Scholarly article on topic 'The role of antiepileptic drugs in sudden unexpected death in epilepsy'

The role of antiepileptic drugs in sudden unexpected death in epilepsy Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Dag Aurlien, Leif Gjerstad, Erik Taubøll

Abstract Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults and is the leading cause of death related directly to seizures. High frequency of generalized tonic-clonic seizures is the most important risk factor, and effective seizure protection is probably the most important measure to prevent these tragic deaths. For several years a potential role of antiepileptic drugs (AEDs) has been discussed, but at present there is wide agreement that choice of AED therapy does not influence the risk. However, although it is well known that the efficacy and safety profiles of AEDs may differ significantly when used in the treatment of genetic epilepsy compared to symptomatic or cryptogenic epilepsy, this has generally been overlooked in epidemiologic studies of possible relationships between AEDs and SUDEP. Consequently important information about drug safety may have been lost. This review challenges the current view that no AED can increase the risk of SUDEP.

Academic research paper on topic "The role of antiepileptic drugs in sudden unexpected death in epilepsy"

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Review

The role of antiepileptic drugs in sudden unexpected death in epilepsy

Dag Aurlien3'*, Leif Gjerstadb, Erik Taub0llb

a Neuroscience Research Group and Department of Neurology, Stavanger University Hospital, Stavanger, Norway b Department of Neurology, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway

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ARTICLE INFO

ABSTRACT

Article history:

Received 25 August 2016

Received in revised form 26 October 2016

Accepted 5 November 2016

Available online xxx

Keywords:

Choice

Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults and is the leading cause of death related directly to seizures. High frequency of generalized tonic-clonic seizures is the most important risk factor, and effective seizure protection is probably the most important measure to prevent these tragic deaths. For several years a potential role of antiepileptic drugs (AEDs) has been discussed, but at present there is wide agreement that choice of AED therapy does not influence the risk. However, although it is well known that the efficacy and safety profiles of AEDs may differ significantly when used in the treatment of genetic epilepsy compared to symptomatic or cryptogenic epilepsy, this has generally been overlooked in epidemiologic studies of possible relationships between AEDs and SUDEP. Consequently important information about drug safety may have been lost. This review challenges the current view that no AED can increase the risk of SUDEP.

© 2016 The Authors. Published by Elsevier Ltd on behalf of British Epilepsy Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults. Among neurological conditions causing loss of potential years of life, SUDEP ranges second only to stroke [1]. SUDEP is the leading cause of death related directly to seizures [2,3].

A potential role of antiepileptic drugs (AEDs) in SUDEP has been discussed for several years, and, at present, the leading interpretation of the existing literature is that there is no scientific evidence that any AED can increase the risk [4-8]. The aim of this review is to identify and discuss the strong scientific reasons for giving greater nuance to this widespread perception.

2. Search strategy and selection criteria

We used PubMed to search for references, and references from relevant articles, using the search terms "epilepsy", "epileptic", "antiepileptic", "drugs", "seizures", "risk factors", "sudden", "death", "genetic", "mechanisms", "cardiac", "arrhythmia" and "psychiatric". Only articles in English and published between 1970 and June 2016 were included.

* Corresponding author at: Neuroscience Research Group and Department of Neurology, Stavanger University Hospital, P.O. Box 8100, Stavanger, NO 4068, Norway.

E-mail address: auda@sus.no (D. Aurlien).

References were selected from the identified articles according to their relevance for this review. Using the combination of search terms "SUDEP and epilepsy and risk factors" 233 articles were identified. Among these all studies using living patients with epilepsy as controls examining a possible connection between individual AEDs and SUDEP were selected and included in the review.

3. Pathophysiological mechanisms and risk factors

SUDEP is defined as "sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration > 30 min or seizures without recovery in between), in which postmortem examination does not reveal a cause of death" [9]. The majority of documented observed cases of SUDEP has occurred in association with a generalized tonic-clonic seizure (GTCS) [10-12], although recent evidence suggests that it may also occur without an associated seizure [13]. The cause in individual cases is usually unknown. Nevertheless, there is considerable evidence that respiratory or cardiac mechanisms, separately or in combination, are often involved [14]. Based on documented cases of SUDEP, in which seizure activity was abruptly followed by flattening of the EEG, electrocerebral shutdown has also been proposed as a separate mechanism [15]. Interestingly, the occurrence of ictal hypoxia significantly increases the risk of concomitant cardiac dysfunction [16].

http://dx.doi.org/10.1016/j.seizure.2016.11.005

1059-1311/® 2016 The Authors. Published by Elsevier Ltd on behalf of British Epilepsy Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Interictally, at the group level, the occurrence of cardiac arrhythmias in individuals with epilepsy does not differ significantly from that in the general population [17,18]. However, arrhythmias occur in a significant proportion of seizures, ranging from benign sinustachycardia or bradycardia [19-23] to potentially serious or fatal arrhythmias, including marked sinus arrhythmia, asystole, bundle-branch block, ST-segment elevation or depression, T-wave inversion, or prolongation or shortening of the QT interval [19-21,24,25].

Several studies have documented an association between SUDEP and high seizure frequency [12,26-28] and a history of frequent GTCSs is probably the single most important risk factor for SUDEP [29-32]. In addition, among several studies focusing on different aspects of predisposition, long duration of epilepsy and use of polytherapy have been the most consistently identified risk factors [33].

4. Inappropriate choice of AED therapy may increase the risk of SUDEP

The importance of effective AED treatment in the prevention of SUDEP has been well documented. Whereas untreated patients have been found to be at the highest risk [12], individuals with uncontrolled seizures that have received add-on therapy in effective dosages have reduced their risk more than seven times compared with placebo [34]. Whether or not single specific AEDs can increase the risk of SUDEP has been much debated in recent years. There appears to be broad agreement that if a significant difference is detected between the proportion of SUDEP victims on a certain AED and the proportion on the same drug among controls, then when evaluating whether there is a causal relationship the numbers should be corrected for the frequency of GTCSs [4,5,35]. Importantly, however, it has not been acknowledged that in correcting for seizure frequency, the influence of AED efficacy, which has been demonstrated to be crucial in the prevention of SUDEP, is simultaneously eliminated [34]. A relationship could be regarded as causal, in the sense that an increased occurrence of SUDEP may be caused by an unfavorable choice of AED that provides inferior protection against GTCSs.

5. Channelopathies and AEDs

Channelopathies are diseases caused by mutations in genes coding for ion channels. They are often genotypically and phenotypically heterogeneous, i.e., a certain genetic disorder may be caused by different mutations, and a given mutation may give rise to different phenotypes in the same family [36,37]. The genetic epilepsies have been associated with mutations in genes coding for sodium-, potassium-, calcium- and chloride channels, as well as the nicotinergic acetylcholine receptor and the gamma-aminobutyric acid (GABA) receptor. Among these, sodium channel mutations are the most common [38,39].

Although non channel mechanisms may be involved, blockade of ion channels is the most important mechanism of action for the majority of AEDs [40]. Many of these are sodium channel blockers and, when used to treat genetic epilepsy, may not only provide inferior efficacy, but even cause seizure aggravation. For example, the sodium channel blockers phenytoin (PHT), carbamazepine (CBZ), and lamotrigine (LTG) [41] can cause paradoxical seizure aggravation, particularly in juvenile myoclonic epilepsy of myoclonic jerks [42], and LTG can aggravate severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome) [43], which is caused by a mutation in the neuronal sodium channel gene SCN1A [44]. Nevertheless, investigations of possible associations between AEDs and SUDEP have been performed only at the group level, without examining the genetic epilepsies separately [4,12,26,27,45-47].

Congenital long QT syndrome (cLQTS) is caused by mutations in genes coding for cardiac ion channels, mainly potassium channels and, in a smaller proportion, sodium channels [48,49]. It is associated with prolongation of the QT interval in the ECG and a propensity to syncope, torsade de pointes arrhythmia, and ventricular fibrillation [48,50]. Several drugs, including antipsy-chotics, antihistamines, and antibiotics, can inhibit the cardiac potassium ion current IKr, and several IKr blocking drugs have been excluded or withdrawn from the market because of an unaccept-ably high occurrence of QT interval prolongation, syncope, and sudden death [51,52]. Importantly, individuals with the cLQTS are particularly vulnerable and should generally avoid IKr-blocking drugs [53].

In recent years, increasing evidence has emerged indicating that cardiac and neuronal channelopathies are overlapping. Many of the cardiac ion channel genes causing cLQTS are also expressed in the brain [54]. Animal studies [55,56], along with clinical studies [57,58] and casuistic reports [59-62], suggest that cardiac channelopathies may also be associated with epilepsy. Evidence for the converse, however, that neuronal channelopathies can predispose a patient to cardiac arrhythmia, is sparse. Nevertheless, in casuistic reports of SUDEP in patients with generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome, there has been discussion regarding whether a genetic disposition to fatal cardiac arrhythmia could occur, as the gene product of SCN1A, NaV1.1, is expressed in the heart of mammals [63,64].

Although non channel or non cardiac mechanisms may possibly be involved explaining an association between an AED and SUDEP a key question is whether drugs with the potential to prolong the QT interval can increase the risk of a fatal seizure-related cardiac arrhythmia in genetically predisposed individuals. This possibility was recently addressed in an Australian study of 61 SUDEP victims, in which genetic analysis revealed mutations indicating a predisposition to cardiac arrhythmia in 13 of the deceased; 7% (4/61) had mutations in LQTS genes and 15% (9/61) had mutations in other cardiac arrhythmia genes [65].

6. Individual AEDs and SUDEP

Several AEDs are associated with abnormalities in the cardiac conduction system and rhythmicity, mainly in predisposed individuals [66-68]. CBZ and intravenous PHT can give rise to sinus bradycardia, sinus arrest, and atrioventricular block [69-71], whereas lacosamide has shown a tendency to induce atrioventric-ular block [72]. In addition, the QT interval can be increased by retigabine (Trobalt European Public Assessment Report, EPAR. Committee for Medicinal Products for Human Use (CHMP): www. ema.europa.eu/ema/) and CBZ and primidone can shorten it [67,73]. PHT, phenobarbital (PB), and LTG have been shown to inhibit the IKr [74,75] and a possible role in SUDEP has been suggested. However, among epidemiological studies focusing on a possible relationship between AEDs and SUDEP, only CBZ and LTG have been suggested as being implicated (Table 1) [12,46,47,76,77].

7. CBZ and SUDEP

CBZ was first discussed as a possible risk factor for SUDEP in a study from the Cardiff Epilepsy Unit in 1998, in which 85% of SUDEP victims that were on AED therapy at the time of death were treated with CBZ, compared with only 38% of controls (p <0.01) [47]. Importantly, in this cohort as many as 10 of the 14 SUDEP victims had idiopathic generalized epilepsy (IGE) [78], and 11/ 14 were on CBZ which, when used in the treatment of IGE, may cause seizure aggravation (Table 1) [79]. Three years later, a Swedish case-control study identified high levels of CBZ as a risk factor for SUDEP [46], although it was emphasized that there was

Table 1

Studies examining possible associations between individual AEDs and SUDEP.

Type of study Cases (n)/ controls (n) AED(s) evaluated Result Interpretation by authors

Timmings, 1998 [47] Review of SUDEP cases, 14/1851 CBZ 11/13 (85%) of SUDEP cases were CBZ possibly involved through pro-

comparison with on CBZ, vs. 38% on CBZ in the arrhythmogenic effect

average CBZ usage in cohort (p <0.01)

the cohort

Nilssonet al., 1999 [26] Nested case-control 57/171 PHT, CBZ, No AED associated with Large cohort and differences in SUDEP criteria

VPA increased risk and selection of cases and controls may explain

the lack of association with CBZ

Nilsson et al., 2001 Nested case-control 57/171 PHT, CBZ, High CBZ levels associated with Association may not be caused by CBZ per se, can

[46] VPA increased risk be a surrogate of poor seizure control

Walczak et al., 2001 Nested case-control 20/80 Not specified Serum concentrations ofPHT and No AED associated with SUDEP

[27] CBZ similar as in controls

Langan etal., 2005 [12] Nested case-control 154 cases. CBZ Significantly increased risk with Confounding factors may be present. Causality

4 controls for CBZ should not be assumed

each case, exact

number not

specified

Hitiris et al., 2007 [45] Nested case-control 62/124 CBZ No association with CBZ Theories why studies differ concerning CBZ and

SUDEP not specified

Hesdorffer et al., 2011 Combined analysis of 289/958 PHT, CBZ, In univariate analysis Increased risk with LTG may be caused by inferior

[76] four nested case- VPA, LTG significantly increased risk with efficacy in IGE or arrhythmogenic effect. Further

control studies LTG in IGE independent studies needed to exclude or

confirm an association

Aurlien etal., 2012 [77] Nested case-control 19/63 CBZ, VPA, Significantly increased risk in Causal association possible in females with

LTG females on LTG genetic epilepsy treated with LTG

Hesdorffer et al., 2012 Combined analysis of 216/831 PHT, CBZ, No AED associated with The study provided a "consistent message that

[4] three nested case- VPA, LTG increased risk after correction for number of GTCS increases SUDEP risk and not AEDs"

control studies the frequency of GTCSs at the

group level

Tomson et al., 2012 Analysis of SUDEP >4631/>3131 LTG No significant increase in SUDEP Wide confidence intervals, clinically significant

[35] incidence in (Exact numbers rates with LTG. Although there influence on SUDEP rates by LTG cannot be

42 GlaxoSmithKline not specified) was no SUDEP among excluded

randomized- individuals with only

controlled trials generalized seizures the

proportion was too low to permit

conclusions for this subgroup of

patients

AED, antiepileptic drug; CBZ, carbamazepine; GTCSs, generalized tonic-clonic seizures; LTG, lamotrigine; PHT, phenytoin; SUDEP, sudden unexpected death in epilepsy; VPA, valproate.

uncertainty regarding whether confounding factors could be present. However, in contrast, two later reports found no association between CBZ and SUDEP [27,45]. Furthermore, a large study that included 216 SUDEP cases concluded after correcting for the frequency of GTCSs, that neither the use of CBZ nor any other AED could increase the risk of SUDEP [4]. No increase in SUDEP risk associated with CBZ in monotherapy was detected in the crude analysis (odds ratio 0.7; 95% CI 0.3-1.4), as opposed to CBZ in polytherapy (odds ratio 2.8; 95% CI 1.5-5.3) [4]. As there was no increase in risk with monotherapy in the crude analysis, correction for seizure frequency, which principally eliminates the influence of AED efficacy, cannot explain the finding of a lack of association between CBZ in monotherapy and SUDEP. Nevertheless, a subgroup analysis of individuals with IGE was not performed, and an increased risk with CBZ in IGE cannot be completely excluded based on this study.

8. LTG and SUDEP

Following a clinical observation of four consecutive cases of SUDEP in females with idiopathic epilepsy that had all been treated with LTG in monotherapy, the question was raised as to whether there could be a connection between treatment with LTG in idiopathic epilepsy and SUDEP [80]. One possible explanation that was discussed was that inhibition of the cardiac IKr current by LTG [74] could cause fatal arrhythmia in genetically predisposed individuals. Additionally, the preponderance of females could reflect up to threefold higher risk of drug-induced torsade de pointes arrhythmia in females [81,82]. In line with this, four years

later the International League Against Epilepsy (ILAE) Commission on Epidemiology; Subcommission on Mortality, concluded from their combined analysis of 289 SUDEP cases from four different case-control studies that, using univariate analysis, treatment with LTG was associated with a significantly increased risk of SUDEP

[76]. Importantly, however, when "IGE" and "not IGE" were analyzed separately, the elevated risk was only present in IGE. Conforming with this, a Norwegian study found that the proportion of female SUDEP victims on LTG was significantly higher than the proportion of living female controls with epilepsy on LTG, and that there was a fivefold higher incidence of SUDEP in females on LTG than in females with epilepsy that were not on LTG

[77]. Again, there were no indications of an increased risk in symptomatic epilepsy; the increased risk associated with LTG treatment was apparently only present in idiopathic epilepsy. At the same time as the Norwegian report was published, a new report concluded that, after correcting for the frequency of GTCSs, neither the use of LTG nor any other AED causes an increased risk of SUDEP, as opposed to a high frequency of GTCSs [4]. As the correction for seizure frequency was performed only at the group level, the patient material with an increased risk (IGE) of SUDEP was diluted by the larger subgroup without an increased risk (not IGE). Consequently, the conclusion that there is no causal relationship between LTG treatment and SUDEP that is based on this analysis, is, in our opinion, not valid for the subgroup with IGE.

Interestingly, however, and supporting the results of the Norwegian study [77], the odds ratio for SUDEP in patients on LTG in monotherapy compared with controls was 6.6 for females (95% CI 0.3-174.9) and 0.4 in males (95% CI 0.1-2.8) [4]. Again, the

analysis was performed only at the group level, and therefore it is possible that the lack of statistical significance could be due to dilution of the material.

The importance of AED efficacy in protection against SUDEP was not acknowledged in the ILAE study that claimed an absence of causal relationship between LTG use and SUDEP [4]. Clinical studies have indicated that LTG in IGE provides inferior seizure protection compared with valproate [83,84], which has been recommended as a first-line drug in IGE because of its efficacy [85]. As the most important risk factor for SUDEP is probably a high frequency of GTCSs, use of LTG in IGE with GTCSs could be expected to result in more SUDEP. In summary, the increased occurrence of SUDEP in patients with IGE on LTG could be partly due to a cardiac side effect in genetically predisposed individuals, and partly due to insufficient efficacy; both factors are of importance and may both contribute to SUDEP.

9. AEDs in psychiatry and neuropathic pain

AEDs are also widely used in the treatment of neuropathic pain and psychiatric disorders. To our knowledge, there is no evidence of an increased occurrence of sudden death associated with neuropathic pain syndromes, but among individuals with psychiatric diseases the incidence of sudden death is significantly elevated [86]. The reasons for this are probably multifactorial, including an increased occurrence of cardiovascular disease in this population [87]. However, several antipsychotics and antidepressants possess the ability to inhibit the IKr and have been associated with increased risk of QT interval prolongation, torsade de pointes arrhythmia, and sudden death [88]. Whether AEDs that can inhibit the IKr contribute to the greater occurrence of arrhythmias and sudden death in patients with psychiatric disorders have not been explored scientifically as far as we are aware. However, combining drugs with IKr blocking properties may be hazardous [74,88]; thus treatment with a combination of an IKr-blocking AED and a psychotropic drug, particularly in patients with a predisposition to cardiac arrhythmia, may put the patients at an unacceptably elevated risk of sudden death.

10. Conclusions

A high frequency of GTCSs is probably the single most important risk factor for SUDEP, and therefore effective AED therapy remains a cornerstone in its prevention. Thus, optimal choice of treatment, according to epilepsy syndrome and seizure type, is key for reducing the risk of SUDEP.

Because the efficacy and safety profiles of AEDs may differ, studies on possible associations between AED treatment and SUDEP should be performed separately for genetic epilepsy and symptomatic or cryptogenic epilepsy.

In patients with a predisposition to cardiac arrhythmia, caution should be exercised when considering the introduction of AEDs with the potential to interfere with cardiac rhythmicity or conduction system. Caution is particularly recommended in prescribing LTG for treatment of females with IGE and GTCSs. Importantly, however, this should not discourage the use of LTG in symptomatic or cryptogenic epilepsy in which there is no scientific evidence suggesting an increased risk.

Advances in detecting mutations that may predispose patients to serious cardiac arrhythmias will hopefully enable clinicians to improve safety in the treatment of people with epilepsy.

Conflict of interest statement

The authors have no conflict of interest.

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