Sleep Medicine 15 (2014) 1433–1439
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Sleep Medicine 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 / s l e e p
Review Article
Cardiorespiratory abnormalities during epileptic seizures Sanjeev V. Kothare a,1,*, Kanwaljit Singh a,b,1 a b
Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Medical Center, New York, NY, USA Department of Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA, USA
A R T I C L E
I N F O
Article history: Received 31 May 2014 Received in revised form 17 July 2014 Accepted 22 August 2014 Available online 3 September 2014 Keywords: Epilepsy Sudden death in epilepsy Cardiac abnormalities Respiratory abnormalities EEG
A B S T R A C T
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in young and otherwise healthy patients with epilepsy, and sudden death is at least 20 times more common in epilepsy patients as compared to patients without epilepsy. A significant proportion of patients with epilepsy experience cardiac and respiratory complications during seizures. These cardiorespiratory complications are suspected to be a significant risk factor for SUDEP. Sleep physicians are increasingly involved in the care of epilepsy patients and a recognition of these changes in relation to seizures while a patient is under their care may improve their awareness of these potentially life-threatening complications that may occur during sleep studies. This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Epilepsy affects nearly 1% of the general population [1,2]. Epilepsy can be classified by seizure type, underlying causes, epilepsy syndromes, and by events taking place during the seizures. Seizure types are broadly classified by whether the source of seizures is localized (focal or partial seizures) or diffusely distributed (generalized seizures) in the brain. Generalized seizures can be further classified according to their effects (tonic–clonic seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures). Focal or partial seizures can be further classified into simple partial (where only a small part of the lobe is affected and the person does not lose awareness of the surrounding) or complex partial (a larger part of the hemisphere is affected and the person loses consciousness and awareness) seizures. Approximately 35% of individuals with epilepsy do not adequately respond to medications and are thus considered “medication resistant.” [3] Sudden death is 20–40 times more common in people with epilepsy (and especially so in poorly controlled seizures) as compared to people without epilepsy. Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in young and otherwise healthy adults with epilepsy (see below for further
details) [4,5]. SUDEP is much less frequently seen in children [6]. Epileptiform discharges are often activated by sleep and tend to occur 14 times more frequently in non-rapid eye movement (NREM) sleep than in wakefulness [7] and, therefore, sleep stage and sleep/ wake state may influence the likelihood for a seizure to occur, with seizures occurring most frequently in NREM sleep, followed by wakefulness, and less likely during rapid eye movement (REM) sleep [8]. As such, the deleterious effects of seizures and SUDEP are more likely to occur when patients emerge from the sleep state [9]. A significant proportion of patients experience cardiac/or pulmonary dysfunction due to seizures (details follow). These changes may worsen the seizure prognosis/outcome and are believed to be related to, at least in part, the occurrence of SUDEP. This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP. Sleep physicians are often involved in the care of epilepsy patients on an increasing frequency and a recognition of these changes in relation to seizures may improve their awareness of these potentially life-threatening complications that occur during sleep studies. 2. Respiratory changes during seizures
* Corresponding author. Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, NY, USA. Tel.: +646 558 0806; fax: +646 385 7164. E-mail address: [email protected] (S.V. Kothare). 1Drs. Singh and Kothare contributed equally and are co-first authors. http://dx.doi.org/10.1016/j.sleep.2014.08.005 1389-9457/© 2014 Elsevier B.V. All rights reserved.
The respiratory center [10] (Fig. 1) consists of four nuclei located in the medulla oblongata and pons of the brainstem. The inspiratory center (also known as the dorsal respiratory group) is located in the dorsal portion of the medulla oblongata and causes
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Fig. 1. Respiratory centers of the brain. Figure sourced from Wikimedia commons and republished under the Creative Commons Attribution 3.0 Unported license. (http://commons.wikimedia.org/wiki/File:2327_Respiratory_Centers_of_the_Brain.jpg).
inspiration when stimulated. The expiratory center (ventral respiratory group) is located in the anterolateral part of medulla oblongata, anterolateral to the inspiratory center. The pneumotaxic center is located in the upper part of pons and it controls the rate and pattern of breathing. This center is inhibited by impulses from the ventral respiratory group. The apneustic center is located in the lower part of pons. This center discharges stimulatory impulses to the dorsal respiratory group to stimulate inspiration, discharges inhibitory impulses to the ventral respiratory group to inhibit expiration, and receives inhibitory impulses from the pneumotaxic center and from the lung stretch receptors – thus in turn limiting inspiration. An abnormal input to these respiratory centers during seizure-associated neuronal activation leads to many of the respiratory changes observed with seizures. Respiratory changes occurring in relation to seizures are seen with generalized as well as focal seizures, especially those arising from the mesial temporal structures. These changes have been repeatedly demonstrated in numerous studies and include central and
obstructive apneas, hypoventilation, hypercapnia, and desaturation with acidosis, bradypnea, and tachypnea [11]. Most important of these changes is the respiratory depression causing central apnea. Figure 2 depicts tachypnea accompanying a tonic seizure followed by postictal central apnea, which could be a mechanism for SUDEP, especially if the patient was in prone position and the apnea was prolonged. Much of the research evaluating the occurrence of respiratory changes in seizures has been done in adults. Bateman et al. (2008) prospectively analyzed the occurrence of ictal hypoxemia in localization-related epilepsy in 56 patients with 304 seizures [13]. They found that ictal hypoxemia was associated with seizure localization (temporal seizures), lateralization (right-sided seizures), male gender, longer seizure duration, and contralateral spread of seizures. Tezer et al. (2009) in a case–control study on two patients reported that apneas were associated in patients with right temporal and paracentral epilepsy [14]. Seyal et al. (2010) reported a severe and prolonged increase of ictal and postictal
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Fig. 2. Tonic seizure with hyperventilation and CO2 washout with central apnea at seizure termination in stage-2 sleep. Tonic seizure (solid arrow) with accompanying hyperventilation and CO2 washout (dashed arrow), with a central apnea at the termination of the tonic seizure in stage-2 sleep. Results suggest that patient lying prone and presenting with prolonged apnea after a seizure may be at an increased risk for SUDEP [12]. This modified montage could be used in the future to further assess the degree of hyper/hypoventilation during seizures.
expiratory carbon dioxide (ETCO2) in 187 seizures in 33 patients [15]. Seyal et al. (2012) also evaluated the occurrence of postictal generalized electroencephalography suppression (PGES) (cerebral shutdown) with respiratory abnormalities and found no association of PGES with postictal central apnea in 102 patients with localization-related epilepsy [16] (see below for more on PGES). In children, the weight of literature evaluating the occurrence of cardiopulmonary abnormalities with seizures is rather limited, with most studies being of a descriptive nature. Southall et al. (1987) reported the occurrence of apnea and hypoxemia in one pediatric patient with complex partial seizures [17]. Hewertson et al. (1994) reported the occurrence of hypoxemic apparent life-threatening events in 17 infants with partial seizures [18]. Hewertson et al. (1996) demonstrated the occurrence of hypoxemia/desaturation, apnea, and sinus tachycardia in the majority of 53 seizures in 10 children [19]. O’Regan and Brown (2005) demonstrated the occurrence of tachypnea, apnea, and hypoxemia in 101 seizures in 37 children [20]. Moseley et al. (2010) demonstrated the presence of ictal hypoxemia in generalized as compared to non-generalized seizures [21]. Singh et al. (2013) analyzed 101 seizures in 26 children and found an association of ictal apnea, bradycardia, and desaturation with younger age, male gender, and symptomatic generalized, left temporal longer-duration seizures [22]. Pavlova et al. (2013) compared 101 seizures in 26 children and 55 seizures in 22 adults and found that ictal apnea and bradycardia occurred more often in children with PGES occurred more often in adult seizures as compared to children [23].
Serotonin and breathing: Serotonin, a neurotransmitter, has been shown to affect brainstem respiratory center excitability. Changes in serotonin levels have been reported in patients with sudden infant death syndrome (SIDS) [24]. Mouse models of epilepsy have shown that selective serotonin reuptake inhibitors (SSRIs) (fluoxetine) reverses respiratory arrest in those animals [25]. Subsequently, a retrospective human study showed that medically refractory epilepsy patients taking SSRIs had reduced chances of ictal desaturation as compared to patients not on SSRIs [26]. The serotonin raphehippocampal pathway may be impaired in epilepsy as shown in a rat model of epilepsy [27] and it has been hypothesized that SSRI usage in epilepsy may help by enhancing the excitability of the brain respiratory centers. In summary, several respiratory changes occur during seizures as a result of abnormal neuronal activation of the respiratory center in the brain. The most serious of these changes are those associated with respiratory depression (such as hypoxemias and central apneas) most commonly observed in young men with symptomatic generalized, contralaterally spreading, left or right temporal, longer-duration seizures. 3. Cardiac changes during seizures Ictal autonomic changes can also cause cardiovascular manifestations [28]. Sympathetic responses are common during most seizures, causing tachycardia, and hypertension. Tonic–clonic
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Fig. 3. Interaction of sympathetic or parasympathetic systems causing cardiovascular manifestations during seizures.
seizures and complex partial seizures of temporal or extratemporal origin often lead to sympathetic activation. However, ictal parasympathetic activity or sympathetic inhibition can also occur, causing bradycardia and hypotension [29,30]. Combinations of sympathetic and parasympathetic activation and inhibition may occur simultaneously or sequentially during individual seizures. As with the research studies exploring cardiac changes in association with seizures, most have been done in adults. Figure 3 shows how the interaction of sympathetic and parasympathetic centers results in various cardiovascular manifestations during seizures. Moseley et al. (2011) analyzed autonomic changes in 218 seizures from 76 patients and reported the occurrence of ictal sinus tachycardia in 57% of seizures, who were on >3 antiepileptic drugs (AEDs) and experienced generalized seizures that had normal brain magnetic resonance imagings (MRIs) [31]. Ictal bradycardia was less common, occurring in 2% of seizures and was associated with seizure clustering, and a history of >50 seizures/month was reported. Surges et al. (2009) followed 74 subclinical seizures (electrographic seizures without clinical accompaniment) in 26 patients and reported insignificant changes in cardiac function during localized electrographic seizures [32]. Nilsen et al. (2010) on the other hand reported that pre-ictal tachycardia was associated with secondary generalization of seizures in 38 patients with partial epilepsy [33]. Surges et al. (2010) found an association with ictal and postictal tachycardia, postictal heart rate variability, and abnormal QTc shortening with secondary generalization in 25 patients with medically refractory temporal lobe epilepsy [34]. In children, Hewertson et al. (1996) demonstrated the occurrence of ictal tachycardia in the majority of 53 seizures recorded in 10 patients [19]. Singh et al. (2013) reported the occurrence of ictal bradycardia in association with younger age, male gender, and symptomatic generalized, left temporal-onset longer-duration seizures [22]. Pavlova et al. (2013) reported that ictal bradycardia occurred more commonly in seizures in children as compared to adults [23].
3.1. Other cardiac changes during seizures Other cardiac abnormalities that may occur include asystole, repolarization anomalies (prolonged or shortened QTc interval), and atrial fibrillation. These possibly may arise from seizures arising from the insular cortex. Seizure-induced cardiac asystole has been reported in some studies. Sehuele et al. (2007) assessed 6827 patients undergoing longterm video-EEG monitoring and ictal asystole was recorded in 10 patients (0.27%), the majority of them (8/10) occurring in temporal lobe epilepsy patients [35]. Lanz et al. (2011) retrospectively analyzed the occurrence of cardiac asystole in 2003 epilepsy patients undergoing long-term EEG monitoring. Out of 2003 patients, only seven patients experienced asystole, all of them occurring in temporal lobe epilepsy patients [36]. Pathogenic cardiac repolarization has been described in epilepsy patients. Electrocardiography (EKG) indicators of abnormal cardiac repolarization during seizures (such as prolonged or shortened QTc interval) are risk factors for lifethreatening tachyarrhythmia and sudden cardiac death. Several studies have indicated the occurrence of peri-ictal QTc interval prolongation in >10% patients of epilepsy [34,37–39]. The co-occurrence of ictal hypoxemia has especially been shown to be a risk factor for prolonged QTc interval [40]. Peri-ictal shortening of QTc interval has also been reported, especially in relation to generalized tonic clonic seizures (GTCS) (Surges et. al 2010) [41]. Peri-ictal changes in heart rate variability have been described in relation to seizures and SUDEP. A recent case report of an epilepsy patient who died of SUDEP described the occurrence of a marked increase of pre-ictal parasympathetic activity and shortened QTc interval followed by a cluster of GTCS, PGES, asystole, and cardiac arrhythmias [42]. Complicating this picture, several antiepileptic medications can also lead to QTc interval abnormalities (QTc prolongation: pregabelin, lamotrigine, valproate, stiripentol, and ketogenic diet; QTc shortening: rufinamide, primidone, phenytoin, and carbamazepine) [43].
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In summary, several cardiac changes occur during seizures as a result of ictal autonomic dysfunction. Sympathetic responses (causing tachycardia and hypertension) are more common as compared to parasympathetic responses (causing bradycardia and hypotension). Younger age, male gender, multiple AEDs, and generalized, temporal lobe, and longer-duration seizures predispose patients to experiencing these cardiac alterations. 3.2. Genetic basis of cardiopulmonary changes in association with seizures A few studies have shown that mutations in genes could lead to predisposition to cardiopulmonary complications during seizures. For example, in mice models and in a human cohort study, mutations in potassium channel-coding genes (KCNQ1, KCNH2, and SCN5A) have been found to predispose a severe form of prolonged QTc interval, thus potentially predisposing the subjects to sudden death in epilepsy. KCNQ1 gene encodes for the cardiac KvLQT1 delayed rectifier channel. In mice, this channel is present in neurons of certain regions of the forebrain and brainstem. Seizures in this model might predispose cardiac arrhythmia [44]. Another study in mice has shown that mutations in Kv1.1 potassium channel-coding genes predisposed mice to early onset of epilepsy, fivefold increase in AV conduction blocks, bradycardia and premature ventricular contraction, and sudden death [45]. 3.3. Sudden unexpected death in epilepsy SUDEP refers to the sudden unexpected death of a seemingly healthy individual with epilepsy. SUDEP is defined as a “sudden, unexpected, witnessed or unwitnessed, non-traumatic and nondrowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration > 30 minutes or seizures without recovery in between) in which postmortem examination does not reveal a cause of death.” SUDEP is the most common cause of death that can be directly attributable to epilepsy [46]. SUDEP most often occurs at night, possibly during sleep [47]. The incidence of SUDEP is 1 in 1000 with epilepsy (general population 1 in 40,000), and 1 in 100–200 with refractory epilepsy, but is four times more likely in adults as compared to children [48]. While potential mechanisms have been postulated, a high seizure frequency remains the biggest conclusively substantiated underlying risk factor. Cardiac arrhythmias [49], respiratory abnormalities [50], or a combination [9,51,52] have been postulated in the causation of SUDEP [53]. The role of breathing in the mechanisms of SUDEP has been understudied and is probably underestimated. Studies have shown age to have a strong effect on the rate and severity of respiratory abnormalities with obstructive sleep apnea syndrome being more common in older individuals [7,54], and more severe after the age of 50 [7]. The peak age for SUDEP in adults, however, is between 20 and 40 years [55]. Given the increased incidence of obstructive sleep abnormalities with age, we believe that the seizure-related breathing disturbances also differ by age group. The interaction between seizures, sleep, and cardiopulmonary function is an important, yet understudied area of investigation and is a growing area of research in epilepsy. A better understanding of mechanisms and association of these cardiorespiratory abnormalities in seizures may offer better insights to causes and, potentially, a better prediction of patients who might experience SUDEP. A recent study [56] collected data from four case–control studies to increase the power to identify risk factors for SUDEP [57–60]. The following risk factors for SUDEP (in 289 cases and 958 living controls) with epilepsy were identified: 1) Multiple (more than three) GTCS per year, 2) multiple AEDs, 3) epilepsy duration, 4) childhood onset of epilepsy, 5) male gender, and 6) symptomatic
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epilepsy. The risk for SUDEP was 37 times greater in persons with early onset of epilepsy (younger than age 16) and eight times in those whose epilepsy began at age 16 or older compared to healthy controls. Although the peak incidence of SUDEP is between ages 20 and 40 years, the study implied that it is those patients who had early onset of epilepsy are more susceptible to developing SUDEP later on in their life. A reanalysis of the data used in the abovementioned study showed that of these six risk factors, the effect of all five tended to decrease once the effect of GTCS frequency was taken into account, meaning that GTCS frequency remained the most important risk factor for SUDEP [61]. Another recently published, large, multicenter study (the Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS) study) performed a comprehensive evaluation of cardiorespiratory arrests in 29 epilepsy patients who died subsequent to an admission to epilepsy monitoring units [62]. This study showed that patients who had subsequently died due to cardiorespiratory arrest had an early postictal tachypnea induced by a generalized tonic clonic seizure followed within 3 min by transient or terminal cardiopulmonary dysfunction (apnea and/or bradycardia culminating in asystole). Where transient, this dysfunction later recurred with terminal apnea and cardiac arrest within 11 min of the end of seizure. There is not a single mechanism to explain the mechanisms of SUDEP. Potential mechanisms may include: 1) cardiac arrhythmias (possibly related to the cardiovascular effects of insular cortex), 2) ventilatory impairment, prolonged apneas, or oxyhemoglobin desaturations triggered by seizures, 3) impaired righting responses leading to suffocation (most patients with SUDEP have been found to be in the prone position), 4) autonomic instability during or after a seizure, and/or 5) postictal serotonin (5-HT) neuronal dysfunction causing depression of breathing, impaired arousal, and repositioning reflexes. Cerebral shutdown is a yet another putative mechanism causing SUDEP that has been put forward. PGES (Fig. 4), which is a hallmark of cerebral shutdown, is defined as the immediate postictal (within 30 s), generalized absence of electroencephalographic activity >10 μV in amplitude, allowing for muscle, movement, breathing, and electrode artifacts [63]. Prolonged PGES may be an independent risk marker for SUDEP. Lhatoo et al. (2010) showed that PGES >50 s increased the risk for SUDEP by a significant margin, and each 1-s increase in PGES duration increased the risk for PGES by 1.7% [63]. It is however not clear whether PGES is an indirect or direct marker of cerebral dysregulation. A recent study examined the relationship between sympathetic and parasympathetic changes (as measured by electrodermal activity and heart rate variability) and PGES in seizure patients, and found that the increase in electrodermal activity response amplitude and decreased parasympathetic modulated power of heart rate variability were directly correlated to prolonged PGES [64]. Therefore, it may be presumed that PGES may serve as a marker of postictal autonomic dysregulation. In another study, 13 patients with PGES and GTCS were compared to 12 random controls, and it was found that patients with PGES were more likely to be motionless postictally and were more likely to have resuscitative interventions (such as suction, oxygen administration, and position altered) performed. PGES in these patients may be a sign of deeper coma, delayed arousal, and a predisposition to SUDEP [65]. Another study compared secondarily generalized convulsive seizures with and without PGES, and found that oxygen desaturation duration and extent as well as peak end-tidal CO2 elevation was greater in patients with PGES [16]. A recent study however failed to find an association between PGES and SUDEP, where they found no significant differences in the presence or duration of PGES between 17 SUDEP cases and matched controls [66]. Several studies have shown that PGES occurs less frequently in pediatric [23,67] as compared to adult seizures [63]. This association of age with PGES may indicate that a developing pediatric brain is
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Fig. 4. Postictal Generalized EEG Suppression (PGES). This figure shows an example of suppression of EEG activity immediately following the ending of a seizure.
less likely to manifest PGES than the mature adult brain, and it may also indicate that to the extent that PGES plays a role in causing SUDEP, it may not be due to “cerebral exhaustion” but due to the existence of a possible “controlling network” inside the brain stem that is activated by seizure activation [23,66].
age, of the male gender, on multiple AEDs, and who have longerduration, temporal lobe, symptomatic generalized seizures. 3. These patients may need additional monitoring, such as additional EEG electrodes, a more careful assessment of their O2 and end-tidal CO2 levels, and EKG monitoring.
4. Conclusion In this paper, we have detailed the type of cardiorespiratory changes that take place in patients with epilepsy in relation to seizures, and how these changes may relate to an increased risk of sudden death in epilepsy. When indicated, patients undergoing sleep studies in patients with epilepsy should have additional EEG electrodes to localize and lateralize seizures, and assess the effect of these seizures on cardiorespiratory functions, including oxygenation and end-tidal CO2. Similarly, in patients undergoing video-EEG monitoring in the epilepsy telemetry unit, additional channels may be supplemented to assess their oxygenation and respiratory effort during and after seizures, especially when these patients experience apneas, or prolonged desaturation during or after their seizures. In those patients who have obstructive apneas, appropriate interventions such as the use of continuous positive airway pressure (CPAP) could be carried out and those who have significant desaturations or central apnea could benefit from a trial of SSRIs. These patients also need more careful monitoring such as the insertion of pacemaker for any possible cardiac asystole, home monitoring in bed, checking for supine position, and maintaining an elevated head position during sleep. 4.1. Practice points for the clinician 1. Sleep physicians need to be aware of potential cardiopulmonary complications in their epilepsy patients when they come for sleep studies. 2. Certain types of patients are potentially more likely to experience these cardiopulmonary complications – those of younger
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.08.005.
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Contents lists available at ScienceDirect
Sleep Medicine 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 / s l e e p
Review Article
Cardiorespiratory abnormalities during epileptic seizures Sanjeev V. Kothare a,1,*, Kanwaljit Singh a,b,1 a b
Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Medical Center, New York, NY, USA Department of Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA, USA
A R T I C L E
I N F O
Article history: Received 31 May 2014 Received in revised form 17 July 2014 Accepted 22 August 2014 Available online 3 September 2014 Keywords: Epilepsy Sudden death in epilepsy Cardiac abnormalities Respiratory abnormalities EEG
A B S T R A C T
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in young and otherwise healthy patients with epilepsy, and sudden death is at least 20 times more common in epilepsy patients as compared to patients without epilepsy. A significant proportion of patients with epilepsy experience cardiac and respiratory complications during seizures. These cardiorespiratory complications are suspected to be a significant risk factor for SUDEP. Sleep physicians are increasingly involved in the care of epilepsy patients and a recognition of these changes in relation to seizures while a patient is under their care may improve their awareness of these potentially life-threatening complications that may occur during sleep studies. This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Epilepsy affects nearly 1% of the general population [1,2]. Epilepsy can be classified by seizure type, underlying causes, epilepsy syndromes, and by events taking place during the seizures. Seizure types are broadly classified by whether the source of seizures is localized (focal or partial seizures) or diffusely distributed (generalized seizures) in the brain. Generalized seizures can be further classified according to their effects (tonic–clonic seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures). Focal or partial seizures can be further classified into simple partial (where only a small part of the lobe is affected and the person does not lose awareness of the surrounding) or complex partial (a larger part of the hemisphere is affected and the person loses consciousness and awareness) seizures. Approximately 35% of individuals with epilepsy do not adequately respond to medications and are thus considered “medication resistant.” [3] Sudden death is 20–40 times more common in people with epilepsy (and especially so in poorly controlled seizures) as compared to people without epilepsy. Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in young and otherwise healthy adults with epilepsy (see below for further
details) [4,5]. SUDEP is much less frequently seen in children [6]. Epileptiform discharges are often activated by sleep and tend to occur 14 times more frequently in non-rapid eye movement (NREM) sleep than in wakefulness [7] and, therefore, sleep stage and sleep/ wake state may influence the likelihood for a seizure to occur, with seizures occurring most frequently in NREM sleep, followed by wakefulness, and less likely during rapid eye movement (REM) sleep [8]. As such, the deleterious effects of seizures and SUDEP are more likely to occur when patients emerge from the sleep state [9]. A significant proportion of patients experience cardiac/or pulmonary dysfunction due to seizures (details follow). These changes may worsen the seizure prognosis/outcome and are believed to be related to, at least in part, the occurrence of SUDEP. This paper details these cardiopulmonary changes that take place in relation to epileptic seizures and how these changes may relate to the occurrence of SUDEP. Sleep physicians are often involved in the care of epilepsy patients on an increasing frequency and a recognition of these changes in relation to seizures may improve their awareness of these potentially life-threatening complications that occur during sleep studies. 2. Respiratory changes during seizures
* Corresponding author. Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, NY, USA. Tel.: +646 558 0806; fax: +646 385 7164. E-mail address: [email protected] (S.V. Kothare). 1Drs. Singh and Kothare contributed equally and are co-first authors. http://dx.doi.org/10.1016/j.sleep.2014.08.005 1389-9457/© 2014 Elsevier B.V. All rights reserved.
The respiratory center [10] (Fig. 1) consists of four nuclei located in the medulla oblongata and pons of the brainstem. The inspiratory center (also known as the dorsal respiratory group) is located in the dorsal portion of the medulla oblongata and causes
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Fig. 1. Respiratory centers of the brain. Figure sourced from Wikimedia commons and republished under the Creative Commons Attribution 3.0 Unported license. (http://commons.wikimedia.org/wiki/File:2327_Respiratory_Centers_of_the_Brain.jpg).
inspiration when stimulated. The expiratory center (ventral respiratory group) is located in the anterolateral part of medulla oblongata, anterolateral to the inspiratory center. The pneumotaxic center is located in the upper part of pons and it controls the rate and pattern of breathing. This center is inhibited by impulses from the ventral respiratory group. The apneustic center is located in the lower part of pons. This center discharges stimulatory impulses to the dorsal respiratory group to stimulate inspiration, discharges inhibitory impulses to the ventral respiratory group to inhibit expiration, and receives inhibitory impulses from the pneumotaxic center and from the lung stretch receptors – thus in turn limiting inspiration. An abnormal input to these respiratory centers during seizure-associated neuronal activation leads to many of the respiratory changes observed with seizures. Respiratory changes occurring in relation to seizures are seen with generalized as well as focal seizures, especially those arising from the mesial temporal structures. These changes have been repeatedly demonstrated in numerous studies and include central and
obstructive apneas, hypoventilation, hypercapnia, and desaturation with acidosis, bradypnea, and tachypnea [11]. Most important of these changes is the respiratory depression causing central apnea. Figure 2 depicts tachypnea accompanying a tonic seizure followed by postictal central apnea, which could be a mechanism for SUDEP, especially if the patient was in prone position and the apnea was prolonged. Much of the research evaluating the occurrence of respiratory changes in seizures has been done in adults. Bateman et al. (2008) prospectively analyzed the occurrence of ictal hypoxemia in localization-related epilepsy in 56 patients with 304 seizures [13]. They found that ictal hypoxemia was associated with seizure localization (temporal seizures), lateralization (right-sided seizures), male gender, longer seizure duration, and contralateral spread of seizures. Tezer et al. (2009) in a case–control study on two patients reported that apneas were associated in patients with right temporal and paracentral epilepsy [14]. Seyal et al. (2010) reported a severe and prolonged increase of ictal and postictal
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Fig. 2. Tonic seizure with hyperventilation and CO2 washout with central apnea at seizure termination in stage-2 sleep. Tonic seizure (solid arrow) with accompanying hyperventilation and CO2 washout (dashed arrow), with a central apnea at the termination of the tonic seizure in stage-2 sleep. Results suggest that patient lying prone and presenting with prolonged apnea after a seizure may be at an increased risk for SUDEP [12]. This modified montage could be used in the future to further assess the degree of hyper/hypoventilation during seizures.
expiratory carbon dioxide (ETCO2) in 187 seizures in 33 patients [15]. Seyal et al. (2012) also evaluated the occurrence of postictal generalized electroencephalography suppression (PGES) (cerebral shutdown) with respiratory abnormalities and found no association of PGES with postictal central apnea in 102 patients with localization-related epilepsy [16] (see below for more on PGES). In children, the weight of literature evaluating the occurrence of cardiopulmonary abnormalities with seizures is rather limited, with most studies being of a descriptive nature. Southall et al. (1987) reported the occurrence of apnea and hypoxemia in one pediatric patient with complex partial seizures [17]. Hewertson et al. (1994) reported the occurrence of hypoxemic apparent life-threatening events in 17 infants with partial seizures [18]. Hewertson et al. (1996) demonstrated the occurrence of hypoxemia/desaturation, apnea, and sinus tachycardia in the majority of 53 seizures in 10 children [19]. O’Regan and Brown (2005) demonstrated the occurrence of tachypnea, apnea, and hypoxemia in 101 seizures in 37 children [20]. Moseley et al. (2010) demonstrated the presence of ictal hypoxemia in generalized as compared to non-generalized seizures [21]. Singh et al. (2013) analyzed 101 seizures in 26 children and found an association of ictal apnea, bradycardia, and desaturation with younger age, male gender, and symptomatic generalized, left temporal longer-duration seizures [22]. Pavlova et al. (2013) compared 101 seizures in 26 children and 55 seizures in 22 adults and found that ictal apnea and bradycardia occurred more often in children with PGES occurred more often in adult seizures as compared to children [23].
Serotonin and breathing: Serotonin, a neurotransmitter, has been shown to affect brainstem respiratory center excitability. Changes in serotonin levels have been reported in patients with sudden infant death syndrome (SIDS) [24]. Mouse models of epilepsy have shown that selective serotonin reuptake inhibitors (SSRIs) (fluoxetine) reverses respiratory arrest in those animals [25]. Subsequently, a retrospective human study showed that medically refractory epilepsy patients taking SSRIs had reduced chances of ictal desaturation as compared to patients not on SSRIs [26]. The serotonin raphehippocampal pathway may be impaired in epilepsy as shown in a rat model of epilepsy [27] and it has been hypothesized that SSRI usage in epilepsy may help by enhancing the excitability of the brain respiratory centers. In summary, several respiratory changes occur during seizures as a result of abnormal neuronal activation of the respiratory center in the brain. The most serious of these changes are those associated with respiratory depression (such as hypoxemias and central apneas) most commonly observed in young men with symptomatic generalized, contralaterally spreading, left or right temporal, longer-duration seizures. 3. Cardiac changes during seizures Ictal autonomic changes can also cause cardiovascular manifestations [28]. Sympathetic responses are common during most seizures, causing tachycardia, and hypertension. Tonic–clonic
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Fig. 3. Interaction of sympathetic or parasympathetic systems causing cardiovascular manifestations during seizures.
seizures and complex partial seizures of temporal or extratemporal origin often lead to sympathetic activation. However, ictal parasympathetic activity or sympathetic inhibition can also occur, causing bradycardia and hypotension [29,30]. Combinations of sympathetic and parasympathetic activation and inhibition may occur simultaneously or sequentially during individual seizures. As with the research studies exploring cardiac changes in association with seizures, most have been done in adults. Figure 3 shows how the interaction of sympathetic and parasympathetic centers results in various cardiovascular manifestations during seizures. Moseley et al. (2011) analyzed autonomic changes in 218 seizures from 76 patients and reported the occurrence of ictal sinus tachycardia in 57% of seizures, who were on >3 antiepileptic drugs (AEDs) and experienced generalized seizures that had normal brain magnetic resonance imagings (MRIs) [31]. Ictal bradycardia was less common, occurring in 2% of seizures and was associated with seizure clustering, and a history of >50 seizures/month was reported. Surges et al. (2009) followed 74 subclinical seizures (electrographic seizures without clinical accompaniment) in 26 patients and reported insignificant changes in cardiac function during localized electrographic seizures [32]. Nilsen et al. (2010) on the other hand reported that pre-ictal tachycardia was associated with secondary generalization of seizures in 38 patients with partial epilepsy [33]. Surges et al. (2010) found an association with ictal and postictal tachycardia, postictal heart rate variability, and abnormal QTc shortening with secondary generalization in 25 patients with medically refractory temporal lobe epilepsy [34]. In children, Hewertson et al. (1996) demonstrated the occurrence of ictal tachycardia in the majority of 53 seizures recorded in 10 patients [19]. Singh et al. (2013) reported the occurrence of ictal bradycardia in association with younger age, male gender, and symptomatic generalized, left temporal-onset longer-duration seizures [22]. Pavlova et al. (2013) reported that ictal bradycardia occurred more commonly in seizures in children as compared to adults [23].
3.1. Other cardiac changes during seizures Other cardiac abnormalities that may occur include asystole, repolarization anomalies (prolonged or shortened QTc interval), and atrial fibrillation. These possibly may arise from seizures arising from the insular cortex. Seizure-induced cardiac asystole has been reported in some studies. Sehuele et al. (2007) assessed 6827 patients undergoing longterm video-EEG monitoring and ictal asystole was recorded in 10 patients (0.27%), the majority of them (8/10) occurring in temporal lobe epilepsy patients [35]. Lanz et al. (2011) retrospectively analyzed the occurrence of cardiac asystole in 2003 epilepsy patients undergoing long-term EEG monitoring. Out of 2003 patients, only seven patients experienced asystole, all of them occurring in temporal lobe epilepsy patients [36]. Pathogenic cardiac repolarization has been described in epilepsy patients. Electrocardiography (EKG) indicators of abnormal cardiac repolarization during seizures (such as prolonged or shortened QTc interval) are risk factors for lifethreatening tachyarrhythmia and sudden cardiac death. Several studies have indicated the occurrence of peri-ictal QTc interval prolongation in >10% patients of epilepsy [34,37–39]. The co-occurrence of ictal hypoxemia has especially been shown to be a risk factor for prolonged QTc interval [40]. Peri-ictal shortening of QTc interval has also been reported, especially in relation to generalized tonic clonic seizures (GTCS) (Surges et. al 2010) [41]. Peri-ictal changes in heart rate variability have been described in relation to seizures and SUDEP. A recent case report of an epilepsy patient who died of SUDEP described the occurrence of a marked increase of pre-ictal parasympathetic activity and shortened QTc interval followed by a cluster of GTCS, PGES, asystole, and cardiac arrhythmias [42]. Complicating this picture, several antiepileptic medications can also lead to QTc interval abnormalities (QTc prolongation: pregabelin, lamotrigine, valproate, stiripentol, and ketogenic diet; QTc shortening: rufinamide, primidone, phenytoin, and carbamazepine) [43].
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In summary, several cardiac changes occur during seizures as a result of ictal autonomic dysfunction. Sympathetic responses (causing tachycardia and hypertension) are more common as compared to parasympathetic responses (causing bradycardia and hypotension). Younger age, male gender, multiple AEDs, and generalized, temporal lobe, and longer-duration seizures predispose patients to experiencing these cardiac alterations. 3.2. Genetic basis of cardiopulmonary changes in association with seizures A few studies have shown that mutations in genes could lead to predisposition to cardiopulmonary complications during seizures. For example, in mice models and in a human cohort study, mutations in potassium channel-coding genes (KCNQ1, KCNH2, and SCN5A) have been found to predispose a severe form of prolonged QTc interval, thus potentially predisposing the subjects to sudden death in epilepsy. KCNQ1 gene encodes for the cardiac KvLQT1 delayed rectifier channel. In mice, this channel is present in neurons of certain regions of the forebrain and brainstem. Seizures in this model might predispose cardiac arrhythmia [44]. Another study in mice has shown that mutations in Kv1.1 potassium channel-coding genes predisposed mice to early onset of epilepsy, fivefold increase in AV conduction blocks, bradycardia and premature ventricular contraction, and sudden death [45]. 3.3. Sudden unexpected death in epilepsy SUDEP refers to the sudden unexpected death of a seemingly healthy individual with epilepsy. SUDEP is defined as a “sudden, unexpected, witnessed or unwitnessed, non-traumatic and nondrowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration > 30 minutes or seizures without recovery in between) in which postmortem examination does not reveal a cause of death.” SUDEP is the most common cause of death that can be directly attributable to epilepsy [46]. SUDEP most often occurs at night, possibly during sleep [47]. The incidence of SUDEP is 1 in 1000 with epilepsy (general population 1 in 40,000), and 1 in 100–200 with refractory epilepsy, but is four times more likely in adults as compared to children [48]. While potential mechanisms have been postulated, a high seizure frequency remains the biggest conclusively substantiated underlying risk factor. Cardiac arrhythmias [49], respiratory abnormalities [50], or a combination [9,51,52] have been postulated in the causation of SUDEP [53]. The role of breathing in the mechanisms of SUDEP has been understudied and is probably underestimated. Studies have shown age to have a strong effect on the rate and severity of respiratory abnormalities with obstructive sleep apnea syndrome being more common in older individuals [7,54], and more severe after the age of 50 [7]. The peak age for SUDEP in adults, however, is between 20 and 40 years [55]. Given the increased incidence of obstructive sleep abnormalities with age, we believe that the seizure-related breathing disturbances also differ by age group. The interaction between seizures, sleep, and cardiopulmonary function is an important, yet understudied area of investigation and is a growing area of research in epilepsy. A better understanding of mechanisms and association of these cardiorespiratory abnormalities in seizures may offer better insights to causes and, potentially, a better prediction of patients who might experience SUDEP. A recent study [56] collected data from four case–control studies to increase the power to identify risk factors for SUDEP [57–60]. The following risk factors for SUDEP (in 289 cases and 958 living controls) with epilepsy were identified: 1) Multiple (more than three) GTCS per year, 2) multiple AEDs, 3) epilepsy duration, 4) childhood onset of epilepsy, 5) male gender, and 6) symptomatic
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epilepsy. The risk for SUDEP was 37 times greater in persons with early onset of epilepsy (younger than age 16) and eight times in those whose epilepsy began at age 16 or older compared to healthy controls. Although the peak incidence of SUDEP is between ages 20 and 40 years, the study implied that it is those patients who had early onset of epilepsy are more susceptible to developing SUDEP later on in their life. A reanalysis of the data used in the abovementioned study showed that of these six risk factors, the effect of all five tended to decrease once the effect of GTCS frequency was taken into account, meaning that GTCS frequency remained the most important risk factor for SUDEP [61]. Another recently published, large, multicenter study (the Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS) study) performed a comprehensive evaluation of cardiorespiratory arrests in 29 epilepsy patients who died subsequent to an admission to epilepsy monitoring units [62]. This study showed that patients who had subsequently died due to cardiorespiratory arrest had an early postictal tachypnea induced by a generalized tonic clonic seizure followed within 3 min by transient or terminal cardiopulmonary dysfunction (apnea and/or bradycardia culminating in asystole). Where transient, this dysfunction later recurred with terminal apnea and cardiac arrest within 11 min of the end of seizure. There is not a single mechanism to explain the mechanisms of SUDEP. Potential mechanisms may include: 1) cardiac arrhythmias (possibly related to the cardiovascular effects of insular cortex), 2) ventilatory impairment, prolonged apneas, or oxyhemoglobin desaturations triggered by seizures, 3) impaired righting responses leading to suffocation (most patients with SUDEP have been found to be in the prone position), 4) autonomic instability during or after a seizure, and/or 5) postictal serotonin (5-HT) neuronal dysfunction causing depression of breathing, impaired arousal, and repositioning reflexes. Cerebral shutdown is a yet another putative mechanism causing SUDEP that has been put forward. PGES (Fig. 4), which is a hallmark of cerebral shutdown, is defined as the immediate postictal (within 30 s), generalized absence of electroencephalographic activity >10 μV in amplitude, allowing for muscle, movement, breathing, and electrode artifacts [63]. Prolonged PGES may be an independent risk marker for SUDEP. Lhatoo et al. (2010) showed that PGES >50 s increased the risk for SUDEP by a significant margin, and each 1-s increase in PGES duration increased the risk for PGES by 1.7% [63]. It is however not clear whether PGES is an indirect or direct marker of cerebral dysregulation. A recent study examined the relationship between sympathetic and parasympathetic changes (as measured by electrodermal activity and heart rate variability) and PGES in seizure patients, and found that the increase in electrodermal activity response amplitude and decreased parasympathetic modulated power of heart rate variability were directly correlated to prolonged PGES [64]. Therefore, it may be presumed that PGES may serve as a marker of postictal autonomic dysregulation. In another study, 13 patients with PGES and GTCS were compared to 12 random controls, and it was found that patients with PGES were more likely to be motionless postictally and were more likely to have resuscitative interventions (such as suction, oxygen administration, and position altered) performed. PGES in these patients may be a sign of deeper coma, delayed arousal, and a predisposition to SUDEP [65]. Another study compared secondarily generalized convulsive seizures with and without PGES, and found that oxygen desaturation duration and extent as well as peak end-tidal CO2 elevation was greater in patients with PGES [16]. A recent study however failed to find an association between PGES and SUDEP, where they found no significant differences in the presence or duration of PGES between 17 SUDEP cases and matched controls [66]. Several studies have shown that PGES occurs less frequently in pediatric [23,67] as compared to adult seizures [63]. This association of age with PGES may indicate that a developing pediatric brain is
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Fig. 4. Postictal Generalized EEG Suppression (PGES). This figure shows an example of suppression of EEG activity immediately following the ending of a seizure.
less likely to manifest PGES than the mature adult brain, and it may also indicate that to the extent that PGES plays a role in causing SUDEP, it may not be due to “cerebral exhaustion” but due to the existence of a possible “controlling network” inside the brain stem that is activated by seizure activation [23,66].
age, of the male gender, on multiple AEDs, and who have longerduration, temporal lobe, symptomatic generalized seizures. 3. These patients may need additional monitoring, such as additional EEG electrodes, a more careful assessment of their O2 and end-tidal CO2 levels, and EKG monitoring.
4. Conclusion In this paper, we have detailed the type of cardiorespiratory changes that take place in patients with epilepsy in relation to seizures, and how these changes may relate to an increased risk of sudden death in epilepsy. When indicated, patients undergoing sleep studies in patients with epilepsy should have additional EEG electrodes to localize and lateralize seizures, and assess the effect of these seizures on cardiorespiratory functions, including oxygenation and end-tidal CO2. Similarly, in patients undergoing video-EEG monitoring in the epilepsy telemetry unit, additional channels may be supplemented to assess their oxygenation and respiratory effort during and after seizures, especially when these patients experience apneas, or prolonged desaturation during or after their seizures. In those patients who have obstructive apneas, appropriate interventions such as the use of continuous positive airway pressure (CPAP) could be carried out and those who have significant desaturations or central apnea could benefit from a trial of SSRIs. These patients also need more careful monitoring such as the insertion of pacemaker for any possible cardiac asystole, home monitoring in bed, checking for supine position, and maintaining an elevated head position during sleep. 4.1. Practice points for the clinician 1. Sleep physicians need to be aware of potential cardiopulmonary complications in their epilepsy patients when they come for sleep studies. 2. Certain types of patients are potentially more likely to experience these cardiopulmonary complications – those of younger
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.08.005.
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