All-cause mortality rates in patients with epilepsy are approximately two to three times higher than the general population and are age dependent.¹^–³ The major contributors of increased mortality are the causes of epilepsy, for example, traumatic brain injury, cerebrovascular disease, brain tumors, and accidents (mostly falls and drowning) or status epilepticus and SUDEP. In contrast, treatment-related mortality, from epilepsy surgery or the adverse effects of antiepileptic medication, is very rare.⁴

SUDEP is defined as the sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy with or without evidence for a seizure and excluding documented status epilepticus, in which postmortem examination does not reveal a structural or toxicologic cause for death.⁵ Where autopsy is not performed, and for the purpose of epidemiological studies, sudden death occurring in benign circumstances with no known competing cause for death is classified as “probable SUDEP.” Cases classified as “possible SUDEP” are usually not included in epidemiological studies of SUDEP incidence. These are cases in which SUDEP cannot be excluded because either the information regarding circumstances of death is too limited to confirm classification as a probable or definite SUDEP or that adequate or complete documentation is available but there is a plausible competing explanation for the death.³ It must be stressed that this defines a category of sudden death in epilepsy, and not a condition, a concept that is sometimes overlooked. Despite an applicable definition, and clear guidance where there is uncertainty, significant variability in use has hampered efforts to integrate findings from multiple studies on epidemiological and risk factor data and hence establish common relevant factors.^6,⁷

Epidemiology

Sudden unexpected death in the general population is extremely rare in young adults with an incidence of 5 to 10/100, 000 person-years, whereas the rate climbs steeply with advancing age to approximately 300/100, 000 person-years in the elderly.⁸ The incidence of sudden death in patients with epilepsy is significantly higher and varies markedly with the population studied.⁹ For example, in population-based studies, the incidence has been reported to be 0.35 and 2.7/1000 person-years, depending on the methodologies employed.^10,¹¹ This increases to between 2 and 5.9/1000 person-years in cohorts of patients attending specialist epilepsy clinics,¹²^–¹⁴ 3.4/1000 person-years in pupils with epilepsy enrolled in a special residential school,¹⁵ and up to 9.3/1000 person-years in epilepsy surgery candidates.^16,¹⁷ The incidence of sudden death in young adults with intractable epilepsy is, therefore, many times that of the general population, with a peak between the ages of 20 and 40 years.¹⁸ In older age groups, the relative increased incidence of SUDEP is too small to measure and is confounded by the occurrence of comorbidity such as cardiovascular, respiratory, or cerebrovascular disease. This makes it difficult to ascribe a sudden death to a “pure” SUDEP category but does not exclude the possibility that there is no additive risk from the epilepsy. There is limited data available on the incidence of SUDEP in children. An incidence rate of approximately 0.1 to 0.2/1000 person-years has been estimated from a number of earlier studies.^19,²⁰ Significant methodological limitations exist, however, including inadequate follow-up periods, difficulties with case-ascertainment, and assumptions regarding the prevalence of epilepsy in community-based studies. A more recent retrospective study with an 18-year follow-up period confirmed a low incidence rate of approximately 0.4/1000 person-years, despite following a cohort of children with refractory epilepsy and learning disability.²¹ This is approximately 10 times lower than the incidence rate for similarly affected adults; the rate for children with uncomplicated epilepsy will be lower still.²² The reason for the discrepancy between children and adults is unknown and is unlikely to be entirely due to methodological constraints, but may be as a result of a different cardiorespiratory response from a developing brain compared to a mature brain, a more intensively supervised environment, the inclusion of specific self-limiting pediatric epilepsy syndromes, lack of comorbidity, or possibly, greater autonomic stability.²³

Risk Factors

There is significant debate regarding risk factors for SUDEP. A large number of variables that may influence the risk of SUDEP have been proposed, and the significance of each has been discussed at length without clear consensus. Relevant and independent risk factors are difficult to establish given the nonindependence of patient, syndrome, seizures, and treatment characteristics. Multiple logistic regression analyses require large cohorts of patients to achieve statistical significance for each of the variables evaluated, and this is difficult to attain.²⁴ Furthermore, the high variability between studies in terms of patient cohorts, definition, choice of control group, methodology, and overall study quality precludes not only a valid meta-analysis, but even a simple meaningful comparison. In a critical review of the literature regarding risk factors for SUDEP, Tellez-Zenteno noted that a clear definition of SUDEP was stated in only 65% of relevant studies. Furthermore, the low frequency of postmortem data was evident in many studies. This lack of consistency significantly undermines the suitability of such studies to comment on SUDEP causality and risk.⁷ The preliminary studies of risk factors in SUDEP were descriptive, providing direction for more meaningful case-control studies. The value of these observations, otherwise, is limited, however, because, in general, these studies lack suitable control groups and comprise small numbers of an often highly selected patient population.

In case-control studies, the choice of control group is important and is dependent on the risk factors to be evaluated. A control group of matched living patients with epilepsy tends to favor the assessment of risk factors exploring lifestyle and clinical issues such as seizure frequency and antiepileptic drug use. A control group of non-SUDEP deaths in epilepsy is more suitable for exploring circumstances of death, such as body position, place of death, and seizures immediately prior to death.

A number of studies assessing risk factors used a case-control design (Table 15-1), this often being the only option for the study of relatively uncommon occurrences, such as SUDEP. However, it also has important limitations. For example, case-control studies traditionally evaluate the probability of being exposed to a risk factor, not the risk of developing a condition. Moreover, case-control studies are subject to several sources of bias, such as selection bias of cases and controls and information and recall bias when collecting data on exposure. These biases are particularly important where an objective definition of the condition of interest is not consistently applied, as is the case in the SUDEP literature.

TABLE 15–1 Case-control and Nested Case-control Studies Examining Risk Factors for SUDEP

An attempt has been made to resolve the SUDEP risk factor literature and disentangle the often contradictory results on the basis of extensive literature reviews and the implementation of a study-validity scoring system and calculation of relative risk factor ratios.⁶ Monte and colleagues stratified studies evaluating risk factors on the basis of fulfillment of a number of variables that were considered to be markers of good quality studies. However, the scoring system used was unvalidated and potentially misleading, with, for example, equal credence attributed to controlled and descriptive studies. Papers not achieving an arbitrary threshold were excluded, and the possibility of the same study population being used more than once was not adequately addressed.⁶ A more simplistic approach was used by Tellez-Zenteno, in which percentages of studies with a positive risk factor were reported. Risk factors that were reported to be significant in more than 50% of studies were a terminal seizure, subtherapeutic antiepileptic drug (AED) levels, high seizure frequency, and a high number of AEDs.⁷

DEMOGRAPHICS

Descriptive studies have almost universally reported that patients with SUDEP are young adults.^10,^11,^13,^14,²⁵^–²⁹ A number of biases exist, however, including, as discussed earlier, the exclusion of patients with significant comorbidity associated with increasing age, such as ischemic heart disease or cerebrovascular disease, identified on postmortem examination.^13,^25,²⁹ Other examples of bias include case identification through self-referral by bereaved relatives, most commonly parents,²⁷ and studies with only small numbers of patients.^10,¹³ Case-control studies are less conclusive. Some studies only included defined age groups and can draw no conclusions regarding other age groups. Nevertheless, it is interesting to note that 70 to 80% of the studied population in a number of case-control studies were less than 45 years old.^18,³⁰ Data regarding age, however, is not available from a number of large studies due to age matching of control subjects.^18,^30,³¹

Of the remaining studies, the use of a cohort of non-SUDEP deaths as a control group may bias the patient group toward a younger age due to exclusion of comorbid conditions more commonly associated with advancing age, such as atherosclerosis, thromboembolism, and metastatic carcinoma,³²^–³⁵ although young age as an independent risk factor has not been universally reported.^36,³⁷ The likelihood of selection bias is corroborated by finding significantly less comorbidity in the SUDEP group than the non-SUDEP group.³⁵ In studies using living control subjects, younger age was not seen more frequently in the SUDEP group, although numbers of SUDEP patients were small.¹²

Although a large number of descriptive studies have suggested that male gender is a significant risk factor for SUDEP,^11,^13,^26,^29,³⁸ this has not been confirmed by the vast majority of case-control studies.^{30–33,35–37}^,39 In addition, a small number of both descriptive and case-control studies have reported a significantly increased standardized mortality rate in female patients, which may be attributable to a lower background rate of death in the female non-SUDEP control group.^10,³⁴

In summary, although not universally accepted, the weight of evidence at the present time suggests that sex is not a strong risk factor for SUDEP. With regard to age, incidence appears lower in children than young adults. Methodological constraints, selective definition, coexisting pathology, the absence of suitable control subjects, and lack of controlled prospective data do not allow any conclusions to be drawn regarding incidence of sudden death related to epilepsy in older age groups.

EPILEPSY CHARACTERISTICS

A number of case-control studies have suggested that early onset of epilepsy is a significant risk factor for SUDEP.^30,^33,^35,³⁶ For example, Nilsson reported an eightfold higher SUDEP risk in patients with an onset of epilepsy between the ages of 0 and 15 years, compared to patients with seizure onset after 45 years of age.³⁰ However, whereas this may reflect a different etiological basis for the epilepsy, it may also merely be a surrogate marker for an increased cumulative lifetime risk of having seizures for a longer period of time, as suggested by other studies.^18,^28,²⁹ Conversely, several reports give a shorter duration of epilepsy being associated with an increased risk of SUDEP, although this is most likely as a result of comparison with an older control population.^32,^33,³⁵ Furthermore, following conditional multiple logistic regression analysis, Walczak showed that a long duration of epilepsy (>30 years) was no longer a risk factor after adjustment for seizure frequency.³⁷

One would expect epilepsy syndrome to be a key factor in defining the risk of SUDEP. Yet, there is only limited evidence to support the association of epilepsy syndrome with an increased risk of SUDEP.^30,³⁶ Discordant results from the relatively few case-control studies that assessed this risk factor and low numbers of patients in each group preclude detailed evaluation or definitive conclusions.³⁴ In the study reported by Nilsson, 7 out of 57 (12%) SUDEP cases had primary generalized epilepsy compared to 12 out of 171 (7%) control subjects. Statistical comparison revealed that there was a higher risk of SUDEP in patients with primary generalized epilepsy compared to patients with focal, symptomatic epilepsy, although this was only significant in men.³⁰ Nevertheless, although idiopathic primary generalized epilepsy (IGE) is usually less refractory to treatment, individuals with IGE are well represented in SUDEP cohorts. It is possible that specific epilepsy syndrome subtypes carry an increased risk of sudden death due to phenotypic expression in other cerebral and possibly cardiac structures. For example, Rett syndrome, typically due to mutations in the MECP2 gene, is associated with brain stem immaturity and autonomic, particularly respiratory, instability in association with epilepsy. In addition to respiratory abnormalities, which include apneustic breathing and hyperventilation, patients with Rett syndrome may also present with a prolonged QT interval and reduced heart rate variability.⁴⁰ The coexistence of cardiac arrhythmia and central apnea may act synergistically in the development of sudden death. Severe myoclonic epilepsy in infancy (SMEI) also appears to be associated with an increased risk of sudden death, although the pathophysiological mechanism remains unclear. A recent report of a pedigree with an SCN1A mutation and two cases of SUDEP is of interest in this respect.⁴² Although some of these conditions represent the most severely affected group of patients and the high mortality rate may be multifactorial, it is possible that more subtle genetic abnormalities, such as channelopathies in, for example, IGE, may also predispose patients to SUDEP. In this regard, it is important to note that a number of functional cardiac conduction abnormalities, such as long QT syndrome, are also channelopathies, and genetic susceptibility is also well documented in sinus node dysfunction and bradyarrhythmias.⁴³ However, no epidemiologic data indicate a higher incidence of epilepsy among relatives of patients with inherited susceptibility to arrhythmia, and a family history of early sudden cardiac death is not reported in SUDEP series. Furthermore, malignant tachyarrhythmias are relatively uncommon in seizures, and ictal respiratory changes have been documented in the absence of cardiac abnormalities. The proposed cardiorespiratory mechanisms of SUDEP will be discussed in more detail later in the chapter. Clearly, scope exists for potentially useful epidemiologic studies looking at the incidence of epilepsy in families of sudden cardiac death victims; additionally, it may be helpful to study the incidence of syncope in patients with idiopathic epilepsy and their relatives.

Controversy exists on whether high seizure frequency is an independent risk factor for SUDEP. Several descriptive and large case-control studies have reported an increased risk of SUDEP in patients experiencing frequent seizures.^28,^30,^31,^33,^37,³⁸ This increased risk is most marked for convulsive seizures¹⁰^–¹² ^,27 ^,28 ^,31 ^,37 rather than nonconvulsive episodes, such as complex partial seizures.³³ Moreover, on logistic regression analysis, Walczak noted that only the frequency of convulsive seizures was relevant, and not the frequency of all seizures combined.³⁷ Conversely, high seizure frequency was not an independent risk factor in a number of other reports, although a number of methodological issues exist.^12,^29,^34,³⁶ For example, in a retrospective case-control study of 42 patients with SUDEP, reported by Kloster and Engelskjon, there was no reported difference in seizure frequency between the SUDEP and non-SUDEP control group. The study was undertaken at a tertiary referral center with both groups having chronic refractory epilepsy and frequent seizures.³⁶ Other negative studies may have been similarly influenced.³⁴ Intuitively, the severity of convulsive seizures may also be important in SUDEP, but this is more challenging to quantify and hence has not been evaluated as a risk factor.

In summary, with regard to epilepsy characteristics, the most important factor, on the basis of currently available data, is the frequency of convulsive seizures. Data with respect to seizure severity does not exist at the present time, whereas data regarding the influence of the pathogenesis of the underlying epilepsy and syndromic diagnosis are also limited to a small number of specific syndromes and requires further study.

ANTIEPILEPTIC MEDICATION

The number of antiepileptic medications (AEDs) taken concomitantly have been reported to be an independent risk factor for SUDEP,³⁸ even after correction for seizure frequency.^30,³⁷ This is not universally reported, however,^12,^18,³⁴^–³⁶ although small numbers of patients and a high frequency of polytherapy in control subjects may be contributory in these negative studies. Langan found that the risk of SUDEP increased with the number of AEDs previously taken, despite correction for seizure frequency, perhaps a surrogate for epilepsy severity. In addition, risk was also increased in those who had never been on AEDs. This is potentially an important group and needs further clarification. It may include those in whom the epilepsy is considered mild and treatment is not recommended, those who decline treatment, or those with recent onset epilepsy who have not yet been assessed or offered treatment. Risk of SUDEP is also increased in those whose treatment history was unclear, which may reflect the risk associated with the lack of treatment and uncontrolled seizures, although the reason for this was not objectively assessed.³¹

Despite several descriptive studies suggesting that subtherapeutic levels of AEDs are a risk factor for SUDEP,^10,^11,^25,²⁹ this has not been corroborated by the majority of case-control studies,^34,^44,⁴⁵ as it is difficult to study as an independent factor. Of note is that postmortem levels of AEDs may not accurately reflect antemortem levels possibly due to, for example, redistribution and continuing metabolism.⁴⁶ In a postmortem study reported by George and Davis, however, so-called subtherapeutic drug levels were detected in 69% of the 52 cases of SUDEP, in 75% of the eight cases where a seizure precipitated an accident causing death, and in 34% of the control population.⁴⁷ This suggests that the increased likelihood of a seizure associated with “subtherapeutic” AED levels, rather than the levels per se, drives the observed elevated mortality rate. Compliance with AED treatment was first proposed as a risk factor for SUDEP in an uncontrolled study by Leestma, who found subtherapeutic AED levels in 68% of SUDEP cases.²⁵ Therapeutic drug monitoring has traditionally been considered a surrogate for medication adherence, although due to the existence of a number of confounding factors, it is clear that the two terms are not interchangeable. For example, in patients with uncontrolled seizures, changes of dose and type of medication are commonplace, and serum levels will not be stable and may frequently be subtherapeutic, despite excellent compliance. More recent studies have attempted to address this by integrating additional clinical information, such as a previous history of noncompliance ²⁹ or an arbitrary judgment regarding the degree of compliance made by the treating physician.³⁴ Despite this, conflicting results have been obtained (Table 15-2). Of paramount importance, however, is the understanding that the evaluation of drug levels or noncompliance as independent risk factors for SUDEP must take into account the presence, frequency, and severity of seizures. The issue of variability of AED use was recently addressed in a study by Williams and colleagues comparing hair AED concentration variability in patients with SUDEP, non-SUDEP epilepsy-related deaths, epilepsy outpatients and epilepsy inpatients. The SUDEP group showed greater hair AED concentration variability than either the outpatient or the inpatient groups, reflecting variable AED ingestion over time. However, these variations cannot distinguish prescribed changes from poor compliance or identify consistent noncompliance over time. Second, it does not provide information on drug-taking behavior immediately before death, as it takes about 5 days for a drug sequestrated into the follicle to appear at the scalp; therefore short-term noncompliance immediately before death is not assessed by this study and may have been overlooked.⁴⁸

TABLE 15–2 Risk Factors Evaluated by Descriptive and Case-control Studies

In summary, therefore, despite the existence of some evidence for serum or hair sample AED variability in SUDEP patients, the issue of AED compliance is far from being satisfactorily resolved. Perhaps one useful conclusion that can be drawn from the studies available is that none has shown a higher risk from therapeutic levels compared to those with subtherapeutic levels.

Despite a number of descriptive and controlled studies, no specific AED has been clearly associated with an increased risk of SUDEP,^18,^29,^32,^36,^37,^44,⁴⁹ although a small number of studies have implicated treatment with carbamazepine as an independent risk factor.^31,^50,⁵¹ For antiepileptic medication in general, proposed mechanisms include perturbed heart rate variability, lengthening of the Q-T interval on the electrocardiogram combined with a mild proarrhythmic effect of epileptic seizure discharges, or excessive postseizure brainstem inhibition producing a blunting or transient abolition of the central hypoxic and hypercarbic respiratory drive, with consequent postictal respiratory arrest.⁵⁰^–⁵² Elevated serum levels of carbamazepine have been associated with an increased risk of SUDEP, even after adjustments for seizure frequency have been made. Frequent drug changes and multiple concomitant AEDs, conventional markers of severe, and unstable epilepsy increased this risk synergistically.⁴⁵ On this basis, it is difficult to know whether a high carbamazepine level is an independent risk factor or is merely representative of challenging epilepsy.

In summary, AED-related factors are likely to be important in relation to SUDEP risk, but the evidence available does not allow us to differentiate risks from uncontrolled seizures and challenging epilepsy from those related to specific drugs, drug combinations, and drug changes, either prescribed or otherwise.

PERIMORTEM FEATURES

There is evidence from both descriptive and controlled studies that a terminal convulsive seizure,^11,^14,^25,^27,^29,^34,^36,⁵³ being found alone in bed,^14,²⁶^–²⁸ ^,34 ^,36 and being in the prone position ^29,³⁶ are independent risk factors for SUDEP. Whereas a small number of descriptive studies have not found an association (Table 15-2), all case-control studies that have evaluated these factors have found a positive relationship with the risk of SUDEP. For example, the descriptive study reported by Ficker failed to find an association between being in bed and SUDEP or evidence for a terminal seizure, although only nine patients were evaluated.¹⁰ In a report by Nashef, following interviews with bereaved relatives, evidence for a terminal seizure was found in 24 of 26 cases, but it is of interest that only two were witnessed. The observation that, in most studies, unwitnessed cases far outnumber those witnessed suggests that enhanced surveillance of patients with epilepsy may be protective.²⁷ This is corroborated by a study of young patients with epilepsy at a special residential school. All sudden deaths that occurred during the period of the study were when the pupils were not under the close supervision of the school, and most were unwitnessed.¹⁵ Similar findings of a protective effect of enhanced supervision at night were also found in a large controlled study, where supervision was defined as the presence in the bedroom of an individual of normal intelligence and at least 10 years old or the use of special precautions, such as checks throughout the night or the use of a listening device.³¹

In some cases when a prone position was not observed, other factors that might compromise breathing were identified. For example, Nashef noted that only five of 26 people were found facedown in the pillow and a sixth with the head in carpet pile. In total, however, in 11 of 26 cases, an extrinsic or intrinsic positional obstruction to breathing amenable to intervention may have contributed.²⁷ Moreover, it is possible that this may be an underestimate, as obstructive apnea can occur in an apparently benign position.⁵⁴

OTHER FEATURES

There is limited evidence for an independent relationship between learning disability and an increased risk of SUDEP. Early descriptive and population-based studies, in which learning disability was determined by observer impressions rather than by formal IQ examination, provided only weak support for this association.^11,⁵⁵ Most recent studies have found no clear correlation.^27,³⁴^–³⁶ ^,39 However, Walczak identified an IQ of less than 70 to be a risk factor for SUDEP, even after accounting for seizure frequency.³⁷ Observational studies are likely to be biased. Nashef found that five of 11 patients with SUDEP had a low IQ, but the study was undertaken at a tertiary referral center with a higher-than-average background incidence of learning disability.¹⁴ Similar bias was introduced in an observational study by Opeskin, where all patients in the study region who died in institutions for the disabled were mandatory coroner’s cases, thus artificially elevating SUDEP cases with learning disability.²⁸ It has been postulated that patients with learning disability are more susceptible to central apnea and positional asphyxia that may cause SUDEP as a result of prolonged postictal encephalopathy,⁵⁶ decreased postictal respiratory drive, and impaired movement and righting reflexes.³⁷ This is likely to reflect associated pathology, rather than the learning difficulty per se. Despite early reports of an increased incidence of structural lesions in patients with SUDEP,^11,^25,⁵⁷ this has not been confirmed by more recent controlled studies.^30,^36,³⁷ Although there is evidence that psychotropic medication can influence the risk of sudden death in general, there is no convincing evidence of this being particularly relevant in SUDEP. Logistic regression analysis on 18 patients with SUDEP suggested an independent association of the risk of SUDEP with the number of concomitant psychotropic medications; however, the study was observational and uncontrolled, and the principal inclusion criteria for the study included any patient prescribed regular antiepileptic medication. Thus, the study population excluded those with epilepsy on no medication and included patients without epilepsy who were prescribed AEDs for an unrelated condition, for example, migraine, neuropathic pain, or psychiatric disorders.³⁸ A single case-control study has also reported an increased risk of SUDEP in women on neuroleptic medication and in men prescribed anxiolytic medication. The explanation for this is unclear and most likely represents an effect of confounding factors.³⁰ A number of more recent case-control studies have failed to identify a similar association.^34,^35,³⁷

In summary, although not universally accepted, the weight of evidence at present suggests that children are at less risk but that neither sex nor a particular adult age group are strong risk factors for SUDEP, with the absence of suitable control subjects and lack of controlled prospective data significant methodological constraints. Seizure frequency appears to be an independent risk factor, particularly with respect to convulsive seizures, and the number of previous or concomitant antiepileptic medications is, most likely, interrelated. SUDEP mostly occurs after a convulsive seizure and is more common in unsupervised patients more often found in bed in the prone position. Supervision is protective. There is no convincing evidence of an independent association between SUDEP and subtherapeutic AED levels or specific AEDs. Structural cerebral lesions and co-prescribed psychotropic medication are also, for the most part, likely to be unrelated to the risk of SUDEP. A number of epilepsy syndromes are associated with an increased risk of sudden death, although evidence for an association with the more common syndromes, such as idiopathic generalized epilepsy, is limited at the present time, and more research is required. Methodologically robust multicenter controlled prospective studies of risk factors for SUDEP are required to definitively evaluate the large number of proposed variables in an independent fashion using, for example, logistic regression analysis. This will be further facilitated by standardization of definitions, case ascertainment, and analysis methods.

Pathophysiology of SUDEP

Pathophysiological mechanisms of SUDEP are likely to be heterogeneous and may be multifactorial. Theories propounded have focused on autonomic disturbance— particularly cardiac arrhythmias and central and obstructive apnea and neurogenic pulmonary edema. In addition, the possibility of structural or functional cardiac pathology predisposing patients with epilepsy to cardiac events has been proposed.

CEREBROGENIC AUTONOMIC CONTROL

The components of the central autonomic network involved in the functional relationships between cortical, subcortical, and somatic regions have been elucidated from experimental and human stimulation and lesional studies. The network comprises the insular cortex, central nucleus of the amygdala, and hypothalamus with interconnections with the mesial temporal and frontal areas.⁵⁸ It has been demonstrated that limbic structures, especially the amygdala and pyriform cortex, modulate hypothalamic function, and stimulation of these foci can elicit both sympathetic and parasympathetic visceromotor autonomic responses.⁵⁹ Both experimental and ictal electrical stimulation of the cingulate gyrus and orbitofrontal cortex also produce changes in respiration and heart rate.⁶⁰^–⁶⁴ Intraoperative stimulation of the left insular cortex produces bradycardia and hypotension, whereas the converse is true of right-sided stimulation.⁶⁵ Unilateral hemispheric inactivation with an intracarotid amobarbital infusion produces bradycardia and reduced sympathetic tone when performed on the right side and tachycardia and reduced parasympathetic tone when applied on the left side.^66,⁶⁷ Similar lateralization findings have been reported in patients undergoing unilateral electroconvulsive therapy.⁶⁸

Other than visual inspection of a standard 12-lead electrocardiogram (ECG), more sophisticated methods to interrogate the cardiac autonomic system have been developed, for example, measures of heart rate variability (HRV). In its simplest form, this is measured in a time domain analysis as the standard deviation of R-R wave intervals.^69,⁷⁰ Frequency domain analysis permits the calculation of high-frequency (HF) and low-frequency (LF) components that assess the relative contribution of parasympathetic and sympathetic autonomic activity.⁷¹ The HF component is attributed to vagal mechanisms, and the LF component reflects sympathetic activity with parasympathetic modulation.⁷² However, measures of HRV may be more complex than purely sympathovagal balance. For example, baroreflex sensitivity modulation may be an important influence.⁷³ More advanced, nonlinear measures of “regularity,” such as entropy, have recently been used that facilitate further analyses of autonomic function.⁷⁴ The balance between parasympathetic and sympathetic regulation is dynamic, and in healthy subjects, cyclic variation is commonly observed during the ventilatory cycle and in sleep.⁷⁵ Reduced HRV has been reported in infants with aborted sudden infant death syndrome,⁷⁶ in heart transplant patients,⁷⁷ and as an independent risk factor for sudden arrhythmic death after myocardial infarction.⁷⁸

CARDIAC MECHANISMS

Structural Cardiac Pathology

The exclusion of cardiac pathology as a contributing factor in SUDEP is challenging due to the presence of, for example, subtle abnormalities that only a detailed microscopic examination of cardiac tissue can elucidate, such as conducting system fibrosis or cardiomyopathy,⁷⁹ tissue decomposition precluding the acquisition of suitable material for evaluation, lack of an appropriate control group for comparison, and the possibility of a functional rather than a structural disorder, such as ion channelopathies or preexcitation syndromes, with normal macroscopic and microscopic examinations being implicated.⁴³ Furthermore, inconsistencies in the methodology and reporting of cardiac abnormalities in SUDEP postmortem reports prevent meaningful comparison of results.^11,^30,^36,⁸⁰

Increased cardiac weight has been observed in male SUDEP cases compared to control subjects,¹¹ although it is likely that this is due to demographic and methodological confounding factors, such as a disproportionate prevalence of excess alcohol consumption in the study population and the derivation of expected cardiac weight from a regression equation based on body height, which has been demonstrated to be less accurate than using body weight.⁸¹ Recent studies, using more convincing methodology, have failed to replicate this earlier finding, and cardiac weight is not considered to differ between SUDEP and non-SUDEP cases.^80,^82,⁸³ Minor, nonspecific pathological change presumed to be nonfatal, such as atherosclerosis, conducting system fibrosis, and diffuse myocardial fibrosis, was identified in 33% (14 out of 42) of SUDEP cases, compared to 16% (six out of 37) of control cases, in an unblinded study reported by Kloster and Engelskjon in 1999.³⁶ This study corroborated earlier findings by Falconer, who demonstrated arterial, interstitial, and subendocardial fibrosis with myofibrillar degeneration in SUDEP cases,⁸⁴ and Natelson, who identified perivascular and interstitial fibrosis and subendocardial myocyte vacuolization in five of seven SUDEP cases. In the latter study, these changes were not seen in the control group, which comprised 13 cases of hanging or drug overdose in otherwise healthy, similarly aged individuals,⁸² although in this unblinded study the pathologist was aware of the relevant clinical information. Interestingly, myocyte vacuolization has also been observed in rats who developed asystole following stimulation of the insular cortex.⁸² Myocyte vacuolization is considered a reversible pathological entity, occurring in the context of subendocardial ischemia.⁸⁵ However, the patients universally had normal appearing coronary arteries. It has been postulated that neurogenic coronary vasospasm may be implicated, and that if recurrent, it may eventually progress to perivascular and interstitial fibrosis.⁸⁶ This may, in turn, predispose the heart to arrhythmogenesis, particularly in the setting of considerable autonomic imbalance during seizures.^87,⁸⁸ The occurrence and significance of these pathological changes in SUDEP is not universally agreed, however. Opeskin failed to identify similar fibrotic changes in SUDEP cases but did demonstrate cardiac conduction system pathology and myocyte vacuolization, although these abnormalities were no more common in the SUDEP group than in the control subjects.⁸⁰ Nevertheless, the pathological changes may still be important in sudden death, but not specific for SUDEP. It is acknowledged that the identification of subtle interstitial and perivascular fibrosis is subjective, and quantitative histopathological evaluations were not performed. Furthermore, the results were not corrected for seizure frequency. More recently, qualitative and quantitative histopathological assessments of myocardial fibrosis were undertaken in SUDEP and age- and gender-matched non-SUDEP cases, and although visual assessment showed significantly more fibrosis in the SUDEP cases, this was not verified on quantitation, further reinforcing the view that a purely qualitative evaluation is subjective and possibly unreliable. Furthermore, no abnormalities of the cardiac conducting system were demonstrated.⁸⁹

Overall, the full characterization of the relationship between myocardial pathology and acute and recurrent seizures remains unclear at the present time. Future studies should utilize standardized histopathological qualitative and quantitative protocols with extensive tissue sampling and correlate findings with clinical data to ensure that accurate and reproducible data is obtained.

Interictal

At the simplest level, interictal cardiac function can be evaluated by visually assessing a standard 12-lead ECG, primarily for evidence of conduction abnormalities, although these are frequently normal ⁹⁰^–⁹² or show only minor, nonsignificant changes.⁹³ However, a recent preliminary study of 128 patients with severe refractory epilepsy and learning disability revealed interictal ECG abnormalities in approximately 60% of patients, including first degree atrioventricular block and poor R-wave progression.⁹⁴ Potentially, a number of important confounding factors exist, though, including whether this study population is adequately representative, whether account was made of the presence of systemic comorbidity or use of psychotropic medication, and whether the conduction abnormalities are clinically significant.

Early experimental studies demonstrated that interictal epileptiform activity was associated with sympathetic and parasympathetic autonomic dysfunction in a time-locked synchronized pattern.^95,⁹⁶ In the first clinical reports, analysis of interictal heart rate variability in 19 patients with refractory temporal lobe epilepsy revealed frequent, high-amplitude fluctuations in heart rate that were most pronounced in poor surgical candidates.⁹⁷ Reduced sympathetic tone, demonstrated by decreased LF power, has been seen in both focal and, albeit less markedly, primary generalized epilepsy.^69,^92,^97,⁹⁸ These findings have been corroborated by more recent studies,^74,^99,¹⁰⁰ although the pattern of interictal autonomic disturbance in patients with epilepsy is contentious. For example, Evrengul reported an increase in LF power and a reduction of HF values consistent with an increase in the sympathetic control of the heart rate in patients with untreated generalized tonic-clonic seizures.⁷¹ It is possible that the disparity between the studies may be, at least partly, due to antiepileptic medication. Tomson showed that patients on carbamazepine had a significantly lower standard deviation of RR-intervals, LF power, and a LF/HF power ratio than matched healthy control subjects. In patients on sodium valproate, only the ratio of LF/HF power was lower.⁶⁹ Interictal autonomic dysfunction associated with carbamazepine use has also been implicated in a number of similar studies. Isojärvi evaluated 84 patients with a variety of epilepsies and observed autonomic dysfunction in only those patients taking carbamazepine.¹⁰¹ Confusingly, rapid withdrawal of carbamazepine has been associated with both increased sympathetic tone during sleep as measured by the LH/HF ratio⁵¹ and a significant reduction in heart-rate variability in both the time and frequency domains with, in particular, a significant reduction in LF power and sympathetic tone.¹⁰² The reason for the divergence between these studies is not clear, but it is important to note that both were small series studies and may have lacked sufficient power to convincingly demonstrate a clear effect. Furthermore, there may have been methodological differences. To address the possible modulatory effect of antiepileptic medication, patients with untreated epilepsy have been studied and shown to have both increased LF power, and thus augmented sympathetic tone⁷¹ and, in a similar study, normal HRV parameters.¹⁰³ Again, it is difficult to satisfactorily explain the variance in the results, although important differences in the study population may be at least partly responsible.¹⁰³ In an interesting study of patients with chronic temporal lobe epilepsy (TLE), postganglionic cardiac sympathetic innervation was quantified using (123)I-metaiodobenzylguanidine-single photon computed tomography (MIBG-SPECT). Cardiac MIBG uptake was significantly less in the TLE patients than in the controls, but did not differ between subgroups with and without carbamazepine treatment. The findings are consistent with either postganglionic transsynaptic degeneration resulting from a prolonged increase in central sympathetic interictal discharges or competitive inhibition of MIBG uptake due to continuously enhanced sympathetic activity. The authors concluded that this may translate into an increased risk of cardiac instability and arrhythmias.¹⁰⁰

Of recent interest in the pursuit for pathophysiological mechanisms of SUDEP is the potential association between cardiac and epileptic ion channelopathies.⁴³ For example, it is well known that long-QT syndrome, a defect of cardiac repolarization typically due to potassium or sodium channel mutations, produces prolongation of the action potential, propensity to malignant tachyarrhythmias, and sudden death.¹⁰⁴ Ion channelopathies are also implicated in familial, monogenic idiopathic epilepsies, such as generalized epilepsy with febrile seizures plus.¹⁰⁵ Direct evidence linking these cardiac inherited gene determinants and SUDEP is lacking at present; however, there is emerging evidence of genetic susceptibility in sinus node dysfunction and bradyarrhythmias, and this more complex pattern of inheritance may have more relevance to SUDEP than monogenic disorders (see review by Nashef et al, 2007⁴³). Future work in this area should include much larger studies of ECG changes and QT interval in patients with epilepsy and epidemiological studies exploring the association between syncope, inherited arrhythmias, and epilepsy.

Overall, there is some evidence for interictal cardiac autonomic dysfunction in patients with both focal and generalized epilepsy, possibly modulated by antiepileptic medication, in particular carbamazepine. Conflicting reports in the literature, however, suggest that the relationship between interictal epileptiform activity, antiepileptic medication, and autonomic function has not yet been fully characterized. This may, at least partly, be due to a lack of standardized analysis methods and heterogeneous study populations. Further work in this field is of paramount importance, as the ability to stratify the risk of SUDEP in individual patients on the basis of interictal autonomic parameters would have valuable management and prognostic implications.

Ictal

There is extensive literature on the presence of ECG changes, for example T-wave inversion, ST segment elevation, and a prolonged QT interval, in patients with intracranial pathology, such as subarachnoid hemorrhage and cerebrovascular accident, despite normal cardiac examination at autopsy (see Samuels, 2007 for review ¹⁰⁶). It is understood that these changes are a manifestation of massive catecholamine release and autonomic dysregulation resulting in ventricular wall motion abnormalities, vasospasm, and subsequent cardiac contraction-band necrosis, rather than being due to established structural cardiac pathology, such as atheroma.^107,¹⁰⁸ Predominantly neurogenic, rather than humorally driven, autonomic dysfunction has been postulated as the cause of ECG abnormalities during convulsive seizures.

Arrhythmias, conduction block, and repolarization ECG abnormalities, such as atrial fibrillation, marked sinus arrhythmia, supraventricular tachycardia, atrial and ventricular premature depolarization, bundle-branch block, high-grade atrioventricular conduction block, ST segment depression, and T-wave inversion have been reported in up to 56% of seizures. Abnormalities appear to be more common in nocturnal, prolonged, and generalized seizures than in focal seizures or those occurring during wakefulness.^59,¹⁰⁹^–¹¹² Tavernor reported minor prolongation of the ictal, compared to interictal, corrected QT interval (QTc) in a group analysis of 11 patients who subsequently died of SUDEP. The same QTc prolongation was not seen in living age- and sex-matched control subjects who also had refractory epilepsy. The authors concluded that prolongation of the QT interval may provoke malignant ventricular tachyarrhythmias, which may be a potential cause of SUDEP.¹¹³ However, although ictal sinus tachycardia is a frequent occurrence, atrial or ventricular tachyarrhythmias are only rarely seen.^91,^109,¹¹⁴

Sinus rate change is the most common cardiac accompaniment to ictal discharge. Sinus tachycardia has been reported in 50 to 100% of seizures and is dependent on the definition used and population studied.90–92,112,114–119 Although the heart rate in ictal tachycardia is typically 100 to 120 beats per minute,⁹⁰ there are reports of rates exceeding 170 beats per minute, even during simple partial seizures.^91,¹¹⁵ Ictal tachycardia is most commonly seen in the early ictal phase, soon after seizure onset,^114,^115,^118,¹¹⁹ or rarely before clear evidence of electroclinical onset.¹¹² This contrasts with ictal bradycardia, which is seen during the late ictal phase or in the immediate postictal period.^120,¹²¹ Some evidence exists for right-sided lateralization and temporal lobe localization in patients with ictal tachycardia,^114,^116,¹¹⁹ corroborating the reports of early experimental and clinical stimulation studies,^65,^68,¹²² although it is important to note that most temporal lobe seizures are associated with ictal tachycardia, irrespective of lateralization. In contrast, in patients with unilateral temporal lobe epilepsy being evaluated with extensive intracranial electroencephalogram (EEG) electrodes, irrespective of lateralization of ictal onset, heart rate was seen to increase incrementally as new cortical regions anywhere in the brain were recruited.¹²³

Although ictal tachycardia is almost universally observed, ictal bradycardia has received more attention due to the potential progression to cardiac asystole and intuitive but unproven association with SUDEP.

The first report of ictal asystole was by Russell in 1906, who noted the disappearance of a young male patient’s pulse during a seizure.¹²⁴ The published literature since that time is, unsurprisingly, mostly case reports or small-series studies, which significantly limit the number and confidence of any conclusions extracted from the data. Ictal bradycardia is observed in <5% of recorded seizures,^91,^114,^118,¹²⁵ but may occur in a higher percentage of patients because a consistent cardiac response to each apparently electroclinically identical seizure is not seen.⁹¹

A recent literature review by Britton revealed that of 65 cases of ictal bradycardia with sufficient EEG and ECG data, seizure onset was localized to the temporal lobe in 55%, the frontal lobe in 20%, the frontotemporal region in 23%, and the occipital lobe in 2% of cases. Information regarding seizure-onset lateralization was available in 56 cases. Seizure onset was lateralized to the left hemisphere in 63%, the right in 34%, and bilaterally in 4%. Interestingly, of 22 cases with EEG data available at the onset of the bradycardia, 12 showed bilateral hemispheric ictal activity, whereas six showed left, and four showed right-sided activity.¹²¹ No control group data is available, however. Nevertheless, it appears that there is a trend toward the left temporal lobe being implicated in ictal bradycardia, but this is not sufficiently specific to be valuable localizing semiological information.^121,¹²⁵ Of greater interest is the frequent observation of bilateral ictal activity during bradycardia.^121,^126,¹²⁷ This may cause a more significant imbalance of parasympathetic and sympathetic dysfunction than unilateral stimulation via either corticocardiac pathways or through connections with subcortical and brainstem regions, which are frequently activated in seizures and that may potentially contribute to a bradycardic response.^128,¹²⁹

Ictal asystole, lasting between 4 and 60 seconds, is reported, albeit rarely, in patients with refractory epilepsy.^54,^91,^112,^126,^130,¹³¹ In addition, experimental data suggests that ictal bradyarrhythmias can lead to complete heart block.⁹⁶ It is possible, however, that bradycardia and asystole are conditions with distinct pathophysiological bases rather than two points on a continuum of cerebrogenic arrhythmias. However, the characteristics of the epilepsy with respect to localization, lateralization, seizure types, and population demographics are identical to those of patients with ictal bradycardia, suggesting that the two entities are possibly linked. Short periods of EEG/ECG monitoring may underestimate the prevalence of ictal asystole. For example, Schuele searched a database of 6825 patients undergoing inpatient video-EEG monitoring and found ictal asystole in only 0.27% of all patients with epilepsy. In contrast, Rugg-Gunn reported on 19 patients with refractory focal epilepsy who were implanted with an ECG loop recorder for up to 18 months. Over 220,000 patient hours of ECG recording were monitored, during which time 3377 seizures (1897 complex partial or secondarily generalized tonic-clonic seizures and 1480 simple partial seizures) were reported by patients. Cardiac rhythm was captured on the implantable loop recorders in 377 seizures. Ictal bradycardia, defined as a rate of less than 40 beats per minute, was seen in 0.24% of all seizures over the study period and 2.1% of the recorded seizures. One patient developed supraventricular tachycardia (rate 120 bpm) lasting approximately 30 seconds, during a complex partial seizure. Seven of the 19 patients experienced ictal bradycardia. Four of these had severe bradycardia or periods of asystole, which led to the insertion of a permanent pacemaker. The small number of patients involved precluded statistical analysis of localization and lateralization data. There was no clear correlation between cardiac events and specific AEDs. Notably, only a small proportion of seizures for every patient were associated with significant cardiac events, despite identical seizure characteristics.⁹¹ The wider significance of these findings remains to be established but may be addressed by a larger UK-based multicenter study that is currently underway. For example, although this study showed asystole in patients with refractory focal seizures, a similar intractable group of patients with generalized epilepsy has not been studied. Nevertheless, the identification and targeting of patients at risk of ictal asystole, preferably with an interictal surrogate marker, is an important goal.

Extrapolation of ictal bradyarrhythmias to a mechanistic explanation for SUDEP remains elusive. This is, at least partly, due to a lack of clinical evidence of common factors shared by patients with ictal bradyarrhythmias and SUDEP and the difficulty in ascertaining the importance of ictal bradyarrhythmias in SUDEP in relation to other proposed mechanisms, including other intrinsic cardiac abnormalities or apnea and hypoxia, which may aggravate arrhythmias.

RESPIRATORY MECHANISMS

It is likely that primary respiratory dysfunction is involved in an important proportion of SUDEP.^54,¹³²^–¹³⁸ Central and obstructive apnea, excess bronchial and oral secretions, pulmonary edema, and hypoxia during seizures are all well documented.^54,^136,¹³⁸^–¹⁴⁰ Central chemoreceptive areas responsible for sensitivity to increases in carbon dioxide have been shown to be located in several areas of the brainstem, including the nucleus tractus solitarii, locus coeruleus, medullary raphe, and ventrolateral medulla, which comprises an extensive network of respiratory neurons, known collectively as the ventral respiratory group, involving the nucleus ambiguous (NA) and Bötzinger and pre-Bötzinger complexes.¹⁴¹ Changes in the arterial partial pressure of CO₂ evoke rapid alterations in respiration.¹⁴² This brainstem network receives supranuclear afferents from cortical areas, such as the rolandic region, or via cranial nerves, such as the trigeminal and glossopharyngeal nerves.⁶⁰ Central apnea can therefore occur secondary to the ictal discharge, acting at either the cortical or medullary level or possibly as a result of secondary endogenous opioid release influencing the brainstem respiratory nuclei directly. During postictal impairment of consciousness, hypercapnia and hypoxia may be less potent respiratory stimuli.

In a study of 17 patients with epilepsy who underwent polysomnography with cardiorespiratory monitoring in a supervised environment, ictal apnea of greater than 10 seconds in duration was demonstrated in 20 of 47 seizures. Oxyhemoglobin saturation decreased to less than 85% in 10 seizures. Central apnea, which may evolve during a focal or generalized seizure, was seen more frequently than obstructive apnea; however, the study was in a controlled environment, and assistance may have minimized the likelihood of obstructive apnea being observed.⁵⁴ Interictal obstructive sleep apnea has been reported to be more frequent in patients with epilepsy than in the general population, although the reasons for this are unclear.¹⁴³ Interestingly, transient bradycardia or sinus arrest has been seen in association with ictal apnea, suggesting that the reported seizure-related arrhythmias may be consecutive to ictal apnea.⁵⁴ Similar findings have been reported in children.¹³⁸ Additional reports of ictal apnea are typically case studies recorded incidentally during video-EEG telemetry.¹³⁴^–¹³⁶ In a study of 135 SUDEP cases, 15 of which were witnessed, observers described respiratory difficulties, such as apnea and obvious respiratory obstruction, in 12 patients, although the conclusions that may be drawn are significantly limited by the quality of the retrieved information and lack of additional relevant cardiorespiratory parameters.¹³⁷ Witnesses have reported a delay between the seizure and time of death, which is more consistent with primary respiratory inhibition followed by respiratory arrest and the development of hypoxia and pulmonary edema, than “primary” ictal cardiac asystole.²⁹ Analogous with reports of patients with ictal bradycardia and asystole, the majority of published cases of ictal central apnea had temporal lobe epilepsy, although this is likely to represent selection bias. No clear lateralizing information is available from the published literature.

Neurogenic pulmonary edema, which may in itself be insufficient to be fatal, has been implicated in theories regarding respiratory dysfunction and SUDEP following a number of postmortem reports and case studies.^11,^29,^133,¹⁴⁰ In a sheep model of ictal sudden death, animals that died had a greater increase in pulmonary vascular pressure and hypoventilation. When airway obstruction was excluded by tracheostomy, central apnea and hypoventilation were observed in all, causing or contributing to death in two, whereas a third animal developed heart failure with significant pathologic cardiac ischemic changes.^132,¹⁴⁴ The apparent protective effect of supervision favors an important primary role for respiratory factors,³¹ as these can be influenced by relatively unskilled intervention, such as airway protection, repositioning, or stimulation. It is unknown what proportion of SUDEP cases may be prevented by such intervention.

SUPPRESSION OF CEREBRAL ACTIVITY

The possibility of progressive suppression and eventually cessation of cerebral activity as a cause of SUDEP, despite normal cardiac function, was introduced with the publication of a case report of an intracranially monitored patient who died of SUDEP. Bird described a seizure starting in sleep in one hemisphere and spreading to the other for several minutes. The EEG pattern on the original side then changed to burst-suppression with spindling spike discharges, followed by complete cessation of activity. The other hemisphere continued to show spike discharges until ceasing suddenly a few seconds later. A pulse artifact on the EEG continued for an additional 2 minutes; there was no recording of respiratory activity. Postmortem examination showed mild congestion of the lungs. It was postulated that the loss of EEG activity was not preceded by anoxia, as both hemispheres were not simultaneously affected.¹⁴⁵

Excessive postictal brainstem inhibition due to seizure-induced release of GABA and other neuroinhibitory peptides may contribute to death in some patients. This may be compounded by antiepileptic medication.⁵⁰ This endogenous seizure-terminating mechanism could result in blunting of the central hypoxic and hypercarbic respiratory drive, resulting in postictal respiratory arrest, subsequent exacerbation of hypoxia, further cardiac destabilization, and death due to hypoxia and secondary cardiac arrhythmia. This is consistent with the observation that SUDEP occurs after a seizure and could be a consequence of failed reestablishment of respiration in the postictal phase.

SUDEP and Epilepsy Surgery

Compelling evidence shows that patients with poorly controlled, predominantly generalized tonic-clonic seizures are at greatest risk of SUDEP, and a seizure is frequently seen as the terminal event. Intuitively, therefore, good seizure control should translate into reduced risk of SUDEP. Sperling evaluated the mortality rates of 393 patients who underwent epilepsy surgery. The standardized mortality ratio (SMR) for patients with recurrent seizures postoperatively was 4.69, with a SUDEP incidence of 7.5/1000 patient-years, whereas in patients who became seizure free, there was no difference in mortality rate compared with an age- and sex-matched population.¹⁴⁶ This compares with the results from Hennessy, who identified an overall postoperative SMR of 4.5 and SUDEP incidence of 2.2/1000 patient-years, although the results were not stratified for postoperative seizure outcome,¹⁴⁷ and Salanova, who found a SMR of 1.8 in those with a good postoperative outcome versus 7.4 in those who failed surgery.¹⁴⁸ In a large, population-based epilepsy surgery cohort, Nilsson failed to demonstrate an association between mortality rates and seizure outcomes, although there was a clear difference between patients who underwent surgery (SUDEP incidence 2.4 per 1000 patient-years) and those who failed presurgical assessment (SUDEP incidence 6.3 per 1000 patient-years).¹⁶ There has been recent interest in the tenet that a common factor predisposes to surgical failure and an increased risk of SUDEP so that patients who respond poorly to surgery also carry an increased risk of SUDEP and that, overall, surgery does not alter the risk of SUDEP.¹⁴⁹ Proposed common factors include TLE, which extends beyond the temporal lobe into the insula, frontal orbital, or frontal operculum region, which may favor ictal arrhythmias, central apnea, and secondary generalization. This, in turn, would increase the risk of SUDEP, and the wide epileptogenic field would translate into a poor postoperative seizure outcome.¹⁴⁹ This is supported by a study by Persson, who reported on 21 patients undergoing temporal lobe surgery and found that postoperative measures of HRV did not differ from preoperative HRV. Patients with a poor outcome after surgery had significantly lower pre- and postoperative HRV than patients with a good outcome, who had similar HRV measures to healthy control subjects.^70,¹⁵⁰ In contrast, Hilz found a postoperative reduction in sympathetic cardiovascular modulation and baroreflex sensitivity in patients undergoing temporal lobe resection, consistent with stabilization of cardiac autonomic control.¹⁵¹

Mortality studies performed in patients with vagal nerve stimulators have shown that excess mortality associated with refractory epilepsy reduced as a function of duration of use. The rate of SUDEP was 5.5 per 1000 patient-years in the first 24 months and 1.7 per 1000 patient-years thereafter, possibly reflecting gradual increase in efficacy over time. Stabilization of measures of heart rate variability post-VNS (vagal nerve stimulation) implantation ¹⁵²^–¹⁵⁴ have paralleled the improved mortality rates, although these findings are not universal.^155,¹⁵⁶

Implications for Management

Despite a wealth of studies reporting on proposed risk factors or mechanisms of SUDEP, this information has not yet been translated into targeted therapeutic interventions and a reduced incidence of SUDEP. Despite this being a fundamental goal in the management of patients with epilepsy, there has been a paucity of studies specifically addressing preventative or therapeutic strategies.

Given the disturbance in cardiac autonomic control in patients with epilepsy, there has been speculation as to whether cardiotropic medication, such as beta-antagonists, may have a protective effect, although no studies have been performed in this regard.¹¹¹ Experimental studies in rats with audiogenic seizures and ictal apnea have shown that selective serotonin reuptake inhibitors have a protective effect,¹⁵⁷ although relevant confirmatory clinical studies are lacking. Of interest, however, is the recent finding of neuropathological evidence of involvement of the medullary serotonergic network in sudden infant death syndrome cases with a significantly lower density of serotonin receptor binding sites, particularly in male SIDS cases compared to controls.¹⁵⁸ Whether pharmacological modulation of the brainstem serotonergic network or cardiac autonomic function results in a protective effect remains to be seen.

The implications of the observed ictal asystole in a small cohort of patients to a larger, more representative group of epilepsy patients is unknown. If this finding is confirmed, the potential role of pacemaker insertion in preventing a proportion of SUDEP cases needs to be assessed.

Supervision of patients with epilepsy has emerged as the only clinically important protective factor, independent of seizure control. The basis for this remains unclear but may relate to body positioning and alleviation of obstructive apnea or possibly brainstem arousal mechanisms.^15,^27,^31,¹³⁷ Strategies to adequately monitor patients with epilepsy at night, evaluating either cardiac, respiratory, or body movement parameters, have been developed, but issues with, for example, high false-positive rates render the devices less user friendly. As a result, there is an urgent need to develop more sophisticated, unobtrusive, reliable, and affordable monitoring equipment.

In the U.K. the NICE guidelines state that tailored information and discussion between the individual, family, and/or caregivers and health care professional should take account of the small but definite risk of SUDEP.¹⁵⁹ Several studies have suggested that the relatives of people who died from SUDEP wished they had known of the risk of sudden death.^27,¹⁶⁰ Whereas it is not certain that knowledge of the risks of epilepsy would necessarily prevent death, some evidence suggests that observation, positioning, and where necessary, stimulation after a seizure may protect against death. It is also likely that patients who know of the risks of epilepsy might be more adherent to AED regimens and the avoidance of trigger factors, thus reducing the frequency of seizures. In contrast, a cohort-controlled study of SUDEP from Australia concluded that because no clear risk factors were modifiable by practical intervention, disclosure to the patient of the possibility of SUDEP was inappropriate.¹⁶¹