changes or early during the attack. In a recent study, heart rate changes occurred several seconds prior to seizure onset as recorded by scalp EEG in 76.1% of seizures and by invasive EEG in 45.7% of seizures.¹² Bradycardia, however, usually is a late manifestation and is of shorter duration. After combined parasympathetic and sympathetic activation, rapid parasympathetic withdrawal occurred approximately 30 seconds before the seizure and sympathetic activation peaked at seizure onset.³⁵

Stimulation of both human insular cortices causes changes in heart rate and blood pressure.²⁴ Neuronal discharges in human mesial temporal structures, amygdala, and hippocampus are synchronized with the cardiac cycle and, to some extent, with the respiratory cycle.⁴⁶ Seizures that have their foci in the temporal lobe propagate easily to the centers in the brain that regulate the activities of the ANS, ie, amygdala and hippocampus. This phenomenon was easier to explain after Leutmezer showed the ictal tachycardia preceded EEG seizure onset by 14 seconds in the temporal lobe and by 8 seconds preceding EEG seizure onset in extratemporal origins of seizures.¹⁵

In both animal models and humans, stimulation and recording studies implicate the amygdala in the control of heart rate, blood pressure, and respiration.⁴⁷ The amygdala receives both direct and indirect projections from the ANS afferents and also projects into hypothalamus and brainstem centers for ANS homeostasis. In a study of 27 temporal lobe seizures monitored by depth and subdural electrodes, Epstein et al documented that limbic ictal involvement is essential for cardioregulatory changes.⁸ Restricted amygdaloid seizure activity, however, generally was insufficient to alter heart rate. They postulated that ictal heart rate changes depend on the volume of the brain involved and not on duration of the attack.

The general level of sympathetic activation is another contributory factor to cardiovascular changes. Increases in sympathetic discharge and plasma catecholamines peak 30 minutes after tonic-clonic seizures.⁴⁸ High-level spinal anesthesia blocked the initial tachycardia and hypertension accompanying a few generalized seizures.⁴ In addition, myocardial fibrosis has been reported to develop in patients with repetitive exposure to catecholamine toxicity. These areas of degeneration and fibrosis can, in turn, serve as new foci for tachyarrhythmias.

Summary

Studies contributing to our understanding of ictal cardiovascular events are based on recordings from ictal events in either animal models or patients with epilepsy, as well as knowledge of central autonomic regulation. Although involvement of the amygdala in the electrical event is postulated to cause most of the autonomic changes, propagation to the whole limbic system seems to be necessary.

Provoked temporal lobe seizures in kindled rats can activate both branches of the ANS. A variety of cardiac arrhythmias and hypotension have been documented with both ictal potentials and interictal spikes in these models; this is described as the "lockstep phenomenon." Most ictal cardiovascular events have been reported in temporal lobe complex partial seizures. Frontal lobe seizures are known to cause bradyarrhythmias more often than tachyarrhythmias. In frontal lobe seizures, time lags between seizure spikes and the induced cardiac changes were longer than in seizures with temporal lobe foci. This is thought to be due to the longer distance of frontal lobe from the limbic system.

Stimulation of left anterior insula in humans can cause bradycardia and depressor responses, whereas stimulation of right insular cortex induces tachycardia and pressor response.

Careful examination of HRV before ictal events indicates combined parasympathetic and sympathetic activation; rapid parasympathetic withdrawal occurred approximately 30 seconds before the seizure, and sympathetic activation peaked at seizure onset.³⁵ This is accompanied by tachycardia before EEG changes or early during the attack. Bradycardia, however, is usually a late manifestation, and is of shorter duration.

Massive sympathetic discharge can be the cause of potentially fatal ictal arrhythmias. Moreover, damage to the myocardium caused by frequent increases in plasma catecholamines can produce areas of degeneration and fibrosis that can serve as new foci for tachyarrhythmias in the interictal state.

Further evaluation of autonomic cardiovascular activity can reveal information about the focality, propagation, and nature of seizure activity.

Respiratory

Apnea, hypoventilation, and hyperventilation occur during and after a GTC seizure. Berger first documented a series of autonomic phenomenon, including apnea, at seizure onset.⁴⁹ Apnea in the context of a partial seizure can occur with bradycardia⁵⁰ or without bradycardia.⁵¹ Nashef et al have reported apnea in 38% of a group of patients with various types of seizures. All of these patients had central apnea, but obstructive apnea also was documented in about 30%. Oxyhemoglobin saturation (SpO₂) dropped to less than 85% in 10 patients with partial seizures of temporal lobe origin.^10,52

The respiratory brainstem control centers are interlinked closely with the cardiomodulatory centers. As such, the potential mechanisms for ictal cardiovascular changes already described also may apply to respiration.⁵³

Gastrointestinal/Abdominal

Ascending abdominal sensations are among the most common early symptoms of partial seizures. These phenomena are associated particularly with seizures arising from mesial temporal foci.^54,55,56,57 Dyspepsia, pain, hunger, borborygmi, nausea, vomiting, belching, urge to defecate, and fecal incontinence also have been reported. Abdominal pain is common, especially in children. Vomiting also can occur in seizures with opercular, inferior temporal, or occipital foci.⁵⁸ Afferent autonomic fibers play a key role in the epigastric sensations, whereas efferent pathways cause belching, vomiting, and defecation.³⁸

Panayiotopoulos syndrome has been classified as a common benign childhood epilepsy with frequent autonomic symptoms, especially vomiting. Panayiotopoulos syndrome is the diagnosis when at least 5 out of the following 8 diagnostic criteria are present: (1) infrequent seizures (up to 5), (2) prolonged seizures (> 5 min), (3) ictal vomiting, (4) ictal eye deviation, (5) ictal autonomic manifestations, (6) ictal behavioral disturbances, (7) gradual suppression of consciousness during seizures, and (8) convulsions.⁵⁹

Urinary

Incontinence and urgency frequently accompany seizures. Incontinence is caused by external sphincter relaxation in GTC seizures and by detrusor muscle contraction in absence seizures.

Genital

Erotic feelings, genital sensations, and orgasm are rare ictal phenomena. During a seizure, genital sensations result from stimulation of postcentral sensory cortex. Sexual arousal is reported in seizures with limbic and temporal lobe involvement. Orgasm can be reached in seizures that involve the hypothalamus.⁶⁰

It is speculated that the Great Russian writer Dostoevsky (1821-1881) suffered from a rare form of temporal lobe epilepsy termed ecstatic epilepsy, also called Dostoevsky epilepsy. It is reported that sexual fantasies and rarely even orgasms were reached by him during his seizures.⁶¹ Dostoevsky alleged (via one of his characters) that when he had a seizure the gates of Heaven would open and he could see row upon row of angels blowing on great golden trumpets. Then 2 great golden doors would open and he could see a golden stairway that would lead right up to the throne of God.

Erectile dysfunction with intact libido in men with epilepsy has been known to researchers since the 1950s.⁶² Hyperprolactinemia resulting from complex partial seizures has been postulated to contribute to male sexual dysfunction in epilepsy.⁶³

Cutaneous

Unilateral or bilateral flushing, erythema, cyanosis, blanching, or pallor can be manifestations of temporal lobe seizures. Piloerection as a seizure manifestation has been reported in 15 patients.⁶⁴ In an animal model, piloerection occurred after stimulation of the amygdala.⁵³ Piloerection often accompanies epigastric sensations, and blanching may accompany nausea.

Pupillary

Mydriasis, miosis, and hippus can occur as manifestations of a partial seizure and can be unilateral.⁶⁵

Interictal Autonomic Changes

Few researchers have evaluated the ANS during the interictal period.

The autonomic cardiovascular reflexes are the most substantial part of autonomic functions. A standardized test battery is used in ANS laboratories. ECG and blood pressure are measured continuously while the patient is undergoing certain physical, postural, and mental changes. With the help of specially designed software programs the heart rate and blood pressure variability are calculated from the data obtained from ECG and blood pressure measurements.

Standard tests for this evaluation include assessment of HRV during rest, deep breathing, Valsalva maneuver, face immersion in cold water, and gravitational challenge with the passive tilt table test.^66,67,68,69 The results are evaluated in both time and frequency domains. HRV during rest, deep breathing, and Valsalva maneuver provides indications of cardiovascular parasympathetic function. Blood pressure variability during Valsalva maneuver, isometric exercise, and orthostatic challenge (ie, tilt table) reflects sympathetic functions.

Evaluation of autonomic cardiovascular reflexes in patients with epilepsy indicates dysfunction of both the sympathetic component^{70,71,72,35,73} and the parasympathetic division.^{74,70,75,72,35,76} Furthermore, hypofunction of autonomic cardiovascular reflexes is postulated to be more prominent in patients who also are at a high risk for SUDEP, including those with more refractory seizure disorders.^70,73 Study of HRV during sleep in 11 children with epilepsy confirmed the above findings.⁷⁷

A newer evaluation method for HRV, fractal correlation properties, evaluated the Approximate Entropy (ApEn) of the RR intervals. Using this method, Ansakorpi et al assessed the HRV in patients with TLE.⁷⁶ After comparison of 24-hour recordings of ambulatory EEG, they showed that, in 19 patients with refractory TLE, the HRV is more significantly impaired when compared with the 25 patients with well-controlled TLE.

Table 3. Review of Some Studies on Interictal Autonomic Cardiovascular Reflexes in Patients with Epilepsy

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Abbreviations: Freq indicates frequency; HRV, heart rate variability; DB, deep breathing; VM, Valsalva maneuver; BP, blood pressure; S, sympathetic; PS, parasympathetic; BM, Baltic myoclonus epilepsy; N, within normal limits; CP, complex partial; SP, simple partial; T, temporal lobe; inc, increased; AED, antiepileptic drugs; dec, decreased; GTC, generalized tonic-clonic; JME, juvenile myoclonic epilepsy; ApEn, approximate entropy.

The mechanism of dysfunction of the ANS in epileptic seizures is likely to be multifactorial. Interictal spikes have been shown to cause arrhythmias in animals.⁴⁰ Also, the autonomic control centers may have undergone physiological or anatomical alterations. Interictal hypometabolism sometimes seen in the area adjacent to the epileptic focus on positron emission tomographic (PET) scanning studies, could, for example, underlie such functional changes.⁸³

Autopsies of patients with epilepsy who experienced sudden unexpected death have shown fibrosis of the cardiac conductive system in 33%.^84,85 Repetitive exposure to catecholamines is known to cause myocardial fibrosis. These fibrotic areas can act, per se, as new foci for cardiac arrhythmias. Also, antiepileptic drugs (AEDs) may play a role in modification of ANS functions. In a study of the cardiovascular reflexes in 24 patients with epilepsy, Devinsky et al documented increased HRV in this group, attributed at least partially to carbamazepine.⁷⁸ Other researchers have reported similar findings.^72,71

Decreased HRV is known to increase the vulnerability of the cardioregulatory centers, leading to an increase in ventricular automaticity, in turn predisposing to arrhythmias. This is particularly crucial, since autonomic cardiac arrhythmias may contribute significantly to the phenomenon of SUDEP.

Relationship Of Autonomic Functions And Sudden Death In Epilepsy

Patients with epilepsy have a mortality rate that is 2-3 times that of the general population because of epilepsy-related deaths. The phenomenon of SUDEP may account for 8-17% of deaths in patients with epilepsy.⁸⁸ SUDEP is defined as sudden, unexpected, nontraumatic, nondrowning death in an individual with epilepsy, witnessed or unwitnessed, where postmortem examination does not reveal an anatomical or toxicological cause for the death. This phenomenon has been discussed in detail in the article Sudden Unexpected Death in Epilepsy.

The incidence of SUDEP is estimated to be 0.35 per 1000 person-years of follow-up in this population. Known associated demographic risk factors for SUDEP include male gender and an average age of 28-35 years.

Seizure-related risk factors include the following:

• Symptomatic epilepsy
• GTC seizure
• Onset at a younger age
• Duration of longer than 10 years
• Higher number of attacks

The following are proposed treatment-related risk factors^{89,90,91,84,92,85,93} :

• Subtherapeutic AED levels
• Higher number of AEDS
• Recent changes in AED regimen
• History of surgical treatment for seizures

Although autopsy, by definition, fails to reveal the underlying cause of death, several autopsy reports confirm a variety of findings in the organs of the victims. In addition to the underlying cerebral pathology in patients with symptomatic epilepsy, cerebral edema, signs of hypoxia in the hippocampal area, and sclerosis of the amygdala have been reported.^84,94,95,96 Mild to moderately severe pulmonary edema with protein-rich fluid and alveolar hemorrhage were seen in 62-100% of all specimens from SUDEP patients.^95,84 Cardiac nonfatal pathological findings, including fibrosis of the conductive system, have been reported in 33% of patients.^84,85

Various pathophysiological events may contribute to SUDEP.

• Respiratory events including airway obstruction, central apnea and neurogenic pulmonary edema are probable terminal events.^95,94,10,97
• Cardiac arrhythmias, during both the ictal and interictal periods, leading to arrest and acute cardiac failure may contribute significantly to SUDEP.^{98,27,6,11,28,12,13,99} Decreased baseline HRV is indicative of impaired autonomic cardiovascular reflexes in epilepsy. This can cause an increase in ventricular automaticity, in turn predisposing to arrhythmias. Catecholamine surges during repeated seizures can cause cardiac conduction system fibrosis and arrhythmias. Anatomic and functional changes in the cardiac and pulmonary function are evident and might be a direct or indirect consequence of autonomic dysregulation.
• Interictal sympathetic-mediated dysregulation of cerebral blood flow is another possible mechanism for SUDEP.^100,101
• A recent seizure might cause central apnea, often associated with bradyarrhythmias.
• Some researchers have speculated about the role of AEDs in SUDEP.^102,92 Use of carbamazepine is associated with impaired cardiac regulation and with increased risk of SUDEP.

These events might develop in combination. For example, central apnea and cardiac bradyarrhythmias might have common central inducing mechanisms. A seizure has been reported to be the immediate terminal event in 30-80% of witnessed SUDEP cases.^95,103 Cardiac arrhythmias are the main postulated mechanism in these cases. Dysfunctions of the autonomic cardioregulatory centers, on the other hand, would increase the automaticity and decrease the threshold for arrhythmias.

In summary, although autonomic dysfunction is known to be associated with epileptogenic activity, its importance as a contributory risk factor to potential fatal outcomes for this population is yet to be determined. Evaluation of autonomic cardiovascular and respiratory reflexes in patients with epilepsy can provide us with valuable information on the mechanism of SUDEP.

Antiepileptic Medications and Autonomic Changes

Antiepileptic medications can have a series of effects on the ANS. Arrhythmia, hypotension, and respiratory depression are frequent adverse effects (Table 4).

Table 4. Autonomic Effects of Antiepileptic Medications

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These medications may have a stabilizing effect on cellular membranes, and thus have anti-arrhythmic properties.

Investigators of a few studies report that administration of carbamazepine decreases HRV and causes parasympathetic hypofunction. Tomson et al compared 10 patients with epilepsy treated with carbamazepine to 23 patients on other AEDs and to age-matched controls. Patients on carbamazepine had significantly lower values for a few parameters of HRV, ie, standard deviation of R-R intervals, low frequency power, and low frequency/high frequency power ratio, than did their matched healthy drug-free controls.⁷¹ Also, abrupt carbamazepine withdrawal can cause decreased HRV.¹⁰²

Findings from both these studies indicate a potential increase in cardiac arrhythmias associated with carbamazepine use and withdrawal. Carbamazepine also can predispose especially elderly patients to bradyarrhythmias by slowing conduction across the atrioventricular node.

However, few recent studies have shown that patients with antiepileptic medications have a less impaired regulation of the autonomic cardiovascular reflexes than other patients with epilepsy who are not being treated. This might be a indication that seizure control may help improve the cardiac autonomic function and the prognosis.⁸⁰

Differentiation Between Seizure and Syncope

Loss of consciousness is a frequent reason for seeking medical care. The most frequent causes are cardiovascular (eg, arrhythmia, decreased blood pressure) or neurological (eg, seizure, stroke).^104,105 Loss of consciousness can be a diagnostic challenge both for neurologists and cardiologists. In 60% of cases, the cause is obvious from the clinical picture.

Syncope can occur with abrupt cessation of the cerebral perfusion for 6-8 seconds, or a reduction of only 20%. Clinical findings suggestive of a cardiovascular pathophysiology are dizziness or lightheadedness before the event and regaining consciousness, shortly after resuming the supine position. In patients with loss of consciousness caused by seizures, clonic jerks, and prolonged confusion after the event are more frequent. Table 5 below highlights the major findings in seizure and syncope that can help distinguish these 2 entities.

Inability to make this distinction correctly may lead to misdiagnosis in approximately 40% of patients and to treatment that is ineffective and potentially dangerous.

At one end of the spectrum, patients who lose consciousness because of acute cardiovascular failure, as in hypotension or arrhythmia, may have myoclonic jerks, tonic spasm, and urinary incontinence during the event.¹⁰⁶ These are probably induced by transient cerebral hypoperfusion, releasing motor centers in the upper brain stem from inhibition. In this group, interictal EEG may be normal. When these patients undergo evaluation of autonomic cardiovascular reflexes, they can show not only decreased HRV, but also syncope during the tilt table test, which may be accompanied by some myoclonic jerks if the tilt is not reversed promptly.

Simultaneous EEG recording during tilt table testing typically shows no evidence of seizure, but rather progressive slowing, sometimes progressing to flattening, a sequence typical of cerebral hypoperfusion.¹⁰⁷ When diagnosed correctly, these patients do not require antiepileptic medications, but rather need further evaluation and treatment of their cardiovascular disorders.

At the other end of the spectrum, patients with epilepsy may have cardiac arrhythmias, including asystole, which in turn can cause loss of consciousness. Many studies, as mentioned above, have documented these cardiovascular events during seizures. When diagnosed appropriately, such patients may benefit more from antiepileptic medications than from treatment of their cardiac pathologies, although a pacemaker can be protective for those with ictal bradyarrhythmias whose seizures cannot be controlled. Ictal asystole with convulsive syncope mimicking secondary generalization is an interesting dilemma that can represent a challenging clinical diagnosis.²⁹

In prolonged QT syndrome, defects in the potassium and sodium channels with superimposed cardiac sympathetic imbalance result in prolongation of the myocyte action potential and trigger ventricular arrhythmias. Patients with this syndrome, especially those with the familial form, have a high rate of seizures and sudden death. Both children and adults with history of loss of consciousness after a seizure require an ECG to rule out this syndrome.^108,109 Treatment with phenytoin can aggravate the associated arrhythmias.

Very little evidence exists to clarify the potential influence of ANS on cortical epileptogenic foci. The general level of excitement in some patients seems to contribute to their seizure susceptibility. ANS also may be involved in certain forms of reflex epilepsy. In addition, cardiac arrhythmias potentially can cause cerebral hypoperfusion, leading in some cases to convulsive activity and rarely to actual cortical epileptic activity.¹¹⁰

Table 5. Features Distinguishing Seizure and Syncope

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Multimedia

(Enlarge Image)

Media file 1: Probable paths of propagation of the epileptic electrical activity to the limbic system and autonomic nuclei.

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Media file 2: A combination of factors may contribute to sudden unexpected death in epilepsy (SUDEP).

Keywords

seizures, epilepsy, autonomic nervous system, ANS, ictal autonomic changes, interictal autonomic changes, relationship of autonomic functions and sudden unexpected death in epilepsy, sudden unexpected death in epilepsy, SUDEP, antiepileptic medications and autonomic changes, differences between syncope and seizure, ictal, bradycardia, tachycardia, asystole, apnea

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