
==== Front
CNS Drugs
CNS Drugs
CNS Drugs
1172-7047
1179-1934
Springer International Publishing Cham

39112912
1112
10.1007/s40263-024-01112-0
Review Article
Antiseizure Medications and Sudden Unexpected Death in Epilepsy: An Updated Review
http://orcid.org/0009-0002-5384-9975
Bosch Anemoon T. 1
http://orcid.org/0000-0001-6041-9661
Sander Josemir W. 12345
http://orcid.org/0000-0003-1435-8970
Thijs Roland D. rthijs@sein.nl

123
1 https://ror.org/051ae7717 grid.419298.f 0000 0004 0631 9143 Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands
2 grid.10419.3d 0000000089452978 Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands
3 grid.83440.3b 0000000121901201 UCL Queen Square Institute of Neurology, London, WC1N 3BG UK
4 grid.452379.e 0000 0004 0386 7187 Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ UK
5 grid.13291.38 0000 0001 0807 1581 Neurology Department, West China Hospital, Sichuan University, Chengdu, 610041 China
7 8 2024
7 8 2024
2024
38 10 807817
15 7 2024
© The Author(s) 2024
2024
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Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic–clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-024-01112-0.

Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsiehttp://dx.doi.org/10.13039/501100006117 Epilepsiefonds (2023-04) Bosch Anemoon T. issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcKey Points

There is no robust evidence that the use of specific antiseizure medications (ASMs) aggravates sudden unexpected death in epilepsy (SUDEP) risk.	
There is some evidence suggesting a protective effect for users of ASM polytherapy, levetiracetam, or statins.	
We found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of seizure detection devices (SDD) on SUDEP occurrence.	

Introduction

Sudden unexpected death in epilepsy (SUDEP) is the most critical cause of epilepsy-related death in people with epilepsy. The incidence of SUDEP is around 1 per 1000 person-years, but individual risk may vary in specific subgroups.[1]

The mechanisms of SUDEP are poorly understood, but epidemiological studies have identified various risk factors.[1] Having frequent tonic-clonic seizures (TCS) appears to be the most substantial risk factor for SUDEP, mainly when unwitnessed at night.[1–4] Preventive strategies could focus on averting TCS or interrupting the seizure-induced SUDEP cascade (see Fig. 1). With the knowledge gap on SUDEP pathophysiology, targeted strategies are lacking.Fig. 1 Opportunities for preventing sudden unexpected death in epilepsy (SUDEP). Epilepsy treatments, including antiseizure medications (ASMs), can avert tonic–clonic seizures. These treatments and concomitant non-epilepsy drugs may also modulate the SUDEP cascade through internal factors. Seizure detection methods could disturb the SUDEP cascade by providing external stimuli (e.g., alerting caregivers or targeted stimulation)

There is some evidence that antiseizure medications (ASMs) and other epilepsy treatments may reduce SUDEP risk by decreasing TCS.[5] It is debated whether specific ASMs may reduce or aggravate this risk beyond seizure control by, e.g., influencing the likely physiological cascade leading to SUDEP. This would require studies that correct for seizure burden. Another challenge is expressing ASM exposure, given the often varying prescriptions over time and the inevitable limitation of determining actual intake.

Alternative preventive strategies could modulate the SUDEP cascade through non-epilepsy concomitant drugs and interventions preventing seizures from going unnoticed. Seizure detection devices can alert for potentially dangerous seizures and allow caregivers to intervene, but the effect on SUDEP is yet unknown.

We review the main risk factors for SUDEP and potential mechanisms. We provide a systematic review of the influence of ASMs and other medications on SUDEP occurrence while considering the above. We also review the evidence of seizure detection devices as an alternative preventative strategy in the context of SUDEP risk.

SUDEP Risk Factors and Mechanisms

Risk Factors for SUDEP

Several clinical factors have been identified that enhance the risk for SUDEP. Having TCS is the major risk factor and seems to be similar to focal to bilateral or generalised tonic-clonic seizures.[1, 6] The risk appears to rise proportionally with the number of seizures.[1] For example, the SUDEP risk for adults with epilepsy who have three or more TCS a year is threefold higher (Odds Ratio (OR) 15) compared to adults with 1–2 TCS (OR 5). If the TCSs are nocturnal, the risk further increases.[2–4]

SUDEP events are mainly unwitnessed, particularly if occurring during the night.[2] Accordingly, sleeping alone may potentiate the SUDEP risk. For example, people with TCS not sharing bedrooms have a 67-fold increased risk compared to a 19-fold risk for those with TCS who have roommates.[3]

Other suggested risk factors include longer epilepsy duration, presence of learning disabilities and male gender, but with only weak circumstantial evidence.[1]

Proposed Mechanisms of SUDEP

SUDEP pathophysiology is largely unknown. Eyewitness reports suggest that SUDEP typically occurs in the postictal phase, especially after a TCS.[7] SUDEP victims are often found in the prone position, and this could be explained by the natural sleeping position or by a fatal seizure leading the victim to end up prone.[8, 9]

The MORTEMUS study reported eleven cases of SUDEP with simultaneous video–EEG recordings.[10] All died in the aftermath of a TCS, mostly occurring from sleep. The nine cases where ECG data was available suggested the same sequence of events: a terminal central apnoea followed by terminal asystole. This seems to suggest that central respiratory problems are the initiating event of SUDEP. Yet it is not understood why the postictal phase in these rare occasions evolves into SUDEP while, in most cases, they do not.

A possible explanation for the underlying mechanism of postictal respiratory dysfunction is that spreading depolarisation interrupts the respiratory control mechanisms in the brainstem.[11] This may be indirectly reflected by the absence of cortical EEG activity before cardiorespiratory failure in all MORTEMUS cases.[10] This phenomenon is also frequently seen in non-fatal TCS.[12] Functional neuroimaging in SUDEP cases, and those at elevated risk suggested alterations to brain structures and networks involved in central autonomic and respiratory control.[13] Apnoea may result from inhibiting brainstem chemoreceptors that, in a healthy state, would stimulate breathing in response to hypercapnia. Serotonin (5-hydroxytryptamine, 5-HT) neurons likely play a vital role in this response.[11] Rodent studies showed an increased risk for respiratory and cardiac arrest after a seizure and subsequent death in knockout models for serotonin receptor genes.[11] Clinical data suggested that selective serotonin reuptake inhibitors (SSRIs) can reduce postictal hypoxia in focal seizures.[14] Other neuromodulators hypothesised to contribute to SUDEP by promoting respiratory depression include adenosine, GABA and opioids.[15]

Another proposed, less well-documented pathway for SUDEP is seizure-induced ventricular fibrillation.[7] This might arise due to seizure-induced ischemia or cardiac repolarisation abnormalities. Documented evidence is, however, lacking as the reported cases were successfully resuscitated.[7] Nevertheless, a community-based study suggested an increased risk for ventricular fibrillation/ventricular tachycardia in people with epilepsy. [16] The majority of cases could be explained by acute cardiovascular pathology and thus labelled as sudden cardiac death (SCD). Still, some cases did not have these signs and could be classified as SUDEP, suggesting an overlap between both conditions. [17] The risk for SCD and seizure-induced arrhythmias can be explained by the high burden of cardiovascular comorbidities in people with epilepsy. [18, 19] Recurring seizures over time could also lead to cardiac structural changes. This concept is known as the ‘epileptic heart’ and could contribute to the SUDEP cascade. [20]

Genetic profiles may alter the susceptibility to SUDEP. Some syndromes are characterised by a notably high SUDEP incidence, including conditions linked to SCN1A, SCN2A, SCN8A and STXBP1 genes.[21] A possible explanation is the high seizure burden among these cases, thus increasing the SUDEP risk. Alternatively, these syndromes are associated with an increased SUDEP susceptibility through factors promoting the internal SUDEP cascade. Post-mortem studies of SUDEP cases have suggested that mutations associated with cardiac arrhythmia are more prevalent among SUDEP victims.[22] It is unclear whether mutations are linked to arrhythmias in these individuals and whether these arrhythmias contributed to SUDEP. There is some evidence that SUDEP may result from increased genetic susceptibility through polygenic rare deleterious variants.[23]

The Role of ASMs, Other Drugs, and Seizure Detection Devices

We searched PubMed, Embase, and Cochrane databases, using terms such as “SUDEP,” “AED,” and “ASM.” The final search was conducted in February 2024. This search yielded 2917 articles, of which we only considered studies with SUDEP as an independent outcome and a control group as relevant. We present the ASM studies per prescribing scenario (starting, adding or discontinuing an ASM and using specific ASMs) and separately discuss the SUDEP studies evaluating other scenarios, including drugs other than ASMs and SDDs.

ASM Prescribing Scenarios

Starting, Adding and Stopping ASM

We found two retrospective studies evaluating the modulatory effect of starting ASM on SUDEP beyond TCS control (Table 1).[26, 27] One combined analysis found a lower SUDEP risk for those using monotherapy [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.3–0.995] compared to those without ASM use.[26] A more recent and extensive study did not find a significant difference in SUDEP risk comparing no ASMs with monotherapy.[27] It is therefore unlikely that ASM monotherapy lowers SUDEP risk beyond the effect of TCS control. Table 1 Articles on sudden unexpected death in epilepsy (SUDEP) risk for starting or adding antiseizure medications (ASMs), whilst correcting for tonic–clonic seizures (TCS) frequency

Reference	Study type	Population	Cases	Controls	Documentation of ASM use	Polytherapy users among SUDEP cases (%)	Polytherapy users among controls (%)	Effect size [OR (95% CI)]	
[24]	Prospective cohort	PWE evaluated at three upper Midwestern epilepsy centres in the USA	20 SUDEP cases, of which 10 definite and 10 probable	80 living controls, matched for enrollment at the same month and center (4 per case)	Medical records, last registered visit	0–2 ASMs: 11 (55%)

> 2 ASMs: 8 (40%)

	0–2 ASMs: 62 (78%)

> 2 ASMs: 15 (19%)

	0–2 ASMs: 1 (ref.)

> 2 ASMs: 3.8 (1.3–11.1)*

	
[25]	Case–control	PWE (aged 16–50) who died suddenly, identified by coroners and neurologists and by interviews with families, in England and Wales between 1989 and 1998	154 SUDEP cases	616 living controls, matched for age and geographic location from 900 groups of family practitioners throughout the UK (4 per case)	Medical records, not further specified	NA	NA	NA, current polytherapy was not an independent risk factor	
[26]	Combined analysis	Populations of 24, 25 and 31	216 SUDEP cases (definite or probable), combined from the three studies (excluding cases with history of heart disease)	831 living controls, combined from the three studies (excluding cases with history of heart disease)	Medical records, not further specified	NA	NA	No ASMs: 1 (ref.)

1 ASM: 0.5 (0.3–0.995)*

2 ASMs: 0.9 (0.4–1.8)

3 ASMs: 2.0 (0.9–4.1)

≥ 4 ASMs: 1.6 ( 0.6–4.1)

	
[27]	Case–control	PWE registered in the national patient register from 1998–2005, who were alive on 30 June 2006, with follow-up until December 2011	255 SUDEP cases (definite or probable)	1148 living controls, matched for age and gender (5 per case)	Drug dispensing 90 days from index date or date of death	No ASMs: 46 (18%) Monotherapy: 113 (44%)

Polytherapy: 96 (38%):

2 ASMs: 65 (25%)

≥ 3 ASMs: 31 (12%)

	No ASMs: 265 (23%)

Monotherapy: 483 (42%)

Polytherapy: 400 (35%);

2 ASMs: 272 (24%)

≥ 3 ASMs: 128 (11%)

	No ASM: 1 (ref.)

Monotherapy: 0.79 (0.44–1.41)

Polytherapy: 0.48 (0.26–0.90)*:

2 ASMs: 0.59 (0.31–1.12)

≥ 3 ASMs: 0.31 (0.14–0.67)*

	
PWE, people with epilepsy; NA, not applicable. * Significant results

Adding an extra ASM has an apparent protective effect on SUDEP in studies that did not control for seizure burden. Pooled data from 112 double-blind, placebo-controlled randomised trials investigating add-on ASMs in adults with refractory focal or generalised epilepsy showed that SUDEP incidence was seven times lower in those receiving an extra ASM compared with the placebo group.[28]

Studies that did not correct for TCS frequency have reported a higher SUDEP risk for those using multiple ASMs versus those on monotherapy or no ASMs. We identified several retrospective controlled studies evaluating the effect of ASM poly- versus monotherapy on SUDEP occurrence whilst correcting for TCS frequency (Table 1).[24–27] Only one case–control found an increased risk for SUDEP when comparing more than two ASMs with less than two ASMs. This effect did not remain in a combined analysis, including two other retrospective studies.[26] This would suggest that the initially reported higher SUDEP risk in those taking multiple ASMs reflected TCS severity.

A significant limitation of these studies is using medical records to determine the ASM regimen. This may not necessarily correspond to the prescription at the time of death and, more importantly, may not resemble the actual intake of the prescribed ASMs. A large-scale Swedish study addressed this concern by using dispensed prescription data from a national register, thus allowing the estimation of ASM usage over time.[27] While dispensing may be a closer estimation of actual ASM usage, it still serves as a proxy as it remains unknown whether the dispensed drugs were actually taken. The Swedish study determined ASM usage by the number of ASMs dispensed within 90 days of death or index date. This study found a lower SUDEP risk among those taking polytherapy (more than one ASM) when accounting for TCS frequency compared to no ASMs (OR 0.48, 95% CI 0.26-0.90). When further specifying polytherapy, risk reduction occurred when three or more ASMs were used (OR 0.31, 95% CI 0.14–0.67).[27] This would suggest a protective effect for polytherapy beyond TCS control.

We found no studies that evaluated the effect of ASM discontinuation on SUDEP rates.

Specific ASMs

We identified 17 papers that evaluated specific ASMs[25–27, 29–42], including four that controlled for TCS frequency (summarized in Table 2). Most ASMs had no effect on SUDEP occurrence, but two sodium-modulating ASMs (NaM–ASM) appeared to aggravate SUDEP risk: carbamazepine (CBZ) and lamotrigine (LTG). Most case–control studies did not investigate CBZ, LTG and SUDEP risk beyond TCS control.[30–42] We identified three studies that evaluated CBZ use accounting for TCS frequency, of which only one reported an increased risk of SUDEP occurrence (Table 2).[25] It was not specified whether CBZ was combined with other ASMs. A combined analysis selecting only users of CBZ as monotherapy, including the study that initially suggested an augmented risk, found no elevated SUDEP risk.[26] Similarly, the Swedish case-control study that evaluated prescription data over the past 90 days also reported no elevated risk for SUDEP when comparing CBZ monotherapy to no treatment.[27] Table 2 Articles on sudden unexpected death in epilepsy (SUDEP) risk for specific antiseizure medications (ASMs), whilst correcting for tonic–clonic seizure (TCS) frequency

Reference	Study type	Population	Cases	Controls	Documentation ASM use	Polytherapy excluded	Drug use among SUDEP cases (%)	Drug use among controls (%)	Effect size [OR (95% CI)]	
[25]	Case–control	PWE (aged 16 to 50) who died suddenly, identified by coroners and neurologists and by interviews with families, in England and Wales between 1989 and 1998	154 SUDEP cases	616 living controls, matched for age and geographic location from 900 groups of family practitioners throughout the UK (4 per case)	Medical records, not further specified	No	CBZ: 74 (48%)	CBZ: 235 (38%)	No CBZ: 1 (ref.)

CBZ: 2 (1.1–3.8)*

	
[26]	Combined analysis	Populations of 24, 25 and 31	216 SUDEP cases (definite or probable), combined from the three studies (excluding cases with history of heart disease)	831 living controls, combined from the three studies (excluding patient with history of heart disease)	Medical records, not further specified	Yes	NA	NA	No ASM: 1 (ref.)

LTG: 0.7 (0.1–3.6)

CBZ: 0.5 (0.2–1.1)

PHT: 0.4 (0.2–1.1)

VPA: 0.4 (0.2–1.01

	
[27]	Case–control	PWE registered in the national patient register from 1998–2005, who were alive on 30 June 2006, with follow-up until December 2011	255 SUDEP cases (definite or probable)	1148 living controls, matched for age and gender (5 per case)	Drug dispensing 90 days from index date or date of death	Yes	No ASM: 46 (18%)

LTG: 27 (11%)

CBZ: 45 (18%)

VPA: 17 (7%)

LVT: 2 (1%)

PHT: 10 (4%)

OXC: 3 (1%)

TPM: 2 (1%)

	No ASM: 265 (23%)

LTG: 104 (9%)

CBZ: 130 (11%)

VPA: 126 (11%)

LVT: 26 (2%)

PHT: 44 (4%)

OXC: 17 (1%)

TPM: 11 (1%)

	No ASM: 1 (ref.)

LTG: 0.93 (0.41–2.12)

CBZ: 1.00 (0.48–2.11)

VPA: 0.52 (0.20–1.30)

LVT: 0.10 (0.02–0.61)

PHT: 0.56 (0.17–1.88)

OXC: 0.58 (0.09–3.69)

TPM: 2.02 (0.29–14.26)

	
[29]	Case–control	PWE, admitted to the EMUs of four tertiary epilepsy centers (USA and Australia) between 1995 and 2013	101 SUDEP cases (definite, probable, possible or near)	199 living controls, matched for admission site, age, sex and year of EMU admission	Medical records, at the time of admissiona	No	LTG 33 (33%)a	LTG 78 (39%)a	No LTG: 1 (ref.)

LTG: 0.58 (0.29–1.17)a,b

	
EMU, epilepsy monitoring unit; PWE, people with epilepsy; NA, not applicable; CBZ, carbamazepine; LTG, lamotrigine; PHT, phenytoin; VPA, valproic acid; LVT, levetiracetam; OXC, oxcarbazepine; TPM, topiramate

*Significant results

aASM use was determined at the time of Epilepsy Monitoring Unit (EMU) admission (median duration of follow‐up to determine SUDEP status after EMU admission was 9.82 years)

bHazard ratio (HR) was used instead of the odds ratio (OR)

We found three studies on the association between lamotrigine (LTG) and SUDEP that corrected for TCS frequency.[26, 27, 29] All studies excluded LTG polytherapy users. No effect on SUDEP occurrence was found. These studies include the combined analysis of the Swedish case–control study, which used prescription data over the past 90 days.[26, 27] The other study was a large-scale study (101 SUDEP cases), which also found no effect for other sodium channel ASMs compared with commonly used non-NaM-ASMs (mostly levetiracetam, valproate and topiramate).[29] This study established LTG and other ASM use at admission in their Epilepsy Monitoring Unit (EMU) and did not validate usage at the end of follow-up, which could last up to 16 years. This could mean that LTG exposure might have been absent during follow-up. A 2021 US Food and Drug Administration warning revived the safety concerns for LTG use. The warning was issued on the basis of vitro data suggesting that LTG exhibits class IB antiarrhythmic activity. A rapid systematic review found that there is not enough evidence to support that LTG is associated with SCD or SUDEP or ECG changes in people with or without epilepsy when compared to other ASMs.[43] This was supported by a pharmacovigilance study that analysed adverse events associated with LTG reported to the FDA for people with epilepsy.[43]

We found one study describing a preventive effect for a specific ASM when correcting for TCS frequency with a limited number of users (n = 28). The Swedish drug prescription register study reported a protective effect on SUDEP (OR 0.10, 95% CI 0.02–0.61) for levetiracetam (LVT), monotherapy when compared with no ASM use.[27]

Other Scenarios: Non-adherence and Dose Changes

In the past, post-mortem studies have shown that SUDEP cases often show ASM levels at a sub-therapeutic level, which may reflect non-adherence.[44–46] These studies were, however, uncontrolled. We identified 14 controlled studies investigating the association between adherence and the occurrence of SUDEP (Online resource 1). Several methods for estimating non-adherence were used, all with limitations that may explain the conflicting results.

Most studies found no association between non-adherence and SUDEP occurrence. [25, 32, 40, 47, 48, 50–53] Some defined non-compliance as sub-therapeutic ASM levels at the last registered visit or after death.[32, 47, 48] The levels at the last visit may not accurately reflect compliance at the time of death, while redistribution may bias post-mortem results. This effect may diverge through varying post-mortem intervals.[55] Other studies determined adherence through monthly monitoring to count remaining pills, where more than two missed doses in the previous month were considered as non-adherence.[50, 51] Other methods used to define non-compliance were stated by treating physicians and family members or collected from medical records.[25, 32, 40, 52, 53]

We found four studies reporting an elevated risk of SUDEP in non-adherence.[27, 38, 49, 54] Two studies assessed variations in ASM hair strand levels, with a more significant variability indicating greater non-adherence.[38, 49] Adherence can be measured over multiple months, assuming hair grows approximately 1 cm a month. The Swedish case–control study used two methods to determine non-adherence while controlling for TCS frequency.[27] Firstly, adherence was based on documentation in medical records, which showed a significant risk compared to when no non-adherence was mentioned (OR 2.75, 95% CI 1.58–4.78). Documentation of adherence in the records was checked for 5 years before the date of death or index date, which, for controls, corresponded to the demise of cases. The second method that established non-adherence was with the prescription database, for which 91–180 days or 181–365 days since the last dispensed ASM were used as cut-offs. No association with SUDEP was found with a similar OR for 181–365 days (OR 2.96, 95% CI 0.46–18.89) compared with the previous method. With this latter method, it is, however, unknown whether ASM was stockpiled. The fourth study evaluated adherence patterns, using ASM prescription and dispensing data from the Australian Pharmaceutical Benefits Scheme (PBS) to calculate the daily polypharmacy possession ratio (DPPR), a measure for the proportion of prescribed pills available for a person each day.[54] This method can account for adherence to multiple drugs and stockpiling. Cluster analysis defined four patterns of adherence to the trajectory of three years: good, declining, poor and very poor. Declining adherence over time was associated with an increased risk for SUDEP.[54] Both hair strand levels and prescription databases allow for the evaluation of adherence over a more extended period, which might be more reliable than information from patient records or statements from the family. The Swedish study used medical records to determine compliance, but in contrast to prior studies, it applied a five-year observation period.

We found three studies investigating the effect of the number of dose changes (Online Resource 2).[31, 38, 48] Studies showed conflicting results as one found an increased risk for SUDEP with a higher number of changes (three to five) compared with few changes (zero to one), and others showed no or a near significant protective effect for frequent dose changes. TCS frequency was not controlled for, so changes might also reflect disease control in this case.

3.6 Medication other than ASMs

Only a few studies evaluated SUDEP risk for non-epilepsy concomitant drugs.[24, 27, 31, 32, 38, 56] We found six studies with a small number (30 or less) or an undefined number of users. They did not report an effect on SUDEP occurrence; the two small-scaled papers reported an association between SUDEP and anxiolytics but had conflicting results (Online Resource 3). One more extensive case–control study reported no significant effect for beta-blockers (n = 133), SSRIs (n = 114), neuroleptics (n = 93) or other antidepressants (n = 53), but lower risk among statin users (n = 87).[27] It is yet unclear whether statins may reduce SUDEP susceptibility through modulating the cascade or a mere effect of associated profiles with statin use (more frequent health visits or comorbidities associated with other mortality risks).

External Factors that May Interrupt the SUDEP Cascade

SDDs may alert caregivers to seizures that would have otherwise been unwitnessed. These devices can identify seizures by detecting autonomic alterations or movements caused by the seizure. We found no studies investigating the effect of SDDs on SUDEP occurrence. Prospective studies to assess the impact of these devices are challenging to set up due to the low incidence of SUDEP, thus resulting in lengthy study duration and ethical constraints in the case of an RCT. We only found studies with indirect proof that enhancing supervision could lower SUDEP risk.[3, 4, 25, 38, 57] Most studies evaluated the protective effect of the presence of a roommate. One study comparing SUDEP rates between two residential care centres evaluated additional measures.[4] Supervision was divided into three grades: (1) no supervision; (2) a listening device or a roommate or physical checks at a minimum of every 15 minutes; and (3) two of the following: a listening device, roommate, additional device (bed motion sensor/video monitoring), or physical checks every 15 min. The centre with the lowest supervision grade had the highest incidence of SUDEP. The data cannot provide direct proof of protection through SDD as the contrasts in supervision were mainly accounted for by implementing an acoustic detection system in one centre.[4]

These findings suggest that witnesses could terminate a potential SUDEP event. Providing direct proof for this assumption is challenging, and the precise mechanisms through which a caregiver can interrupt the SUDEP cascade are unknown. A major limitation is that SDDs cannot prevent SUDEP by itself. A caregiver must also respond to the alarm. A single example of this importance is demonstrated by a report of a 20-year-old male who suffered a seizure, which an SDD detected.[58] The caregivers, however, did not respond promptly to the alarm and arrived 15 minutes after the start of the seizure, at which point the man had deceased.

Conclusions and Recommendations

ASMs can prevent the occurrence of SUDEP by averting TCS. The protective effect of ASMs has been evidenced in various clinical scenarios (starting and adding ASM) and, with weaker evidence, by evaluating indirect markers of non-adherence. The efficacy of ASMs in reducing TCS frequency, and thereby SUDEP risk, may vary across epilepsy syndromes. Valproic acid seems more effective in reducing TCS in people with genetic generalized epilepsy, [59, 60] while there is limited data specifically comparing ASM efficacy for the prevention of focal to bilateral TCS.[61] We found no indication that starting ASMs modulates SUDEP risk beyond the effect of TCS control but did find some signs of a protective effect for polytherapy. Some studies have suggested that sodium channel-blocking agents exert SUDEP risk, possibly by impeding cardiac conduction or autonomic control. We found insufficient evidence that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect for levetiracetam but required validation in larger cohorts. While evidence suggests in broad populations specific ASMs do not confer an increased risk for SUDEP, drug-related risks may exist due to the underlying cause of epilepsy or comorbidities, for instance, people with long QT syndrome using ASM risk of cardiac events compared to non-ASM users.[62, 63] Evidence indicates an enhanced risk for SUDEP when non-adherence is evaluated for longer. As non-adherence is likely to promote SUDEP risk by resulting in increased seizure frequency, this risk is expected to increase in time. Only a few studies evaluated the impact for non-epilepsy concomitant medications and SUDEP. Still, available evidence suggests an overall lack of effect for psychotropic drugs and a possible protective effect for statin use. Definite results would require larger study populations and consideration of potential confounders such as comorbidities and frequency of health visits. We found no controlled studies evaluating the effect of SDD on SUDEP risk, yet we found indications that increasing nocturnal supervision through other means may have a protective effect. So far, analysing medication regimens in SUDEP cases has not helped strengthen SUDEP’s mechanistic understanding. SSRIs did not appear to influence SUDEP risk, and epidemiological studies have not confirmed the hypothesis that sodium channel-blocking agents could facilitate SUDEP by promoting the propensity to arrhythmia. The only compounds that emerged as possible protective agents included levetiracetam and statins, but these findings were not anticipated. Whether these results relate to the mode of action remains to be explored.

Considering various confounders and limitations, more research is needed to unveil the association between medications and SUDEP (Fig. 2).Fig. 2 Confounders and limitations that should be considered when evaluating the effect of anti-seizure medications (ASMs) on sudden unexpected death in epilepsy (SUDEP). TCS, tonic–clonic seizures

The assessment of ASM exposure should include the full range of ASM and other drug usage and correspond to exactly what someone is taking at the time of death. Information should not solely be obtained from medical records, but should ideally include drug dispensing data. Compliance will remain an obstacle, as none of the approaches can reliably estimate actual intake and adherence levels are known to be low.[64] When evaluating a specific ASM, it is preferable to restrict analyses to monotherapy users, but this would create bias as SUDEP typically occurs among refractory cases. Therefore, the association between specific ASM exposure and SUDEP should include separate analyses for those using monotherapy and polytherapy.[27] If a specific ASM seems to augment SUDEP risk, combined analyses could strengthen the evidence to establish a dose-dependent effect and by animal studies or observational clinical studies demonstrating the mode of action. ASMs could modulate the SUDEP cascade by direct effects (i.e., altering cardiorespiratory response to seizures) or long-term structural changes (e.g., promoting brain stem atrophy). Unveiling these different effects requires distinct investigations of ASM exposure. Structural changes can only be evaluated when studying long-term ASM exposure. The best time frame will depend on the research question.

A significant limitation of SUDEP research is the lack of available or reliable clinical data. The globally declining autopsy rates are concerning, and it is critical to know how trustworthy a probable SUDEP diagnosis is.[65] SUDEP is likely heterogeneous. Some preventive strategies may not be able to prevent all SUDEP. The advances in home monitoring may promise to offer bio-signals at the time of death and improve SUDEP phenotyping. Future SUDEP classification systems should acknowledge the diversity in pathomechanisms between SUDEP cases. To understand the effect of SDDs as a preventive strategy better, we need retrospective studies evaluating SUDEP incidence in populations using SDD and using no SDD while considering the care setting and the adherence of the carriers to respond to the alarms. It is crucial to understand better how caregivers attend to a seizure, which intervention could help, and how we could enhance the potential protective measures of these interventions. Seizure detection might also provide opportunities for future targeted preventive strategies. Devices identifying seizures in real time could intervene within the SUDEP cascade at a crucial moment. The type and timing of this intervention would require a better understanding of SUDEP mechanisms.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 19 KB)

Acknowledgements

A.T.B. and R.D.T are supported by EpilepsieNL (2023-04). The Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie and EpilepsieNL (2023-04) support R.D.T. J.W.S. is based at UCLH/UCL Comprehensive Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. The Dr Marvin Weil Epilepsy Research Fund, the Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, Netherlands, and the UK Epilepsy Society support his research.

Declarations

Funding

EpilepsieNL (2023-04) and the Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, supported this work (for ATB and RDT). The funders were not involved in the study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Conflicts of interest

A.T.B. has no disclosures. R.D.T. reports lecture and consultancy fees from Medtronic, UCB, Angelini Pharma, Theravarance, Zogenix, Novartis, LivAssured, and Arvelle, and grants from Medtronic and NewLife Wearables. J.W.S. or his department has received grants from Eisai, Angelini Pharma and UCB. He has received personal compensation for serving on the Advisory Boards or Speaker’s Bureau for UCB and Angelini Pharma.

Availability of data and material

Data sharing is not applicable as no data were generated or analysed during the study.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author contributions

Study conception and design was performed by A.T.B. and R.D.T.; data collection was carried out by A.T.B.; analysis and interpretation of results was carried out by A.T.B., R.D.T., and J.W.S.; and draft manuscript preparation was performed by A.T.B. All authors reviewed the results and approved the final version of the manuscript.
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