Witnessed SUDEP cases

Witnessed SUDEP cases are infrequent. In a study of 15 witnessed SUDEP cases, 12 occurred in association with a GTCS.11 In two cases, the patient was postictal, and in one case, the patient was suspected to have an aura preceding death. In 12 cases, witnesses commented that the individuals had difficulty breathing, suggesting a respiratory component to the cause of death. Seven of the 15 cases occurred while in bed, suggesting that sleep and the patient's level of arousal and the position of the face, mouth and chest may predispose epilepsy patients to SUDEP.11

Video EEG-monitored SUDEP cases

Fortunately, EMU SUDEP cases are extraordinarily rare. In two cases, death occurred after GTCS triggered respiratory dysfunction, hypoxaemia and cardiac events.20 ,21 In another case, seizures followed by asphyxia while in the prone position led to death.22 In other cases, postictal cessation of cerebral function was followed by cardiorespiratory failure.23 ,24 Although these case reports are limited, their conclusions were supported by the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS),25 a retrospective review of SUDEP and near-SUDEP cases from 147 EMUs across the world. This study detailed the events surrounding 16 SUDEP cases, of which 11 had VEEG at the time of death. In all 11 monitored cases, GTCS immediately preceded death. Of the 14 SUDEP cases for which position of the patient could be assessed, 13 were in the prone position at the time of cardiorespiratory arrest, often with the face partly tilted to one side.

It was not possible to evaluate cardiac or respiratory activity during the fatal seizure for any of the patients. Among the 11 VEEG monitored cases, there were nine patients in whom heart rate and breathing movements could be assessed by an expert panel from the time the GTCS ended until death occurred. Seizures were followed by a short period of normal or increased heart and respiratory rates, after which there was “early postictal parallel collapse of respiratory and cardiac rates, which was observed in every patient during the first 3 min postictally”. This was accompanied by postictal generalised EEG suppression (PGES). The early cardiorespiratory collapse was terminal in three of the patients. In the remaining six patients, there was transient restoration of cardiac function associated with abnormal and possibly ineffective respiration, likely aggravated by the prone position. Respiration then progressively deteriorated until terminal apnoea occurred, followed by terminal asystole. In every case, terminal apnoea occurred first, and the heart rate continued for a variable period of time before terminal asystole (figure 1). Analysis of individual cases reveals that in many patients breathing was markedly abnormal or absent for long periods during which there was a heart rate that could often be normal for a significant period of time (figure 2). These data must be interpreted with the understanding that blood pressure was not measured and it is possible that there was some ventilation that occurred but was not seen on videotape.

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Figure 1

Patterns of postictal cardiorespiratory functions in video EEG-monitored sudden unexpected death in epilepsy (SUDEP) cases. Nine cases of SUDEP demonstrating the individual patterns of postictal cardiorespiratory function before death are illustrated. Transient episodes of apnoea (>10 s), asystole (>5 s) and bradycardia (<45 bpm) are shown, together with terminal apnoea and asystole. Cardiorespiratory abnormalities were always observed during the first 3 min postictally, often concomitantly. In each case, terminal apnoea proceeded terminal asystole for varying lengths of time. From Ryvlin, Lancet Neurology, 2013.25

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Figure 2

Cardiorespiratory function in video EEG-monitored sudden unexpected death in epilepsy (SUDEP) cases. Individual patterns of postictal cardiorespiratory functions from SUDEP cases, starting from the end of each fatal seizure, in patients with video EEG-monitored SUDEP for which both respiration and heart rates could be measured by an expert panel. The black arrows indicate the early postictal collapse of respiratory and cardiac rates during the first 3 min postictally, leading to immediate death in three patients (A–C). A similar pattern was observed in another case (D) for which transient arrest of recording occurred. In other cases (E–I), cardiorespiratory functions were transiently and partially restored, until terminal apnoea occurred, followed by terminal asystole. From Ryvlin, Lancet Neurology, 2013.25

Seizure-induced respiratory changes

In 1899, Hughlings Jackson reported that, with “slight epileptic attacks, les petits maux, the patient ‘turns blue’ or ‘purple’”.26 Over the following century, the notion that seizures could impair breathing was supported by scattered reports describing hypoventilation (including apnoea) and oxygen desaturation in patients with either generalised or focal seizures.27–29 The frequency with which seizures result in respiratory dysfunction was not fully appreciated until recently, because hypoventilation (including apnoea) can easily go unnoticed unless respiratory parameters are directly measured. Respiratory monitoring has rarely been employed in EMUs. For example, none of the SUDEP cases in the MORTEMUS study included any measurements of breathing, even SaO₂. Recently, however, investigations that have employed respiratory monitoring techniques used in polysomnography, including the analysis of respiratory effort (using respiratory inductance plethysmography belts), oronasal airflow (using nasal pressure transducers and oronasal thermistry), SaO₂ and end tidal CO₂ (ETCO₂), have shed light on the frequency and severity of peri-ictal respiratory dysfunction.

It is clear from these studies that ictal respiratory dysfunction is common during seizures and can be severe. In a study by Nashef et al30, 10 of 17 (59%) patients undergoing long-term video EEG monitoring exhibited apnoea concurrent with seizures, with SaO₂ falling below 85% in six. More recently, Bateman et al31 analysed 304 seizures in 56 patients with intractable localisation-related epilepsy. In this cohort, SaO₂ decreased below 90% in 33.2% of seizures and below 70% in 3.6% of seizures. Desaturation was not limited to generalised seizures: indeed, the SaO₂ decreased below 90% in 34% of partial seizures. Central apnoea or hypopnoea occurred with 50% of 100 seizures in which nasal airflow and respiratory effort were measured, while mixed or obstructive apnoeas were present in 9% of seizures. Analysis of ETCO₂ levels in this study31 and in a subsequent one32 by the same investigators, revealed that seizures were frequently associated with severe and prolonged increases in ETCO₂ levels, to a level exceeding 50 mm Hg in 11 of 33 patients and in 35 of 94 recorded seizures. Other investigators have reported a similar frequency of ictal hypoxaemia in adults and children with epilepsy.33–35

Intrinsic pulmonary dysfunction

Interestingly, hypercapnia and oxygen desaturation appear in many patients to extend well into the postictal period, during which time respiratory effort has been reported to be qualitatively preserved or even increased, suggesting the possibility of intrinsic pulmonary dysfunction.32 ,36 Conceivably, seizures may cause ventilation/perfusion mismatch through alterations in pulmonary blood flow and/or venous return. In the absence of direct measurements of minute ventilation or blood gases, however, the evidence in support of the hypothesis that intrinsic pulmonary dysfunction is a major contributor to peri-ictal hypoxaemia, or to SUDEP itself, is currently circumstantial.

Pulmonary oedema of varying severity has been found on autopsy in many SUDEP cases.25 ,37–39 However, in the majority of cases, the oedema is mild and not felt to be significant enough to cause death.25 The aetiology of the oedema is not clear. Some have postulated that the oedema is a consequence of pulmonary vascular causes and terminal cardiac arrest.1

Prone positioning and postictal loss of arousal

Given the frequency and severity of seizure-induced respiratory abnormalities, it is perhaps surprising that death does not occur more often. If peri-ictal respiratory dysfunction is capable of causing death, what additional factors are required for SUDEP to occur? It may be that ictal respiratory dysfunction is only dangerous in certain circumstances. As noted above, patients who die of SUDEP are frequently found prone in bed.11 ,25 In such a position, the mouth and nose may be wholly or partly occluded, and it may take more muscular effort to expand the chest, increasing the risk of rebreathing or asphyxia if the patient fails to achieve arousal. As noted in the MORTEMUS study, “patients who died of SUDEP were not seen to take any corrective action to optimise their position and remained in the same position from seizure end until death”. The epilepsy patient has therefore apparently lost the normal arousability from hypercapnia,40 which should occur from seizure-induced hypoventilation. Possible mechanisms for this include suppression of brainstem arousal centres and loss of consciousness that occurs in GTCS and complex partial seizures. Serotonergic neurons in the midbrain contribute to the ascending arousal system, whereas serotonergic neurons in the medulla stimulate breathing.40–42 Both are activated by hypercapnia. Postictal depression of serotonergic activity could impair breathing and reflexive repositioning if the mouth and nose are obstructed by bedding.

Sleep and breathing

The temporal clustering of deaths at night25 also suggests the possibility that SUDEP risk is influenced by circadian or sleep-wake processes that influence breathing and vigilance.43 Breathing during sleep differs from that during wakefulness in a variety of ways that have the potential to increase risk. Breathing is inherently unstable at sleep onset as respiratory stimuli related to wakefulness and behavioural influences are withdrawn.44 Many otherwise healthy participants exhibit hypoventilation or frank apnoea during this transition. Sleep is associated generally with a reduction in the ventilatory response to hypoxia and hypercapnia as well as with a reduced response to ventilatory loading.45–47 Upper airway dilator tone also decreases during sleep (particularly rapid eye movement sleep), leading to obstructive apnoeas in susceptible individuals.48 Interestingly, recent studies suggest that sleep apnoea may be more common in patients with epilepsy49 ,50 and may be linked to poor control of seizures.51 Finally, circadian influences may also play a role in SUDEP. A circadian propensity to seizure occurrence has been shown in animals,52 while seizures themselves affect sleep-wake processes differently depending on their circadian timing.53 In addition, the circadian timing system plays an important role in modulating vigilance and control of breathing.54 ,55 To date, this area has received little attention.

Secondary cardiac effects from pulmonary dysfunction

Rather than being viewed as entirely ‘respiratory’ or ‘cardiac’ in aetiology, some deaths may reflect individual cardiac susceptibilities to peri-ictal respiratory dysfunction. Peri-ictal hypoxaemia has been shown to be associated with QT prolongation and shortening,56 suggesting that in some cases abnormalities in cardiac repolarisation may be induced by respiratory dysfunction. Similarly, hypoxaemia reliably leads to bradycardia when the patient is apnoeic.57 ,58 In a study performed in the 1940s,59 participants who fainted in response to acute hypoxia exhibited pronounced bradycardia, muscle vasodilation and apnoea, when compared with those who did not, providing an early illustration of individual differences in the response to acute hypoxia.60 Conceivably, the association between certain cardiac gene mutations and SUDEP risk may be partly mediated by cardiac susceptibility to peri-ictal respiratory dysfunction.

Collectively, these data indicate that peri-ictal respiratory dysfunction is common and can be severe, at least among patients admitted to inpatient EMUs.25 Little is known about the mechanisms responsible for this dysfunction. Peri-ictal hypoxaemia is associated with EEG evidence of contralateral spread61 as well as with PGES.36 Conceivably, these associations may reflect the spread of seizures into respiratory control centres of the brainstem.2 In the 1950s, it was shown that apnoea could be produced by the intraoperative stimulation of various targets within the frontal and temporal lobe.62 Whether a similar mechanism is responsible for peri-ictal respiratory dysfunction is not known.

Animal models of SUDEP and serotonin dysfunction as a molecular mechanism

Additional evidence supporting a respiratory mechanism for SUDEP comes from animal models and the study of the molecular mechanisms underlying the control of breathing. Some mouse species and genetically altered mice develop spontaneous or provoked seizures, which leads to death. These mouse models have allowed researchers to examine the cardiorespiratory events proceeding death. In both DBA/1 and DBA/2 mice, audiogenic seizures lead to respiratory arrest and death.63–65 In DBA/1 mice, seizure-induced death is prevented by resuscitation using a polyethylene tube placed over the nostrils of the mice and connected to a rodent respirator.63 In DBA/2 mice, similar findings are observed as oxygenation prevents death after seizure.64 Fluoxetine, which is a selective serotonin reuptake inhibitor, has been shown to reduce the incidence of respiratory arrest in DBA/166 and DBA/2 mice65 ,67 after audiogenic seizures, suggesting serotonin (5-HT) may play a role in the molecular mechanisms underlying seizure-induced hypoventilation. Additionally, 5-HT receptor expression in DBA mice exhibits abnormal levels, including reductions of 5-HT2C levels.68

5-HT neurons found in the medullary raphe act as central chemoreceptors that regulate PCO₂ and pH and project to key respiratory neurons throughout the brainstem to stimulate breathing.69 Lmx1b^f/f/p mice, which lack >99% of 5-HT neurons in the central nervous system by genetic deletion in utero, exhibit high rates of apnoea and death during the early postnatal period along with defects in arousal to an increase in ambient CO₂ during sleep.40 ,70 Compared to littermate controls, Lmx1b^f/f/p mice have a lower seizure threshold and increased seizure-induced mortality, suggesting that serotonin neurons raise the seizure threshold and decrease seizure-related mortality.71 Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of the Lmx1b^f/f/p mice as well as the littermate controls was reduced by mechanical ventilation during the seizure. Both of these findings suggest that death ensued first from respiratory failure, followed by terminal asystole. In another study, deletion of 5-HT_2c receptors in mice led to recurrent seizures and sudden death.72 These various rodent models suggest serotonin dysfunction may play a role in SUDEP. Translating these findings to humans, in a retrospective study of patients with medically refractory partial epilepsy, serotonin reuptake inhibitors were found to be associated with reduced severity of ictal hypoxaemia.73 Imaging findings help support a role for brainstem respiratory dysfunction in the pathophysiology of SUDEP. Compared to controls, MRI revealed greater volume loss in the mesencephalon in two individuals who died from SUDEP compared to 30 individuals with temporal lobe epilepsy (TLE).74

Summary

There is growing evidence supporting respiratory dysfunction as a cause of SUDEP. Although some have been long-time proponents of a respiratory dysfunction theory for SUDEP,30 this is a major divergence from the previous majority, which held that SUDEP was primarily due to cardiovascular dysfunction. Although serotonin has been implicated in mouse models of SUDEP, many questions remain regarding the potential mechanisms and triggering factors involved in peri-ictal hypoventilation that leads to death.

Seizure-induced cardiac changes

In the general population, sudden cardiac death has garnered considerable scientific and public attention. Unlike many sudden cardiac deaths, no structural cause of death can be found in SUDEP.10 However, seizures do induce a variety of transient cardiac effects. These include changes in heart rate, arrhythmias, asystole and various other ECG abnormalities, some potentially lethal. Additionally, epilepsy may predispose patients to cardiac autonomic dysfunction. Genetic diseases known to affect the heart may also result in epilepsy, predisposing certain epilepsy patients to SUDEP.

Seizures induce various transient heart rate changes. In a study by Opherk et al,75 of 102 seizures in 41 patients, 99% of the seizures led to an increase in heart rate. In this study, sinus tachycardia (HR>100 bpm) occurred in 100% of generalised seizures and 73% of non-generalised seizures. In a separate study by Leutmezer et al,76 of 145 seizures in 58 patients, tachycardia was observed in 86.9% of seizures. This was significantly more common with mesial TLE than with non-lesional TLE or extra-TLE. Including all studies, an increased heart rate has been recorded in 64–100% of seizures.76 Other than sinus tachycardia, ECG abnormalities have been observed in 21.5% of seizures and 37% of patients.34 These changes are mostly benign. Seizure-induced bradycardia is an infrequent event. In the study by Leutmezer et al,76 bradycardia was observed in only 1.4% of seizures. Overall, it occurs in less than 2% of all seizures. Ictal asystole (commonly defined as RR intervals longer than 3–5 s) is extremely rare. Only 5 of 1244 patients exhibited asystole concurrent with an ictal event.77 A retrospective study of 6825 patients undergoing long-term video EEG monitoring reported that ictal asystole occurred in only 0.27% of patients.78 The rarity of asystole does make it a rational candidate for a mechanism of SUDEP or at least a subset of SUDEP cases.

Seizures can induce other ECG abnormalities in addition to changes in heart rate. In a study of 102 seizures and 41 patients, only 6 seizures (6%) were associated with potentially serious ECG abnormalities occurring in only 4 patients (10%).75 These included ST segment depression and T-wave inversion. The benign abnormalities included premature atrial depolarisations, atrial bigeminy, premature ventricular depolarisations, ventricular couplets and first degree and second degree atrioventricular block, Mobitz I. In a study of 43 patients and 105 seizures, clinically significant ictal prolongation of the QTc interval using Bazett's formula was found in 16.2% of seizures, whereas shortened QTc intervals were observed in 4.8% of seizures.34

Unfortunately, many of these studies lacked measurements of respiratory rate, tidal volume, alveolar ventilation, oxygen saturation or other information about breathing. Therefore, it is unclear whether changes in heart rate, arrhythmias, asystole and other ECG abnormalities were secondary to seizure-induced respiratory changes. Hypoxaemia, hypoventilation and/or apnoea as well as other changes in breathing have known effects on heart rate and rhythm, likely through secondary autonomic changes. As discussed in the respiratory section, seizure-induced QT changes have been associated with seizure-induced hypoventilation and oxygen desaturation.56 Further supporting the suggestion that cardiac changes can sometimes be secondary to seizure-induced respiratory effects, in a study of over 250 seizures in 56 patients, one case of peri-ictal bradycardia was reportedly followed by asystole.31 In this case, the patient had concurrent oxygen desaturation to less than 50%, suggesting that bradycardia and asystole may have been secondary to hypoxaemia due to hypoventilation.

Heart rate variability

Heart rate variability (HRV) is a measure of the beat-to-beat variability of the heart and results from modulation of the sinoatrial node by the autonomic nervous system.79 Reduced HRV has been associated with increased cardiac mortality and sudden cardiac death.79 Studies have shown that HRV is reduced in people with poorly controlled epilepsy compared with well-controlled participants and normal controls.80 ,81 A separate study showed that TLE was associated with reduced HR variability, which was more pronounced during the night than during the day.82 However, unlike previous studies, the alteration in autonomic regulation of HRV was similar in patients with both refractory and well-controlled TLE.82 Another study, although limited by small sample size, compared seven SUDEP cases with seven age-matched controls and found no difference in HRV.83 Further study is needed to determine whether HRV plays a role in the pathophysiology of SUDEP or whether it may be a biomarker for SUDEP.

The cause of seizure-induced transient cardiac changes and reduced HRV is unclear, but is likely due to modulation of autonomic output. One possible mechanism is that seizures activate pathways that project to neurons in the brainstem that control autonomic output to the cardiovascular system.84 Others have suggested that transient cardiac effects and possibly reduced HRV are secondary to the response of the autonomic nervous system to apnoea and oxygen desaturation frequently seen in seizures.2 Further study of epilepsy patients and animal models is needed to define the mechanisms of seizure-induced cardiorespiratory effects, and the importance of these autonomic changes in the pathophysiology of SUDEP.

Molecular mechanisms—ion channels

Genetic mutations in ion channels that are expressed in the brain and heart may result in epilepsy. Evidence for this mostly comes from human genetic studies and rodent models containing these ion-channel mutations. In some of these mouse models, epilepsy occurs and seizures result in cardiac dysfunction that leads to death. Examples of these channelopathies include congenital long QT syndrome (LQTS), Dravet Syndrome and hyper-SUMOylation of Kv7 channels present in the brain.

LQTS is an inherited cardiac disorder resulting in abnormal cardiac ventricular repolarisation characterised by QT interval prolongation and abnormal T-waves.85 LQTS patients are susceptible to polymorphic ventricular tachycardia and torsades de pointes, resulting in syncopal episodes and even sudden cardiac death in young, otherwise healthy individuals. A total of 15 genes have so far been implicated in LQTS pathogenesis.86 However, 90% of the genetically identified mutations are found in three genes and their encoded proteins. Two are potassium channels, Kv7.1 (KCNQ1; type 1 LQTS (LQT1)) and Kv11.1 (KCNH2; type 2 LQTS (LQT2)) and one is a sodium channel, Nav1.5 (SCN5A; type 3 LQTS (LQT3)).86

These ion channels are expressed in the heart, and their mutations were first identified as causing cardiac pathology, but many of these proteins are also expressed in the brain. Some patients with congenital LQTS, especially LQT2, have syncopal episodes that appear seizure-like, suggesting that some patients may actually have epilepsy as well.87 In a study of 610 patients with LQTS, 10 (1.6%) patients were diagnosed with a seizure disorder by an epileptologist on the basis of clinical findings of seizures and EEG studies.86 Seven of the 10 patients had LQT2. Goldman et al88 studied a LQTS mutation in Kv7.1 in mice and found that this potassium channel was expressed in the heart as well as neurons in the brain. EEG recordings from these mice revealed epileptiform discharges and appeared to have spontaneous seizures.

In summary, patients with congenital LQTS have increased risk of sudden death, and some patients with LQTS have been found to have epilepsy.86 However, it is unclear whether patients with congenital LQTS and epilepsy are at increased risk of SUDEP. Additionally, it is uncertain how many patients in previous SUDEP reports had concurrent congenital LQTS.

Dravet syndrome is a rare disorder that results in severe childhood-onset epilepsy characterised by febrile and afebrile, generalised and unilateral, clonic or tonic–clonic seizures that occur in the first year of life.89 As the children age beyond 1 year, they develop myoclonus, atypical absence and partial seizures. Unfortunately, all seizure types are resistant to AEDs and therefore risk of SUDEP is high, probably more than other infantile epilepsies, often occurring in young children (<5 years) but also in adults. Developmental delay becomes apparent within the second year of life and is followed by cognitive impairment and personality disorders.89 80% of patients with Dravet syndrome have a mutation in SCN1A, the gene that encodes the sodium channel Na_v1.1 that is present in the brain and heart.

A mouse model of Dravet syndrome (Scn1a heterozygous KO) recapitulates components of the human phenotype including epilepsy, and provides an avenue for understanding the pathophysiology of SUDEP.90 These mice have suppressed interictal resting HRV, episodes of ictal bradycardia that correlate with tonic phases of GTCS and death after prolonged ictal-onset bradycardia. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in the Scn1a heterozygous DS mice. Muscarinic antagonists decrease bradycardia and seizure-induced death, suggesting that vagal parasympathetic output may cause lethal bradycardia in SUDEP.90 However, because the study of this mouse model lacked respiratory monitoring during seizures, it is unclear if this mutation led to worsening respiratory dysfunction, and, additionally, whether these cardiac findings were secondary to seizure-induced hypoventilation and/or apnoea and oxygen desaturation. As discussed previously, apnoea associated with oxygen desaturation can lead to bradycardia.

Other ion channel modifications that result in epilepsy in mice have been discovered. Qi et al91 showed that deletion of SENP2 in the mouse brain resulted in hyper-SUMOylation of Kv7 channels. These mice developed spontaneous seizures, which resulted in cardiac abnormalities and death. Again, respiratory monitoring was not performed during seizures and the period of time proceeding death. Therefore, it is unclear whether apnoea and oxygen desaturation resulted in these cardiac changes, or whether the apnoea and oxygen desaturation was more severe because of the mutation.

Summary

Cardiac changes occur during seizures. Increasing evidence suggests genetic mutations in ion channels, present in the brain and heart, may increase the risk of epilepsy and SUDEP. Although rodent models with these genetic mutations demonstrate cardiac changes during seizures prior to death, it is unclear whether these cardiac events are caused by hypoventilation and oxygen desaturation during seizures. Future studies using a combination of cardiorespiratory monitoring in SUDEP animal models, similar to the study by Buchanan et al,71 will help clarify these issues.

Adenosine

Adenosine is a modulator of synaptic transmission and neuronal activity, exerting most of its functions via activation of the excitatory and inhibitory adenosine receptors.95 Additionally, adenosine may have effects on brainstem mediated cardiorespiratory function.94 In a study by Shen et al,94 mice were treated with pharmacological inhibitors responsible for metabolising adenosine, after which seizures were induced. These mice were protected from seizures for the first 15 min, but eventually developed seizures and died. If the mice were treated with caffeine (an adenosine receptor antagonist) at seizure onset, however, their survival time was significantly increased compared with their untreated counterparts. Shen and colleagues concluded that adenosine may contribute to seizure-induced death. More research is required on the effects of caffeine on cardiorespiratory function in the peri-ictal period in mouse models.