**1. Introduction**

112 Novel Aspects on Epilepsy

Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J.L., Moss, A.J., Towbin, J.A.,

arrhythmia, long QT syndrome. *Cell*, Vol. 80, pp. 805-811, ISSN 0092-8674 Wang, Z., Tristani-Firouzi, M., Xu, Q., Lin, M., Keating, M.T., & Sanguinetti, M.C. (1999).

Weber, Y.G., Storch, A., Wuttke, T.V., Brockmann, K., Kempfle, J., Maljevic, S., Margari, L.,

arrhythmias. *Nat Genet*, Vol. 12, pp. 17-23, ISSN 1061-4036

*Cardiovasc Electrophysiol*, Vol. 10, pp. 817-826, ISSN 1045-3873

Vol. 109, pp. 1834-1841, ISSN 1524-4539

(2004/09/15), pp. 1283-1291, ISSN 0735-1097

(1999/06/04), pp. 817-825, ISSN 0006-8950

seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. *Nat Genet*, Vol. 19, (1998/08/11), pp. 366-370, ISSN 1061-4036 Wang, Q., Curran, M.E., Splawski, I., Burn, T.C., Millholland, J.M., VanRaay, T.J., Shen, J.,

Timothy, K.W., Vincent, G.M., de Jager, T., Schwartz, P.J., Toubin, J.A., Moss, A.J., Atkinson, D.L., Landes, G.M., Connors, T.D., & Keating, M.T. (1996). Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac

& Keating, M.T. (1995). SCN5A mutations associated with an inherited cardiac

Functional effects of mutations in KvLQT1 that cause long QT syndrome. *J* 

Kamm, C., Schneider, S.A., Huber, S.M., Pekrun, A., Roebling, R., Seebohm, G., Koka, S., Lang, C., Kraft, E., Blazevic, D., Salvo-Vargas, A., Fauler, M., Mottaghy, F.M., Munchau, A., Edwards, M.J., Presicci, A., Margari, F., Gasser, T., Lang, F., Bhatia, K.P., Lehmann-Horn, F., & Lerche, H. (2008). GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. *J Clin Invest*, Vol. 118, (2008/05/03), pp. 2157-2168, ISSN 0021-9738 Westenskow, P., Splawski, I., Timothy, K.W., Keating, M.T., & Sanguinetti, M.C. (2004).

Compound mutations: a common cause of severe long-QT syndrome. *Circulation*,

Timothy, K.W., Carlquist, J., January, C.T., Keating, M.T., & Splawski, I. (2004). An intronic mutation causes long QT syndrome. *J Am Coll Cardiol*, Vol. 44,

during epileptic seizures: prevalence and definition of an objective clinical sign.

R.C., Stephenson, J.B., Kullmann, D.M., & Hanna, M.G. (1999). A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. *Brain*, Vol. 122 ( Pt 5),

Zhang, L., Vincent, G.M., Baralle, M., Baralle, F.E., Anson, B.D., Benson, D.W., Whiting, B.,

Zijlmans, M., Flanagan, D., & Gotman, J. (2002). Heart rate changes and ECG abnormalities

Zuberi, S.M., Eunson, L.H., Spauschus, A., De Silva, R., Tolmie, J., Wood, N.W., McWilliam,

*Epilepsia*, Vol. 43, (2002/08/16), pp. 847-854, ISSN 0013-9580

Epilepsy is one of the most frequent neurological disorders, both in children and adult persons. About 0.5-1% of general population suffer from epilepsy, which means that 50 million people in the world are affected. First years of life and very late adulthood are periods in human's life particularly predisposing to developing epilepsy. Patients with repetitive seizures may have a significantly lower quality of life, with frequent absences from work or school caused by seizures, difficulties in social life, frequent injuries, necessity of polytherapy and the risk of life-threatening situations, such as status epilepticus (Józwiak, 2007). People with epilepsy have also a two to three fold increased risk of death as compared to the age-matched general population and may die unexpectedly without a clear structural or pathologic identifiable cause. Increased risk of death primarily affects young adults mostly with drug resistant epilepsy and accounts for a large proportion of deaths among people with epilepsy. This condition is called sudden unexpected death in epilepsy (SUDEP).

SUDEP is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without the evidence of a seizure, excluding *status epilepticus*, and without a toxicological or anatomical cause of death in *postmortem* examination (Tomson et al, 2008). Diagnosis of SUDEP is sometimes difficult since *post-mortem* examination is not always available. Annegers (1997) suggested six criteria to consider the etiology of death as being SUDEP: 1. The diagnosis of epilepsy; 2. Death in a victim in a reasonable state of health; 3. Death should occur suddenly; 4. During normal activities and in benign circumstances; 5. Without a medical cause; 6. Not directly caused by a seizure or *status epilepticus* (Annegers, 1997). In this way, definite SUDEP cases need to have a *post-mortem* examination to ensure patient did not have a concomitant disease that can justify death and probable cases are considered that with clinical findings suggestive of SUDEP but where necropsy is not available. These strict criteria may hamper the diagnosis of SUDEP in many cases and, in these lines, other authors suggest that a formal *post-mortem* examination may be replaced by a verbal autopsy, contributing to a more realistic assessment of SUDEP incidence (Lathers & Schraeder, 2009).

Sudden Unexpected Death in Epilepsy: An Overview 115

levels may cause cardiac arrhythmias potentially fatal (Garaizar, 2000). Although SUDEP has not been clearly associated with the use of any particular AED, some case-control studies have pointed to an association between SUDEP and polytherapy with AED and frequent dose changes independent of seizure frequency (Tomson et al, 2005). All currently available AED have been associated with SUDEP, but two specific drugs, carbamazepine and lamotrigine were considered by some authors as potentially increasing SUDEP risks. A review of Cardiff Epilepsy Unit data shows that carbamazepine was disproportionately represented in patients suffering SUDEP, achieving almost 85% of the cases described in

Carbamazepine has a potential effect inducing lengthening of the ECG Q-T interval combined with a mild pro-arrhythmic action. This may cause transient cardiac instability leading to arrhythmic death (Timmings, 1998). Abrupt withdrawal of CBZ may lead to enhanced sympathetic activity in sleep as evidenced by heart frequency analysis and this increased activity in the setting of seizure-induced hypoxia could predispose to SUDEP (Hennessy et al, 2001). Isolated reports have described patients suffering of SUDEP or syncope associated with hyponatraemia generated by syndrome of inappropriate secretion of antidiuretic hormone (Kloster & Børresen, 1999; Ruiz et al, 2007). Interesting in all cases, patients were chronically using association of carbamazepine/oxcarbazepine and lamotrigine. Others authors have already suggested that current available studies do not support the hypothesis that CBZ is associated with a higher risk of SUDEP (Opeskin et al, 1999). In this way, it is unclear whether polytherapy, frequent dose changes, and high carbamazepine levels per se represent a risk factor or just reflect an unidentified aspect of an unstable, more severe form of epilepsy (Nilsson et al 2001). Anyway, a search for syndrome of inappropriate secretion of antidiuretic hormone in patients on carbamazepine and

With respect to lamotrigine, it has recently been shown that this DAE inhibit the cardiac rapid delayed rectifier potassium ion current and consequently increase the risk of cardiac arrhythmia and sudden unexpected death. Although Leestma et al (1997) suggested that the rate of SUDEP in patients using lamotrigine was unrelated to the drug, Aurlien et al (2007) registered in ten years, four consecutive cases of SUDEP in non-hospitalized patients that were all being treated with lamotrigine in monotherapy. However, as with other potential

In this way, to estimate the risk of SUDEP, Walczak et al (2001) determined SUDEP incidence and risk factors in a prevalence cohort of people with epilepsy enrolled prospectively. Most of the patients had been intensively evaluated and detailed information regarding possible risk factors for SUDEP was defined. In this study four thousand, five hundred seventy-eight patients were enrolled. One hundred eleven patients died during follow up, 28 of them of SUDEP. Three apparently independent risk factors for SUDEP were proposed: presence of tonic-clonic seizures, mental retardation and the number of anticonvulsant drugs used. Authors considered presence of tonic-clonic seizures as a major risk factor, since the great majority of patients that is in suspicion of SUDEP had history of experienced tonic-clonic seizure just before death, or circumstances of death when was carefully examined showed an evidence of tonic-clonic seizure preceding death. Also, death has been directly related to

oxcarbazepine, and in cases of sudden death in epilepsy, is recommended.

risk factors, there are no systematic studies that may confirm these suspicions.

generalized convulsive seizures in an animal model of SUDEP (Faingold et al, 2010).

Based in this study, DeGiorgo et al (2010) validated a SUDEP-7 inventory. Inventory is composed by seven items which scores were based on the log of the odds ratio of the main

some SUDEP series (Timmings, 1998).

SUDEP incidence rates are variable depending on the cohort studied, being directly affected by seizure frequency. In this way, it range from 0.35 per 1,000 person-years of follow-up in population-based studies to 9.3 per 1,000 person-years in patients with refractory epilepsy (Asadi-Pooya & Sperling, 2009; Ryvlin et al, 2009), with an intermediate incidence of 1- 2/1,000 person-years in patients with chronic epilepsy. The highest rates occur in patients with 20 to 40 years old (Tomson et al, 2005).

Interest in sudden unexpected and unexplained death in individuals with epilepsy was rekindled during the early 1980s and more recently by antiepileptic drug (AED) trials, medico legal issues and epidemiologic studies (Annegers, 1997). Although, if we search in PUBMED database the word SUDEP, approximately 250 articles are found and most of them reports small series of patients or describe single patient cases, with few articles reporting large controlled series (case-control or cohort studies). Moreover, most articles that tried to identify SUDEP risk factors report few cases, being observational studies. In this way, definition of potentially risk factors is essential. No single risk factor is common to all SUDEP cases, suggesting multiple mechanisms or trigger factors are involved (Tomson et al, 2005). Most deaths of SUDEP are unwitnessed and occur at home, usually in bed and presumably overnight, in association with a seizure (Opeskin & Berkovic, 2003; Kloster & Engelskjøn, 1999). Many victims have pulmonary oedema on *postmortem* examination, and some show ischemic damage of the heart despite normal coronary arteries. Nevertheless, the precise reason for a particular seizure being fatal in an otherwise healthy individual is as yet undetermined (McGugan, 2000).

Studies suggested that patients suffering of SUDEP had a significant longer mean duration of epilepsy compared with controls and that more people succumbing of SUDEP had had a seizure within the previous year (Hiritis et al, 2007). Interestingly, considering all deaths in epilepsy, patients that died of SUDEP are reported to die at younger ages than non-SUDEP deaths. Other possible related risk factors described in the literature are male sex, generalized tonic-clonic seizures, high seizure frequency, specific AEDs, polytherapy with several AEDs, mental retardation, psychiatric illness, psychotropic co-medication and an earlier epilepsy onset (Vlooswijk et al, 2007; Lear-Kaul et al, 2005). Summarizing all citations, main risk factors seems to be young age, high seizure frequency, frequent generalized tonic-clonic seizures, nocturnal seizures, poor drug compliance, medical refractory epilepsies, high number of antiepileptic drugs and long duration of epilepsy, but this still need confirmation with controlled studies (Téllez-Zenteno et al, 2005; Ryvlin et al, 2009).

A cohort study accompanied 3,688 subjects aged 15 to 49 years with more than four prescriptions for AED. Patients were followed since first AED prescription to one of the options: age 50 years, death, or last registration on system. In this group were observed 163 deaths and 153 death certificates were examined to identify potential SUDEP cases. There were 18 definite/probable SUDEPs and 21 possible SUDEPs, yielding a minimum incidence of 0.54 SUDEP per 1,000 person-years and a maximum of 1.35 SUDEP per 1,000 personyears. Main risk factors observed were male sex, number of AEDs ever prescribed, prescription of psychotropic drugs and in males with a history of treatment with three or more AEDs. Authors suggested that a 1.7 fold increased risk of SUDEP might be associated for each increment in maximum number of AED administered (Tennis et al, 1995). Although, this increase may simple reflect severity of epilepsy and not the directly effect of AED in increasing SUDEP risk. A causal relationship of SUDEP with antiepileptic drugs administration has not been proved, but the sudden decrease of antiepileptic drugs serum

SUDEP incidence rates are variable depending on the cohort studied, being directly affected by seizure frequency. In this way, it range from 0.35 per 1,000 person-years of follow-up in population-based studies to 9.3 per 1,000 person-years in patients with refractory epilepsy (Asadi-Pooya & Sperling, 2009; Ryvlin et al, 2009), with an intermediate incidence of 1- 2/1,000 person-years in patients with chronic epilepsy. The highest rates occur in patients

Interest in sudden unexpected and unexplained death in individuals with epilepsy was rekindled during the early 1980s and more recently by antiepileptic drug (AED) trials, medico legal issues and epidemiologic studies (Annegers, 1997). Although, if we search in PUBMED database the word SUDEP, approximately 250 articles are found and most of them reports small series of patients or describe single patient cases, with few articles reporting large controlled series (case-control or cohort studies). Moreover, most articles that tried to identify SUDEP risk factors report few cases, being observational studies. In this way, definition of potentially risk factors is essential. No single risk factor is common to all SUDEP cases, suggesting multiple mechanisms or trigger factors are involved (Tomson et al, 2005). Most deaths of SUDEP are unwitnessed and occur at home, usually in bed and presumably overnight, in association with a seizure (Opeskin & Berkovic, 2003; Kloster & Engelskjøn, 1999). Many victims have pulmonary oedema on *postmortem* examination, and some show ischemic damage of the heart despite normal coronary arteries. Nevertheless, the precise reason for a particular seizure being fatal in an otherwise healthy individual is as yet

Studies suggested that patients suffering of SUDEP had a significant longer mean duration of epilepsy compared with controls and that more people succumbing of SUDEP had had a seizure within the previous year (Hiritis et al, 2007). Interestingly, considering all deaths in epilepsy, patients that died of SUDEP are reported to die at younger ages than non-SUDEP deaths. Other possible related risk factors described in the literature are male sex, generalized tonic-clonic seizures, high seizure frequency, specific AEDs, polytherapy with several AEDs, mental retardation, psychiatric illness, psychotropic co-medication and an earlier epilepsy onset (Vlooswijk et al, 2007; Lear-Kaul et al, 2005). Summarizing all citations, main risk factors seems to be young age, high seizure frequency, frequent generalized tonic-clonic seizures, nocturnal seizures, poor drug compliance, medical refractory epilepsies, high number of antiepileptic drugs and long duration of epilepsy, but this still need confirmation with

A cohort study accompanied 3,688 subjects aged 15 to 49 years with more than four prescriptions for AED. Patients were followed since first AED prescription to one of the options: age 50 years, death, or last registration on system. In this group were observed 163 deaths and 153 death certificates were examined to identify potential SUDEP cases. There were 18 definite/probable SUDEPs and 21 possible SUDEPs, yielding a minimum incidence of 0.54 SUDEP per 1,000 person-years and a maximum of 1.35 SUDEP per 1,000 personyears. Main risk factors observed were male sex, number of AEDs ever prescribed, prescription of psychotropic drugs and in males with a history of treatment with three or more AEDs. Authors suggested that a 1.7 fold increased risk of SUDEP might be associated for each increment in maximum number of AED administered (Tennis et al, 1995). Although, this increase may simple reflect severity of epilepsy and not the directly effect of AED in increasing SUDEP risk. A causal relationship of SUDEP with antiepileptic drugs administration has not been proved, but the sudden decrease of antiepileptic drugs serum

controlled studies (Téllez-Zenteno et al, 2005; Ryvlin et al, 2009).

with 20 to 40 years old (Tomson et al, 2005).

undetermined (McGugan, 2000).

levels may cause cardiac arrhythmias potentially fatal (Garaizar, 2000). Although SUDEP has not been clearly associated with the use of any particular AED, some case-control studies have pointed to an association between SUDEP and polytherapy with AED and frequent dose changes independent of seizure frequency (Tomson et al, 2005). All currently available AED have been associated with SUDEP, but two specific drugs, carbamazepine and lamotrigine were considered by some authors as potentially increasing SUDEP risks. A review of Cardiff Epilepsy Unit data shows that carbamazepine was disproportionately represented in patients suffering SUDEP, achieving almost 85% of the cases described in some SUDEP series (Timmings, 1998).

Carbamazepine has a potential effect inducing lengthening of the ECG Q-T interval combined with a mild pro-arrhythmic action. This may cause transient cardiac instability leading to arrhythmic death (Timmings, 1998). Abrupt withdrawal of CBZ may lead to enhanced sympathetic activity in sleep as evidenced by heart frequency analysis and this increased activity in the setting of seizure-induced hypoxia could predispose to SUDEP (Hennessy et al, 2001). Isolated reports have described patients suffering of SUDEP or syncope associated with hyponatraemia generated by syndrome of inappropriate secretion of antidiuretic hormone (Kloster & Børresen, 1999; Ruiz et al, 2007). Interesting in all cases, patients were chronically using association of carbamazepine/oxcarbazepine and lamotrigine. Others authors have already suggested that current available studies do not support the hypothesis that CBZ is associated with a higher risk of SUDEP (Opeskin et al, 1999). In this way, it is unclear whether polytherapy, frequent dose changes, and high carbamazepine levels per se represent a risk factor or just reflect an unidentified aspect of an unstable, more severe form of epilepsy (Nilsson et al 2001). Anyway, a search for syndrome of inappropriate secretion of antidiuretic hormone in patients on carbamazepine and oxcarbazepine, and in cases of sudden death in epilepsy, is recommended.

With respect to lamotrigine, it has recently been shown that this DAE inhibit the cardiac rapid delayed rectifier potassium ion current and consequently increase the risk of cardiac arrhythmia and sudden unexpected death. Although Leestma et al (1997) suggested that the rate of SUDEP in patients using lamotrigine was unrelated to the drug, Aurlien et al (2007) registered in ten years, four consecutive cases of SUDEP in non-hospitalized patients that were all being treated with lamotrigine in monotherapy. However, as with other potential risk factors, there are no systematic studies that may confirm these suspicions.

In this way, to estimate the risk of SUDEP, Walczak et al (2001) determined SUDEP incidence and risk factors in a prevalence cohort of people with epilepsy enrolled prospectively. Most of the patients had been intensively evaluated and detailed information regarding possible risk factors for SUDEP was defined. In this study four thousand, five hundred seventy-eight patients were enrolled. One hundred eleven patients died during follow up, 28 of them of SUDEP. Three apparently independent risk factors for SUDEP were proposed: presence of tonic-clonic seizures, mental retardation and the number of anticonvulsant drugs used. Authors considered presence of tonic-clonic seizures as a major risk factor, since the great majority of patients that is in suspicion of SUDEP had history of experienced tonic-clonic seizure just before death, or circumstances of death when was carefully examined showed an evidence of tonic-clonic seizure preceding death. Also, death has been directly related to generalized convulsive seizures in an animal model of SUDEP (Faingold et al, 2010).

Based in this study, DeGiorgo et al (2010) validated a SUDEP-7 inventory. Inventory is composed by seven items which scores were based on the log of the odds ratio of the main

Sudden Unexpected Death in Epilepsy: An Overview 117

Fig. 1. Main possible mechanisms involved in SUDEP. Epileptic seizures act directly in lung, heart and brain, with multisystem dysfunction. In brain, repetitive epileptic seizures and antiepileptic drugs may act leading to brain volume loss and developing aberrant pathways.

SUDEP, but this may be associated to morphological abnormalities. Considering respiration,

Monitoring of seizures and respiratory function with pulse oximetry has shown that ictal respiratory changes accompany tonic-clonic seizures and even partial seizures, especially those of temporal lobe origin in both, children and adults. This changes diminished central drive that may be associated or not with peripheral airway obstruction (Blum, 2009). The finding of pulmonary edema in 86% of patients that suffered SUDEP at *postmortem*

Investigators have documented a range of respiratory parameters (respiratory effort, airflow, oxygen saturation) in conjunction with time-locked audio-video electroencephalograms and electrocardiograms to provide a more complete picture of the physiologic changes that occur during seizures. Apnea, mainly central, was present in all patients with generalized seizures and approximately one third of patients with complex partial seizures (Walker & Fisch, 1997). In other group of patients with partial seizures without secondary generalized convulsions, 34.8% of seizures had desaturations below 90%,

In heart, dysfunctions causing bradychardia or tachycardia *per se* could culminate in

examination may support this obstructive theory (Salmo & Connolly, 2002).

mechanisms involved are related to decreased ventilation.

**2.1 Respiratory mechanisms** 

risk factors reported previously (Walczak et al, 2001) (Table 1). Authors suggested that a high index will be correlated with a major risk of patient to have SUDEP and that this data could be correlated with others suspected risk factors. Although this inventory was the first attempt to stagger patients in a numeric way, it was not fully accepted and it is not being used in SUDEP literature. A validation with a larger cohort of patients is required to demonstrate if it can contribute to identify patients at major risk.


Table 1**.** SUDEP-7 inventory, from DeGiorgio et al, 2010.
