Sudden Unexpected Death in Epilepsy: An Overview

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Sudden Unexpected Death in
Epilepsy: An Overview
Vera C. Terra1, Américo C. Sakamoto1,
Hélio R Machado1 and Fulvio A. Scorza2
1Centro de Cirurgia de Epilepsia (CIREP). Departamento de Neurociências e
Ciências do Comportamento. Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo. Ribeirão Preto, São Paulo,
2Disciplina de Neurologia Experimental. Universidade Federal de São Paulo,
Escola Paulista de Medicina (UNIFESP/EPM), São Paulo,
Brasil
1. Introduction
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 post-
mortem 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).

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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 person-
years. 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

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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

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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.
SUDEP RISK FACTOR SCORES
1. More than three tonic clonic seizures in last year 0 or 2
2. One or more tonic-clonic seizures in last year 0 or 1
3. One or more seizures of any type over the last 12 months 0 or 1
3. More than 50 seizures of any type per month over the last 12 5. months 0 or 2
4. Duration of epilepsy of ≥ 30 years 0 or 3
5. Current use of three or more antiepileptic drugs 0 or 1
6. Mental retardation, intelligent coefficient < 70 or too impaired test 0 or 2
Table 1. SUDEP-7 inventory, from DeGiorgio et al, 2010.
2. Mechanisms of SUDEP
SUDEP is probable related to a set of risk factors that may involve structural, functional and
genetic causes (Figure 1). As well as risk factors, the pathophysiology of SUDEP remains
unclear, but a post-ictal central or obstructive apnea or a cardiac arrhythmia seems to
represent the most likely mechanisms (Ryvlin et al, 2009). Experimental studies have
suggested that damage to the central nucleus may be of functional significance in patients
with SUDEP in particular with regard to their susceptibility to cardiac arrhythmias. In this
way, neuronal loss was observed in the medial division of the lateral amygdaloid nucleus in
SUDEP cases, but it seems not to be a specific finding since this pattern was present in
patients that did not suffered SUDEP (Thom-M et al, 1999). Corroborating the hypotheses of
neuronal loss, there are evidences of heat shock protein positive neurons in the
hippocampus in SUDEP, suggesting an ante-mortem neuronal injury (Thom et al, 2003).
Physiologic studies in humans during seizures identified in some cases a central apnea,
occasionally followed by asystole; in others patients, cardiac arrhythmia, of reflex neural
origin, have been detected (Garaizar, 2000; Hennessy et al, 2001). The cardiac mechanism of
greatest interest is the precipitation of arrhythmias by seizure discharges via the autonomic
nervous system (Jehi & Najm, 2008). Studies assessing autonomic tone with functional tests
as deep breathing, Valsalva maneuver, isometric exercise, cold pressor and tilt-table
observed a higher vasomotor tone, higher sympathetic tone, lower parasympathetic tone,
lower parasympathetic reactivity and more severe dysautonomia in the refractory epilepsy
subjects. In this way, refractoriness may lead to an alteration in cardiovascular autonomic
regulation, which might be a predisposing factor for SUDEP (Mukherjee et al, 2009).
There are few studies reporting genetic mutations in patients with SUDEP and most of them
evaluated genes responsible for long QT syndrome. Recent studies demonstrated mutations
in the SCN5A and KCNH2 genes coding for the cardiac sodium channel alpha subunit and
raises the possibility that the mutation may explain both the epilepsy and the sudden death
(Aurlien ET AL, 2009; Tu et al, 2010) and since, channelopaties may be another risk factor for
SUDEP to be considered in patients with epilepsy.

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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.
In heart, dysfunctions causing bradychardia or tachycardia per se could culminate in
SUDEP, but this may be associated to morphological abnormalities. Considering respiration,
mechanisms involved are related to decreased ventilation.
2.1 Respiratory mechanisms
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
examination may support this obstructive theory (Salmo & Connolly, 2002).
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%,

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31.8% had desaturations below 80% and 12.5% had desaturations below 70%, which was
significantly correlated with seizure duration and with electrographic evidence of seizure
spread to the contralateral hemisphere. In this study, central apneas or hypopneas occurred
in 50% of 100 seizures and mixed or obstructive apneas occurred in 9% of these seizures.
Considering these findings, authors concluded that ictal hypoxemia occurs often in patients
with localization-related epilepsy and may be pronounced and prolonged even with
seizures that do not progress to generalized convulsions (Bateman et al, 2008).
Interestingly other study observed a close temporal relationship between spread of seizures
to the contralateral hemisphere and the onset of seizure-associated apnea. Apnea onsets are
more tightly linked to time of contralateral spread than to time of seizure onset, suggesting
that contralateral seizure spread in patients with temporal lobe epilepsy may be a risk factor
for ictal-related respiratory dysfunction (Seyal & Bateman, 2009). This finding did not alter
the ability of postictal respiratory function, respiratory rate and amplitude that is even
increased after the end of the seizures (Seyal et al, 2010).
Ictal/postictal hypoventilation may contribute to SUDEP with the resulting hypoxemia and
acidosis leading to inadequate cortical function recovery and eventual cardiac failure
(Bateman et al, 2010; Lhatoo et al, 2010). Alternatively, excessive post-seizure brainstem
inhibition might result in blunting or transient abolition of central hypoxic and hypercarbic
respiratory drive, with consequent post-ictal respiratory arrest, hypoxia exacerbation and
death due to hypoxia/insufficient re-establishment of respiration and terminal cardiac
arrhythmia (Timmings, 1998).
Corroborating this hypoventilation theory, studies of audiogenic seizure susceptible mice
with generalized convulsive seizures demonstrated that electrocardiographic activity was
detectable for four to six minutes after respiratory arrest and death was reversible with
ventilation. If not reversed these animals die from respiratory arrest after generalized
seizure, that is, die of SUDEP (Faingold et al, 2010).
2.2 Cardiac mechanisms
Cardiac arrhythmogenesis and cryptogenic epilepsy can be due to ion channel dysfunction
and may coexist in the same patient, leaving them more susceptible for recurrent
arrhythmias. In this way, epileptic survivors of near-sudden cardiac death may be at
significantly greater risk of suffering of SUDEP (Badheka et al, 2010). Cardiac mechanisms
involved in SUDEP may be associated with heart rate dysfunction, morphology of cardiac
waves, anatomic disorders or what some authors refer as brain collapse. Considering this
last hypothesis, recently there is a description of a patient submitted to ambulatory EEG that
suffered a generalized tonic-clonic seizure that abruptly ended with cessation of all cerebral
electrical activity and after a few seconds patient evolved to asystole and death. The
circumstance was typical of SUDEP and in this case seems to be related to abrupt
irreversible cerebral electrical shutdown during a seizure (McLean & Wimalaratna, 2007).
Also, the circadian heart-rate variability might be of relevance to SUDEP risk. Studies
evaluating heart rate observed that patients with epilepsy may have one or more
abnormalities of rhythm and/or repolarization during or immediately after seizures.
Abnormalities included asystole, atrial fibrillation, marked or moderate sinus arrhythmia,
supraventricular tachycardia (Figure 2), atrial premature depolarization, ventricular
premature depolarization and bundle-branch block (Nei et al, 2000). Electrocardiogram

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(ECG) abnormalities is more frequently observed in patients with refractory focal epilepsies
(Surges et al, 2010), generalized tonic-clonic seizures and prolonged complex partial seizures
(Nei et al, 2000). In this way, ictal or postictal dysregularion of the autonomic nervous
system, affecting heart rate variability may contribute to SUDEP incidence.
Fig. 2. Ictal tachycardia in a patient with temporal lobe epilepsy. Cardiac rate is illustrate
one minute before seizure onset (pre), one minute after seizure onset (1 min), five hours
after seizure end (5 hours) and 8 hours after seizure end (8 hours).
Heart rate abnormalities may be relative to tachycardia or asystole and heart rate variability
reflects the integrity of vagus nerve-mediated autonomic control of the heart (DeGiorgio et
al, 2010). Tachycardia is the main cardiac abnormality observed during seizures (Walker &
Fisch, 1997) and fatal tachyarrhythmia as one plausible cause for SUDEP. This arrhythmia is
more frequently observed during generalized tonic-clonic seizures, but tachycardia may be
observed also in complex partial seizures (Surges et al, 2010). Evaluating the different
studies, we observed interesting findings. Person et al (2007) observed that there was no
major effect of epilepsy on heart rate variations in patients with untreated epilepsy, recently
diagnosed. However, when patients were used as their own controls, heart rate variability
was significantly lower after initiation of the treatment with AED and even more during the
night, when the risk of SUDEP seems to be higher (Persson et al, 2007). Considering this
hypothesis, Surges et al (2009) evaluated retrospectively the heart rate variability in 14
patients with chronic epilepsy (seven of them died from SUDEP). Authors could not
determine a clear-cut ECG abnormality that may be considered as a predictor for SUDEP.
However, in other studies, authors observed an elevation of heart rate immediately after
seizures, which were maintained for 5-6 hours postically, indicating a long-term postictal
disturbance of the autonomous nervous system, suggesting that seizures may cause
prolonged heart dysfunction (Toth et al, 2010; Pinto et al, 2011).
Although seizure-induced asystole is a rare complication and tended to follow a period of
apnea, epilepsy can be correlated to severe bradycardia or asystole (Walker & Fisch, 1997).
The event appeared mainly in focal epilepsies and ictal bradycardia and asystole have been
implicated in the etiology of SUDEP. Some authors suggested that this abnormality is most

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related to left side lateralization and that abnormally long postictal periods with altered
consciousness might be associated with reduced cerebral perfusion because of ictal asystole.
This could be related or not to central ictal apnea (Rocamora et al, 2003). In this way, Zubair
et al (2009) described a patient with a history of complex partial seizures and drop attacks
that presented during the video-monitoring a complex partial seizure with brady-
arrhythmia followed by asystole. This patient was treated with a cardiac pacemaker and on
follow-up, despite patient continued to present simple and complex partial seizures, drop
attacks disappeared, confirming its cardiogenic origin.
Considering morphology of QRS complex, co-registered EEG and ECG showed a significant
increase in the mean corrected QT (QTc) during interictal discharges, when compared
retrospectively patients that died of SUDEP and patients that were still alive (Tavernor et al,
1996). Comparing patients with chronic epilepsy and normal matched control, the mean
interictal QTc among epilepsy patients was significantly shorter than the QTc in the control
group. Duration of the epilepsy, type of seizures and number of antiepileptic drugs were not
significantly correlated to QTc. Nevertheless, patients with cryptogenic temporal lobe
epilepsy had a mean QTc significantly shorter than patients with symptomatic epilepsy (Teh
et al, 2007). Shortening of QTc also occurred in patients during the early postictal phase and
significantly more often in secondarily generalized tonic-clonic seizures (Surges et al, 2010).
Other authors reported the opposite, i.e. a significant lengthening of corrected QT cardiac
repolarization time during some epileptic seizures considering this QT abnormality a
potential risk factor for SUDEP (Brotherstone et al, 2010).
Anatomic examination of the heart of patients that died from SUDEP demonstrated an
increased weight in some cases, suggesting that cardiac pathology including cardiac
conduction pathology and coronary artery atheroma may contribute to SUDEP. In some of
the epileptic deaths subtle abnormalities of the conduction system were identified and these
may contribute to death by causing cardiac arrhythmia, when associated with apnoea,
bradycardia or other cardiac arrhythmia related to an epileptic seizure (Opeskin et al, 2000).
In patients with SUDEP, histological evaluation reveled foci of fibrotic changes that
predominated in the deep and subendocardial myocardium of the SUDEP cases. Patient in
this group were mainly young women with a mean late epilepsy onset, and infrequent
seizures (P-Codrea et al, 2005). Authors suggested that fibrosis may be the consequence of
myocardial ischemia as a direct result of repetitive epileptic seizures and these changes,
when coupled with the ictal sympathetic storm, may lead to lethal arrhythmias (P-Codrea et
al, 2005).
2.3 Brain mechanisms involved in SUDEP
The limbic system is often seen as a structure that ties together higher functions with
autonomic and motor control to generate integrated behavior (Figure 3). This includes
cortical control of the heart rate, particularly considering operculo-insulo-mesiotemporal-
orbital pathway and the cingulate cortex (Devinsky et al. 1995). Simulation of the cingulate
cortex may produce tachycardia or bradycardia (Pool et al. 1949). Asystole observed after
cingulate cortex stimulation suggest a cortical control of heart rate on physiological basis. A
parasympathetic-mediated pathway that involves the limbic system is possible the way
bradyarrhythmia occur and may be implicated for the mechanism of SUDEP (Leung et al,
2007).

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Fig. 3. Left mesial temporal sclerosis, a main cause of refractory epilepsy and observed in
some patients that died from SUDEP.
Data from intracranial EEG records demonstrated that bradyarrhythmic episodes were
mostly associated with temporal lobe seizures, nevertheless, seizure involvement of insular
cortex or cingulated cortex could not be excluded (Altenmüller et al. 2004, Devinsky et al.
1997; Rossetti et al. 2005; Kahane et al. 1999). Also, some studies suggest amygdala central
nucleus damage may contribute to SUDEP considering that his structure can play a role in
respiratory timing (Nashef et al, 1996; Stollberger & Finsterer, 2004; Ryvlin et al, 2006; So,
2008; Surges et al, 2009.
Therefore, studies demonstrated a reduction of sympathetic cardiovascular modulation after
temporal lobe epilepsy surgery that might result from decreased influences of interictal
epileptogenic discharges on brain areas involved in cardiovascular autonomic control.
Temporal lobe epilepsy surgery seems to stabilize the cardiovascular control in epilepsy
patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive
bradycardiac counter-regulation, and might contribute to reduce the risk of SUDEP (Hilz et
al, 2002). Moreover, left temporal lobe epilepsy surgery is associated with a reduction (but
not a normalization) of the overall mortality associated with chronic epilepsy. In patients
with right-sided mesial temporal lobe sclerosis however, the postoperative mortality has
remained similar to other groups with medically intractable seizures (Hennessy et al, 1999)
Interestingly, laterality of epileptic foci has been reported as related to ictal
bradyarrhythmia, with left-side-onset being often observed, although the cerebral patient
dominance may also need to be taken into account (Kahane et al. 1999; Tinuper et al. 2001).
The laterality observed made researchers suspect parasympathetic system activation may be
more influenced by the lef side or dominant hemisphere (Oppenheimer et al, 1992). The
induction of bradyarrhythmia by direct stimulation of the left insular cortex but not the
right insular cortex corroborates this hypothesis (Leung et al, 2007).
Others brain regions such as the cerebellum may be involved with breathing and cardiac
control (Lutherer et al, 1983; Harper et al, 2000; Xu et al, 2001; Harper, 2002; Xu & Frazier,
2002; Harper et al, 2005.). Cerebellum has been correlated with regulation of blood pressure
(limiting extreme changes in blood pressure with hypotension or hypertension) and
breathing rhythm (Harper et al, 2005). Patients with epilepsy frequently have abnormalities

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of cerebellum, especially diffuse atrophy and this finding is probable related to chronic use
of AEDs, age, presence of generalized tonic-clonic seizures, duration of epilepsy, or the
seizure activity itself, causes also related to SUDEP occurrence (Engel, 1993; Specht et al,
1997; Sandok et al, 2000; Lawson et al, 2000; Hagemann et al, 2002). In respect to AED, it
seems that prolonged use of phenytoin or phenytoin intoxication may induce severe
irreversible cerebellum volume loss that chronically may predispose individuals to SUDEP
(Masur et al, 1990; Ney et al, 1994). Cerebellum lesions or dysfunction is reported in patients
with sudden infant death syndrome, a sleep-related syndrome suspected of resulting from a
failure of enhanced respiratory efforts that compensate transient hypotension. This
syndrome may also be related to an inability to recover from an excessive CO2 challenge
(Martin et al, 1996; Harper, 1998; Harper et al, 2000a; Harper et al, 2000b). Moreover,
cerebellum injury was reported in patients with congenital central hypoventilation
syndrome, a condition with deficient response to hypercapnia and hypoxia, with possible
dysfunction of cerebellum, thalamic nuclei, basal ganglia and limbic structures (Harper et al,
2000b; 2005). In adults, a high incidence of obstructive apnea is observed in patients with
olivopontocerebellar geneneration (Chokroverty et al, 1984). Considering all together, these
evidences may suggest cerebellum lesion may directly affect the ability of central nervous
system to react to acute respiratory and cardiac changes, such as apnea and hypopnea, or
extreme hypotension or arrhythmia. These dysfunctions may be quite common in patients
with epilepsy, especially during generalized tonic-clonic seizures, with a repetitive exposure
to this risk in patients with refractory epilepsies. These dysfunctions seem also to be more
evident during sleep, time when SUDEP is more common and, in this way, cerebellum
lesion with consequent functional impairment may be a main risk factor for SUDEP
occurrence and methods to prevent it, such as use of lower doses of AED should be
considered.
Considering that parasympathetic activity is possible involved in SUDEP mechanisms, it is
interesting to evaluate the effect of vagus nerve stimulation (VNS) on SUDEP incidence.
VNS is a non-pharmacological therapy approved by the FDA for treatment of patients with
epilepsy who are unsuitable candidates for epilepsy surgery. The precise mechanism of
action of VNS remains unknown, but available evidence suggests that central autonomic
nervous system pathways are involved, since vagus nerve influences many regions of
central nervous system, through its extensive connectivity with nucleus of solitary tract
which projects to reticular formation, hypothalamus, hippocampus, amygdale, dorsal raphe
nucleus, locus ceruleus, thalamus and cerebral cortex. The most frequently VNS adverse
effects typically occur during stimulation, but there are no apparent effects of VNS on
vagally mediated visceral function (Schachter, 2006). In many series of patients chronically
implanted with VNS, SUDEP cases are reported (Annegers et al, 1998; 2000; Ardesch et al,
2007; El Tahry et al, 2010). However, a cohort study of 791 implanted with VNS system
(Annegers et al, 1998) and extended for 1,819 individuals (Anneger et al, 2000) showed a
similar mortality and SUDEP rates to those reported from cohorts of severe epilepsy.
Experimental models of epilepsy had demonstrated VNS-induced changes in hippocampal
neurotransmitter levels, increasing hippocampal noradrenaline concentration. VNS also
increased the latency between pilocarpine infusion and the onset of epileptiform discharges,
and reduced the duration and severity of pilocarpine-induced limbic seizures (Klein &
Ferrari, 2009). Other authors demonstrated an increase in the number of cells in the dentate
gyrus, dentritic complexity and BDNF expression after acute or chronic VNS stimulation

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(Raedt et al, 2011). However, although these morphological and functional changes have
been described, there was not a significant impact on the incidence of SUDEP, suggesting
that another factor, such as better seizure control might be involved.
2.4 Experimental models
Experimental models of epilepsy are fully studied in different research centers, but there are
few models that can mimic SUDEP. Maybe the most related model in the literature is the
one described by Szabó et al (2005) of genetic idiophatic epilepsy in baboons. Authors
studied the occurrence of natural death in these animals and the pathological findings in
necropsy (Szabó et al, 2009). Overall, animals with epilepsy died early than no epileptic
animals and, considering group with epilepsy, animals that had a definite cause of death
died significantly younger age than those epileptic animals whose cause of death could not
be determined. Predominant causes of death in these animals with epilepsy were infection
and trauma. Interestingly animals with unknown cause of death had a history of more
frequent seizures and a longer duration of epilepsy. Autopsy of animals with unknown
cause of death revealed pulmonary edema and chronic fibrotic changes in the myocardium
and since animals were in a good health and died suddenly and unexpectedly the cause of
death was considered SUDEP. This interesting model may be the best one available to study
mechanisms and risk factors of SUDEP in human since clinical and pathological findings are
very close in both species. In this way, authors suggested that phylogenetic similarities
between species may permit transpose research information and contribute to elucidation of
this devastating complication.
Other experimental models were described in the literature that confirms the suspicions of
respiratory and cardiac mechanism involved in SUDEP genesis (Tupal et al, 2006; Scorza et
al, 2009). In these models it was raised the possibility that an imbalance in neurotransmitter
level, especially serotonin, may contribute to autonomic changes. Serotonin down regulation
was observed in a model of epileptic mice that have respiratory changes and death
following epileptic seizures. Pharmacological enhancement of serotonin in this model
reduced significantly seizures related respiratory arrest. One other model of experimental
epilepsy (epilepsy-prone rats – GEPR) with decreased hippocampus serotonin receptor
shows an increase in seizure susceptibility, but it is not possible yet to exclude the role of
other neurotransmitters in this model. Studies with positron emission tomography in
patients with epilepsy have shown conflicting results about serotonin receptor expression,
with reports of decreased, increased or unchanged binding (Theodore, 2003). In this way,
although more studies are needed to elucidate this issue, it seems plausible to consider, at
least with respect to serotonin levels in experimental epilepsy, that there is a cause effect
relation between serotonin deficiency and respiratory abnormalities and seizure
susceptibility and this may be considered as a possible factor influencing SUDEP risk.
3. Patient information and prevention
There is no consensus regarding the information if risk of SUDEP should be delivered to all
patients with epilepsy, but it seems reasonable to individualize this information according to
patient particularities (Ryvlin et al, 2009). Some authors recommend universal discussion of
SUDEP considering that patients and their families have the right to know about the risks of
epilepsy and the reasons for treatment, while others consider that SUDEP should be discussed

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124
only with patients at high risk (Brodie & Holmes, 2008). This controversial issue has greater
weight due the reports of patients with idiopathic epilepsies, with rare seizures that suffered
SUDEP and considering these patients are more susceptible to poor drug compliance and then
tonic-clonic seizures, it should be advisable to discuss this matter with them.
A study conducted in Ingland found that people with epilepsy wanted to know more
information about the causes of epilepsy and other matters, such as SUDEP (Prinjha et al,
2005). However, a study conducted in Australia demonstrated that risk factors for SUDEP are
not amenable to modification and in this way, discussion of SUDEP with patients could not
alter outcome. Authors consider that information of SUDEP may adversely affect patients and
families quality of life and suggested that an open and frank discussion of SUDEP risk should
be reserved to those patients that seek the information (Beran et al, 2004).
The mechanisms underlying SUDEP are unclear, and there are no effective preventative
therapies (Brodie & Holmes, 2008). However, even without precise knowledge of the
underlying pathogenic mechanism(s), SUDEP prevention could start with the identification
of the most prominent risk factors. SUDEP seems to occur more commonly during sleep and
it preferentially affects young adults with medically intractable epilepsy (especially tonic-
clonic seizures), individuals who also have neurologic comorbidity, and patients receiving
antiepileptic drug polytherapy (Asadi-Pooya & Sperling, 2009). Considering SUDEP is
probable a multifactorial event and not all risk factors are determined, now prevention
should be centered on that most potential suspected risk factors, with effective seizure
control, an optimal antiepileptic drug compliance, night supervision (since almost all deaths
occur at night), control of tonic-clonic seizures, prevention of airway obstruction and
postictally respiratory stimulation (Tao et al, 2010; Ryvlin et al, 2009; Langan et al, 2005;
Langan et al, 2000). Also patients should routinely be investigated for the presence of ictal
arrhythmias and whenever necessary the insertion of a pacemaker may be indicated,
preventing life-threatening cardiac arrest, syncope and trauma (Strzelczyk et al, 2008).
Ideally, caregivers should be able to deliver appropriate first aid after epileptic seizures with
the guarantee of properly airway flow, stimulation to decreases the duration of postictal
apnea and encourage epilepsy patients to sleep in the supine position. It is not clear whether
these practices will prevent SUDEP, but they may be reasonable measures to suggest when
discussing this issue with patients (Walczak et al, 2001). This prophylaxis orientation should
be a routine during epilepsy patient attendance (Jehi & Najm, 2008).
Early identification of patients at risk of SUDEP would offer a unique opportunity for
intervention to prevent this devastating condition (Jehi & Najm, 2008). Compliance with
treatment clearly influences the frequency of tonic-clonic seizures, being of paramount
importance in SUDEP prevention. Also compliance should be encouraged since it may
prevent SUDEP in an epilepsy population with rare seizures, which is less closely followed.
Physicians should make an effort to control tonic-clonic seizures with the fewest
antiepileptic drugs as possible since politherapy has been also implicated as a risk factor for
SUDEP (Walczak et al, 2001).
There are few studies that examined thoroughly brain of patients that suffered SUDEP
especially that areas considered to have a main function on respiratory and cardiovascular
regulation and these issues represent a specific line of research in the SUDEP field that
should be investigated. Early and successful epilepsy surgery for drug-resistant epilepsy
may significantly reduce the risk of SUDEP, thus patients with definite pharmacologic
refractory epilepsies should be referred to an epilepsy surgery center (Shuele et al, 2007).

Sudden Unexpected Death in Epilepsy: An Overview
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Confirming this statement studies involving epilepsy surgery programs clearly suggested
that successful epilepsy surgery reduces the impending risks of SUDEP. In cohorts in whom
the estimated risk of SUDEP is almost 1% per year without surgery, SUDEP incidence was
significantly lower following epilepsy surgery (Schuele et al, 2007; Jehi & Najm, 2008).
Although, not all refractory epilepsy patient is eligible for surgery and in this way,
clarification of risk factors and establishment of the mechanisms of SUDEP are important so
that as many people as possible can be saved from SUDEP (Bells & Sander, 2006). Further
large-scale, multicenter, case-control or cohort prospective studies are needed to assess the
role of AEDs and other potential risk factors in order to form a basis for treatment strategies
aiming seizure control and prevention of SUDEP (Tomson et al, 2005). Postmortem
examinations of all potential SUDEP patients are also essential, with a dedicated forensic
protocol that will permit the correct differential diagnosis (So, 2006).
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