Evidence review: Modifiable risk factors for epilepsy related mortality

National Guideline Centre (UK)

Evidence review: Modifiable risk factors for epilepsy related mortality

Epilepsies in children, young people and adults: diagnosis and management

Evidence review 18

NICE Guideline, No. 217

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2022 Apr.

ISBN-13: 978-1-4731-4513-9

1. Modifiable risk factors for epilepsy-related mortality, including SUDEP, and the magnitude of risk of those factors

1.1. Review question

What are the modifiable risk factors for epilepsy-related mortality, including SUDEP, and what is the magnitude of risk of the factors?

1.1.1. Introduction

Epilepsy is associated with a number of risks, including a risk of injury, including head injury, and mortality in the form of drowning and accidents. One significant cause of epilepsy-related mortality is Sudden Unexpected Death in Epilepsy (SUDEP). Overall, the rate of SUDEP is around 1 in 1000 people with epilepsy per year.

This review examines modifiable risk factors for epilepsy-related mortality, including SUDEP, to inform the approach to the management of seizures and the provision of information to people with epilepsy, their families and carers.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Prognostic evidence

1.1.4.1. Included studies

Four cohort⁷^, ¹⁰^, ²²^, ³⁰ studies and seven case-control¹⁵^, ²³^, ²⁶^, ³⁵^, ³⁶^, ³⁹^, ⁴⁰ studies assessing the modifiable risk factors for epilepsy-related mortality (including SUDEP) were included within the review.

The following modifiable risk factors were investigated, but not limited to:

Sleeping unsupervised / living alone
Prone sleeping position
Uncontrolled/frequent Generalised Tonic Clonic Seizures (GTCS)
Nocturnal GTCS
Substance abuse/alcohol dependence
Anti-seizure medication (ASM) polytherapy
Other drug polytherapy
Insufficient ASM therapy/any changes in prescription of drugs that could increase seizure rate
Sleep deprivation / irregular sleep

Within the eleven studies included within the review, the risk factors considered were: different seizure types; comorbidities; seizure frequency; anti-seizure medications; changes to medications; substance abuse/alcohol dependence and psychosocial factors (education, living conditions and supervision).

Of the studies included, one³⁹ study looked at adults followed up over one to five years; three¹⁰^, ²⁶^, ³⁰ studies assessed adults who were followed up for longer than five years; one²² study investigated children who were followed up for over five years; one⁷ study which looked at a mixed population of children and adults followed up between one to five years and five¹⁵^, ²²^, ³⁵^, ³⁶^, ⁴⁰ studies with a mixed population who followed up the participants for over five years.

See also the study selection flow chart in Appendix A, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.

1.1.4.2. Excluded studies

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the prognostic evidence

Table 2

Summary of studies included in the evidence review - Adults >18 years (follow up 1 – 5 years).

Table 3

Summary of studies included in the evidence review - Adults >18 years (follow up >5 years).

Table 4

Summary of studies included in the evidence review – Children <18 years (follow up > 5 years).

Table 5

Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up 1 - 5 years).

Table 6

Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up >5 years).

1.1.6. Summary of the prognostic evidence – Adults >18 years (follow up 1 – 5 years)

Table 7

Clinical evidence summary: one to five seizures per month.

Table 8

Clinical evidence summary: Over five seizures per month.

Table 9

Clinical evidence summary: One to three tonic-clonic seizures per year.

Table 10

Clinical evidence summary: Over three tonic-clonic seizures per year.

1.1.7. Summary of the prognostic evidence – Adults >18 years (follow up > 5 years)

Table 11

Clinical evidence summary: Seizure frequency.

Table 12

Clinical evidence summary: Number of anti-seizure medications.

Table 13

Clinical evidence summary: Adherence status: Nonadherence of medications.

Table 14

Clinical evidence summary: Adherence status: Untreated Epilepsy.

Table 15

Clinical evidence summary: Polytherapy.

Table 16

Clinical evidence summary: Alzheimer’s Disease.

Table 17

Clinical evidence summary: Brain tumour.

Table 18

Clinical evidence summary: Meningitis.

Table 19

Clinical evidence summary: Stroke.

Table 20

Clinical evidence summary: Charlson Comorbidity Index.

Table 21

Clinical evidence summary: CNS infections.

Table 22

Clinical evidence summary: Metastatic Cancer.

Table 23

Clinical evidence summary: Solid Tumour (no metastasis).

Table 24

Clinical evidence summary: Depression.

Table 25

Clinical evidence summary: Diabetes (no complications).

Table 26

Clinical evidence summary: Peripheral vascular disease.

Table 27

Clinical evidence summary: Traumatic brain and head injury.

1.1.8. Summary of the prognostic evidence – Children <18 years (follow up > 5 years)

Table 28

Clinical evidence summary: Abnormal neurological examination.

Table 29

Clinical evidence summary: Abnormal cognitive function.

Table 30

Clinical evidence summary: Status Epilepticus (ever).

Table 31

Clinical evidence summary: Metabolic / Structural Aetiology.

1.1.9. Summary of the prognostic evidence – Mixed population of children <18 years and adults >18 years (follow up 1 – 5 years)

Table 32

Clinical evidence summary: Tumour aetiology.

Table 33

Clinical evidence summary: Vascular lesion aetiology.

Table 34

Clinical evidence summary: Trauma aetiology.

Table 35

Clinical evidence summary: Infection aetiology.

1.1.10. Summary of the prognostic evidence – Mixed population of children <18 years and adults >18 years (follow up >5 years)

Table 36

Clinical evidence summary: Seizure frequency - >10 seizures per year (at baseline).

Table 37

Clinical evidence summary: Seizures prior to SUDEP.

Table 38

Clinical evidence summary: Seizure frequency – (3 – 12 seizures past year).

Table 39

Clinical evidence summary: six to ten tonic-clonic seizures (previous 3 months).

Table 40

Clinical evidence summary: eleven to twenty tonic-clonic seizures (previous 3 months).

Table 41

Clinical evidence summary: Twenty-one to fifty tonic-clonic seizures (previous 3 months).

Table 42

Clinical evidence summary: Over fifty tonic-clonic seizures (previous 3 months).

Table 43

Clinical evidence summary: History of generalized tonic-clonic seizures.

Table 44

Clinical evidence summary: Focal seizures.

Table 45

Clinical evidence summary: Focal and generalized seizures.

Table 46

Clinical evidence summary: Undetermined seizures.

Table 47

Clinical evidence summary: Substance abuse.

Table 48

Clinical evidence summary: Alcohol dependence.

Table 49

Clinical evidence summary: Alcoholism.

Table 50

Clinical evidence summary: Local symptomatic seizures.

Table 51

Clinical evidence summary: Local cryptogenic seizures.

Table 52

Clinical evidence summary: Undetermined seizures.

Table 53

Clinical evidence summary: Anti-seizure medication therapy - monotherapy.

Table 54

Clinical evidence summary: Anti-seizure medication therapy – Polytherapy (≥2 medications).

Table 55

Clinical evidence summary: Anti-seizure medication therapy – Two anti-seizure medications.

Table 56

Clinical evidence summary: Two antiseizure medications.

Table 57

Clinical evidence summary: Three antiseizure medications.

Table 58

Clinical evidence summary: Anti-seizure medication therapy – Polytherapy (> 3 anti-seizure medications).

Table 59

Clinical evidence summary: three to four anti-seizure medications.

Table 60

Clinical evidence summary: Over four anti-seizure medications.

Table 61

Clinical evidence summary: No anti-seizure medications.

Table 62

Clinical evidence summary: Monotherapy – Carbamazepine.

Table 63

Clinical evidence summary: Monotherapy – Carbamazepine.

Table 64

Clinical evidence summary: Monotherapy – Lamotrigine.

Table 65

Clinical evidence summary: Monotherapy – Valproic Acid.

Table 66

Clinical evidence summary: Monotherapy – Phenytoin.

Table 67

Clinical evidence summary: Monotherapy – Levetiracetam.

Table 68

Clinical evidence summary: Monotherapy – Oxcarbazepine.

Table 69

Clinical evidence summary: Monotherapy – Topiramate.

Table 70

Clinical evidence summary: Monotherapy – Other anti-seizure medication.

Table 71

Clinical evidence summary: Nonadherence.

Table 72

Clinical evidence summary: One to two changes in dose of antiseizure medication (per year).

Table 73

Clinical evidence summary: Three to five changes in dose of antiseizure medication (per year).

Table 74

Clinical evidence summary: Antipsychotic medication.

Table 75

Clinical evidence summary: Anxiolytic medication.

Table 76

Clinical evidence summary: Asthma.

Table 77

Clinical evidence summary: Sharing household but not sharing a bedroom.

Table 78

Clinical evidence summary: Living alone.

Table 79

Clinical evidence summary: Secondary education.

Table 80

Clinical evidence summary: Primary education.

Table 81

Clinical evidence summary: Same room supervision at night.

Table 82

Clinical evidence summary: Special supervision at night (regular checks throughout the night or the use of a listening device).

See Appendix F for full GRADE tables.

1.1.11. Economic evidence

1.1.11.1. Included studies

No health economic studies were included.

1.1.11.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

1.1.12. Economic model

This area was not prioritised for a new cost-effectiveness analysis.

1.1.13. Evidence statements

1.1.13.1. Effectiveness

None.

1.1.13.2. Economic

No relevant economic evaluations were identified.

1.1.14. The committee’s discussion and interpretation of the evidence

1.1.14.1. The outcomes that matter most

The two outcomes for this evidence review were death related to epilepsy or sudden unexpected death in Epilepsy (SUDEP). This was to ensure that the modifiable risk factors being assessed were in the context of the impact they would have on mortality and SUDEP. This was important as modifiable risk factors could be assessed in people who have been diagnosed with epilepsy, and the recommendations would potentially have the greatest impact for the person with epilepsy, their families, or carers, as well as the clinicians managing their epilepsy.

1.1.14.2. The quality of the evidence

The majority of results were of low or very low-quality evidence for all the stratifications for the outcomes of epilepsy-related mortality or SUDEP. The main reasons for this were: the risk of bias, indirectness for not adjusting for modifiable confounders and crossing of the null line. There were cohort studies and case-control studies included within this review. As all the studies were observational studies, they had to show adjustment was made for potential confounders. The evidence was downgraded if the study did not adjust for at least two of the four non-modifiable risk factors specified (age, gender, developmental/intellectual disability, and duration of epilepsy). Evidence of adjusting shows that the results are what they would be if all other variables were set to be the same across the risk factor and no risk factor group. In turn, this increases our confidence that the results are not confounded. Where the confidence interval of the odds, hazard or risk crossed one, or the null line, this signified that the result is consistent with no effect from the risk factor. This allowed the results to be divided into significant factors and non-significant factors. The committee took note of all these different elements in the quality assessment of the evidence to decide on recommendations.

There were several outcomes within some of the stratifications that were of moderate or high-quality evidence. Within the adults (follow up over 5 years) adherence, polytherapy, neurological conditions and Charlson Comorbidity Index; mixed population (follow up 1 - 5 years) tumour aetiology; and mixed population (follow up over 5 years) undetermined seizures, substance abuse, alcohol, dependence, polytherapy (2 or more anti-seizure medications or more than 3 anti-seizure medications, use of levetiracetam, non-adherence and living conditions were all of moderate to high quality and significant outcomes. The committee discussed all of the factors in relation to their quality and significance and decided those that were modifiable were important to consider for recommendations.

1.1.14.3. Benefits and harms

People with epilepsy are at increased risk (approximately 7 – 12% cumulative lifetime risk) of premature mortality and SUDEP so the identification of risk factors, particularly modifiable risk factors is of benefit to people with epilepsy and their families and carers. This can provide important information of their own risk but also what steps can be taken to manage the risk.

In adults who were followed up from one to five years there did not appear to be a significant difference in risk of death or SUDEP resulting from 1 – 5 seizures a month, >5 seizures a month, 1 – 3 tonic clonic seizures per year or > 3 tonic clonic seizures per year. However, for adults followed up over five years, being on more ASM’s led to an almost doubling of the odds of SUDEP compared to less ASMs; non-adherence of ASM’s led to an almost 3.5 times greater odds of death compared to being adherent to medications, and people with polytherapy (2 or more anti-seizure medications) had three-quarters the hazard of mortality as people not on polytherapy.

Comorbidities such as brain tumours, meningitis and stroke had almost two times the hazard of mortality compared to no neurological comorbidities. Although not modifiable risk factors, these conditions are important in a cumulative risk calculation.

Unexpectedly, the evidence showed that depression led to one-fifth of the risk of premature mortality compared to no depression, and having peripheral vascular disease led to approximately half the odds of mortality compared to the odds experienced without peripheral vascular disease. This is contrary to the understanding in current clinical practice that depression and peripheral vascular disease are modifiable risk factors that increase the risk of premature mortality. However, a higher score on the Charlson co-morbidity index, which is a measure of co-morbidities including cardiovascular disorders such as heart failure, stroke and peripheral heart disease as well as other chronic conditions, is associated with an increase in mortality. In children followed up for more than five years, having an abnormal neurological exam confers a hazard of mortality that is 12 times greater than the hazard experienced without an abnormal neurological exam and having abnormal cognitive function confers a hazard of mortality that is almost 4 times greater than the hazard experienced without abnormal cognitive function. Knowledge of the magnitude of these risk factors can contribute to the approach to epilepsy management.

Within a mixed population of children and adults who were followed up for one to five years, the evidence showed having a tumour has a hazard of mortality that is 4.5 times greater than the hazard experienced without having a tumour.

In studies of a mixed population followed up for over five years, there were several significant risk factors that had an impact on the risk of premature mortality. For example, having over ten seizures per year has almost six times greater odds of SUDEP than the odds experienced with less than ten seizures per year, and having a history of generalized tonic clonic seizures has almost fourteen times greater odds of SUDEP than the odds experienced without a history of generalized tonic clonic seizures. In relation to medication and treatment of epilepsy, some results showed that three to five changes in dose of ASM per year has a risk of SUDEP that is nearly ten times greater than the risk experienced with no changes in ASM over a year and people on three ASM has an odds of SUDEP ten times greater than the odds experienced with monotherapy.

The committee agreed that these modifiable risk factors shown to have an impact on premature mortality or SUDEP could be grouped into a recommendation focused on treating seizures adequately with medication and adherence to medication. The committee agreed that focal to bilateral tonic-clonic seizures should be listed along with generalised tonic-clonic seizures as these more often cause convulsive seizures and are increasingly associated with drug-resistant epilepsy. In addition to this, social and lifestyle factors also showed an impact on premature mortality. For example, special supervision at night had about half of the odds of SUDEP compared to people with no supervision overnight and living alone has an odds of SUDEP that is five times greater than the odds when sharing a household and bedroom. The committee recognised the importance of these findings and included them as part of the recommendations to discuss whether night-time supervision might be helpful for some people who have seizures during sleep and are at higher risk of mortality. The committee discussed the challenges surrounding such an intervention and how it would not be feasible or appropriate in many circumstances but acknowledged parents or carers reported gaining some reassurance from the use of a night monitor in a child’s room.

The committee noted the importance of ongoing dialogue between the person with epilepsy, their families or carers, and their clinicians about the general management of their epilepsy, medications and seizures, which can help in tailoring treatment and enhance adherence to medications. A person’s risk of premature mortality or SUDEP can change at different stages in their life, which can be affected by how well their epilepsy is managed but also different environmental factors which indirectly affect their risks, such as stress and lifestyle choices. So, conversations around the risks of premature mortality need to be adapted according to risk factors which are relevant at the time of follow up.

The committee acknowledged it is important to note that the modifiable risk factors identified in the evidence are not the only risk factors that may have an impact on the risk of premature mortality and SUDEP. The committee agreed that the evidence base was limited with respect to many of the biologically plausible risk factors that had been included in the review protocol and were aware that absence of evidence did not equate to ‘evidence of absence’. They, therefore, suggested that discussions about modifiable risk factors between clinician and patient should not be limited to those mentioned in the recommendations and may include other risk factors such as sleep deprivation or sleeping position, and drug polytherapy.

1.1.15. Cost effectiveness and resource use

No health economic evidence was identified for this review question.

The committee discussed the clinical evidence presented and noted that people with epilepsy should be supported to understand their individual risk of mortality, including SUDEP, from the time of their epilepsy diagnosis and throughout the duration of their care. The committee acknowledged that the prospect of SUDEP could be extremely worrying for people with epilepsy causing increased anxiety and depression, worsening people’s quality of life. Therefore, support from health care professionals for people with epilepsy to understand their individualised risk is instrumental in improving patient’s quality of life. In addition, for those patients who are at greater risk of premature mortality, the committee discussed that healthcare workers should work with patients to reduce this risk. The committee noted that these recommendations are reflective of current practice and so are not expected to result in a substantial resource impact.

The committee also discussed the modifiable risk factors and co-morbidities associated with the risk of epilepsy-related mortality. It was noted that modifiable risk factors and co-morbidities should be discussed with people upon an initial diagnosis of a person’s epilepsy as well as throughout the duration of treatment. The committee acknowledged that in current practice, the degree to which modifiable risk factors are discussed with people varies. However, because the information provided on the modifiable risk factors of SUDEP is discussed at existing appointments people attend, this recommendation is not expected to result in a substantial resource impact.

Night-time supervision for people with epilepsy was also discussed. The committee noted that night-time supervision could be especially beneficial for people who have seizures during their sleep and have been assessed to be at high risk of epilepsy-related mortality as intercepting a person’s nocturnal seizure can be lifesaving. There are, however, significant implications associated with night-time monitoring. Night-time monitoring of people living in residential care should already be provided; however, the committee noted that, if possible, the level of supervision should be increased. This is because onset of a seizure when sleeping can start suddenly and unexpectedly, therefore without regular monitoring, there may be little benefit of monitoring at all. Overall, increasing the levels of monitoring of people residing in residential care should not result in a significant resource impact as there should already be night-time staff on shift able to conduct monitoring. The committee did, however, note that for places that do not currently provide regular monitoring, an additional member of staff may be required if the workload of night-staff is already high.

The committee acknowledged that night-time supervision for people with epilepsy not residing in care could be extremely challenging. Monitoring can be achieved through the use of baby monitors or other technologies which provide an alert to a parent, guardian, or partner when a person with epilepsy is experiencing a seizure. The purpose of the recommendation made by the committee is to inform people of the risks of night-time seizures and to make sure the correct approach to monitoring is adopted if appropriate. Advice on a person’s individualised risks of night-time seizures and the best way to monitor these can be provided by health care professionals. In general, the cost of monitoring devices is incurred by careers, guardians, or patients. Therefore, this recommendation is not expected to lead to a significant resource impact.

The committee also discussed that monitoring may not be possible for adults living alone or in other settings such as living in a house with friends. The committee noted that in these circumstances, the risks and the benefits should be assessed with the help of a healthcare professional for the appropriate course of action to be taken.

1.1.16. Other factors the committee took into account

The committee acknowledged the importance of the 2020 MBRRACE-UK report, which focuses on improving the lives of pregnant women and mothers. The report highlighted that 13% of women died from epilepsy and stroke during or up to six weeks after their pregnancy. In relation to the recommendations made as part of this review, the report urges for the risk related to night-time seizures, uncontrolled seizures, and ineffective treatment to be discussed with pregnant women to reduce the risk of premature mortality and SUDEP.

1.1.17. Recommendations supported by this evidence review

This evidence review supports recommendations 10.1.1 – 10.1.4 in the NICE guideline.

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40.: Zhang WW, Si Y, Chen T, Chen D, Liu L, Deng Y et al. Risks of probable SUDEP among people with convulsive epilepsy in rural West China. Seizure. 2016; 39:19–23 [PubMed: 27235892]

1.1.17.1. 1.1.14.2. Economic evidence – included studies

[List references of studies included in the economic evidence review]

Appendices

Appendix A. Review protocols

A.1. Review protocol for [add key area, for example, unplanned hospital admission]

Download PDF (249K)

A.2. Health economic review protocol

Download PDF (183K)

Appendix B. Literature search strategies

This literature search strategy was used for the following reviews:

What are the modifiable risk factors for a further seizure after a first seizure, and what is the magnitude of risk of those factors?
What are the modifiable risk factors for epilepsy-related mortality, including SUDEP, and what is the magnitude of risk of the factors?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.²⁰

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

Appendix E. Forest plots

E.1. Adults >18 years (follow up 1 – 5 years)

Download PDF (138K)

E.2. Adults >18 years (follow up >5 years)

Download PDF (178K)

E.3. Children <18 years (follow up >5 years)

Download PDF (132K)

E.4. Mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

Download PDF (130K)

E.5. Mixed population of children <18 years and adults >18 years (follow up > 5 years)

Download PDF (350K)

Appendix F. GRADE tables

F.1. Adults >18 years (follow up 1 – 5 years)

Download PDF (187K)

F.2. Adults >18 years (follow up >5 years)

Download PDF (318K)

F.3. Children <18 years (follow up >5 years)

Download PDF (181K)

F.4. Mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

Download PDF (170K)

F.5. Mixed population of children <18 years and adults >18 years (follow up > 5 years)

Download PDF (644K)

Appendix G. Economic evidence study selection

Download PDF (177K)

Appendix H. Economic evidence tables

None.

Appendix I. Health economic model

No original economic modelling was undertaken for this review question.

Appendix J. Excluded studies

J.1. Clinical studies

Download PDF (142K)

J.2. Health Economic studies

Download PDF (122K)

FINAL

Evidence reviews underpinning recommendations 10.1.1 – 10.1.4 and research recommendations in the NICE guideline.

Developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK586315PMID: 36395298

Table 1PICO characteristics of review question

Population	Inclusion: People with a diagnosis of epilepsy. Exclusion: New-born babies with acute symptomatic seizures
Prognostic variable(s) under consideration	Sleeping unsupervised/living alone Prone sleeping position Uncontrolled/frequent Generalised Tonic Clonic Seizures (GTCS) Nocturnal GTCS Substance abuse/alcohol dependence ASM polytherapy Other drug polytherapy Insufficient ASM therapy/any changes in prescription of drugs that could increase seizure rate Sleep deprivation/irregular sleep
Confounding factors	No key confounders that have to be adjusted for have been identified, but the analysis report must demonstrate that it has tried to avoid bias arising from plausible potential confounders (the modifiable factors listed above plus other non-modifiable factors) by an appropriate method
Outcomes	Death, related to epilepsy SUDEP Follow up: any available but stratify according to: <1 yr., 1-5 yrs., >5 yrs.
Study design	A longitudinal design, such as prospective/retrospective cohort studies. Case-control studies will be allowed, provided they meet criteria.

Table 2Summary of studies included in the evidence review - Adults >18 years (follow up 1 – 5 years)

Study

Population

Analysis

Prognostic variable(s)

Confounders

Outcomes

Comments

Walczak 2001³⁹

Cases = 20

Controls = 80

Participants were prospectively enrolled after evaluation at three upper mid-western epilepsy centres. A surveillance system was set up to identify deaths in this prevalence cohort.

Prospective case control study with multivariate analysis

Number of seizures (number per month)

Number of tonic-clonic seizures (per year)

Number of seizures (number per month)

Number of tonic-clonic seizures (per year)

Risk of SUDEP

Table 3Summary of studies included in the evidence review - Adults >18 years (follow up >5 years)

Study

Population

Analysis

Prognostic variable(s)

Confounders

Outcomes

Comments

Faught 2008¹⁰

N=33,658

The study population was selected based on ≥18 years of age; ≥ one neurologist visit with a diagnosis of epilepsy or nonfebrile convulsions; ≥ two pharmacy dispensing’s for anti-seizure medications

Retrospective open cohort study design. Multivariate analysis with Cox regression models

Adherence

Use of ASM polytherapy

Epilepsy related comorbidity

Adherence status

Gender

Age

Race

Use of ASM polytherapy

Epilepsy related comorbidities

Mortality

Ryu 2015²⁶

N=104

individuals who had died, had a diagnosis of epilepsy registered on the death certificate and were treated for epilepsy at the centre in the study period, and met the criteria for SUDEP

Case control study with multivariate regression analysis

Seizure frequency

Number of ASM’s

Age at onset

Duration of disease

Aura

Family history of epilepsy

Psychiatric conditions

Epilepsy classification

Seizure frequency

Seizure related to lesion on MR imagine

Number of ASMs

Type of ASM

Risk of SUDEP

Si 2018³⁰

N = 456

The number of patients included in the study were those with epilepsy who died and deceased patients without epilepsy as comparison.

Prospective cohort study with logistic regression analysis

CNS infections

Metastatic cancer

Solid tumour without metastasis

Depression

Diabetes without complications

Peripheral vascular disease

Traumatic brain and head injuries

Age

Gender

CNS infections

Metastatic cancer

Renal disease

Solid tumour without metastasis

Anoxic brain injury

Cardiac arrhythmias

Encephalopathy

Depression

Paraplegia, hemiplegia

Diabetes without complications

Peripheral vascular disease

Traumatic brain and head injuries

Mortality

Table 4Summary of studies included in the evidence review – Children <18 years (follow up > 5 years)

Study

Population

Analysis

Prognostic variable(s)

Confounders

Outcomes

Comments

Nickels 2012²²

n= 467

All children ages 1 month through 17 years diagnosed with new-onset epilepsy while resident in Olmsted County from 1980 to 2009 and had follow-up beyond the initial epilepsy diagnosis were included

Cohort study with multivariate Cox regression models

Abnormal neurological examination

Abnormal cognitive function

Status epilepticus, ever

Metabolic/ structural aetiology

Neurologic examination cognitive function previous status epilepticus mode of onset, aetiology usage of ≥ 2 ASM’s seizure frequency intractable at last follow up

Mortality

Table 5Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

Study

Population

Analysis

Prognostic variable(s)

Confounders

Outcomes

Comments

Chen 2005⁷

n=263

Participants were prospectively recruited patients with epilepsy who were at least 17 years old and newly referred to the outpatient epilepsy clinics

Prospective cohort study with Cox proportional hazards regression model

Aetiology of seizure / epilepsy

Age of onset

Frequency

Imaging

Type of seizure

Aetiology

Medication

Age

Gender

Mortality

Table 6Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up >5 years)

Study	Population	Analysis	Prognostic variable(s)	Confounders	Outcomes	Comments
Langan 2005¹⁵	Cases = 151 Controls = 534 People with epilepsy who died suddenly between the ages of 16 and 50 years were identified by coroners and neurologists and by interviews with bereaved families	Case control study with backward stepwise conditional logistic regression	History of generalized tonic clonic seizures No of tonic clonic seizures in previous 3 months Total number of anti-seizure medications Carbamazepine usage Supervision Asthma	History of generalized tonic clonic seizures No of tonic clonic seizures in previous 3 months Total number of anti-seizure medications Carbamazepine usage Supervision Asthma	Risk of SUDEP	Supervision at night was defined as the presence in the bedroom of an individual of normal intelligence and at least 10 years old or the use of special precautions. Special precautions involved regular checks throughout the night or the use of a listening device.
Nilsson 1999²³	Cases = 57 Controls = 171 Cases were individuals who had died with a diagnosis of epilepsy registered on the death certificate and who after review of medical and necropsy records were found to meet SUDEP criteria.	Nested case control study with multivariate analysis	Seizure frequency during last year Epilepsy type Number of ASM Changes in dose of ASM per year Anxiolytic medication Antipsychotic medication	Seizure frequency during last year Epilepsy type Number of ASM Changes in dose of ASM per year	Risk of SUDEP
Sveinsson 2020³⁶ (Sveinsson a)	Cases n = 255 Controls n=1148 All deaths with epilepsy written on the death certificate (n = 1,276), were eligible SUDEP cases.	Case control study with conditional logistic regression and individual modelling	ASM therapy Monotherapy Nonadherence	ASM therapy Medication Time since last dispensed ASM Nonadherence	Risk of SUDEP	Model 3 from analysis used within review: adjusted for the same variables as model 2 together with history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year
Sveinsson 2020³⁵ (Sveinsson b)	Cases n = 255 Controls n=1148 All deaths with epilepsy written on the death certificate (n = 1,276), were eligible SUDEP cases.	Case control study with conditional logistic regression and individual modelling	Type of Epilepsy Living conditions Highest education Alcohol dependence Substance abuse	Age Sex Generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation Living conditions Antiepileptic drugs	Risk of SUDEP	Model 3 from analysis used within review: Adjusted for age, sex, generalized tonic-clonic seizure frequency and nocturnal generalized tonic-clonic seizures last year, living conditions and epileptic drugs.
Zhang 2016⁴⁰	Probable SUDEP n = 35 Control n = 105 Patients with convulsive epilepsy	Case control study with multivariate logistic regression analysis	Seizure frequency Seizure free prior (prior to SUDEP)	Onset age Seizure frequency at baseline (n/year) Seizure free prior to probable SUDEP (1 month)	Risk of probable SUDEP

Table 7Clinical evidence summary: one to five seizures per month

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)
SUDEP - Male	No seizures as reference
SUDEP - Male	20 (1 study) 1 - 5 years	⊕⊝⊝⊝ VERY LOW¹^,²^,³^,⁴ due to risk of bias, indirectness, imprecision	OR 3.40 (0.5 to 23.12)
SUDEP - Female	No seizures as reference
SUDEP - Female	20 (1 study) 1 - 5 years	⊕⊝⊝⊝ VERY LOW¹^,²^,³^,⁴ due to risk of bias, indirectness, imprecision	OR 5.70 (0.6 to 54.15)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Outcomes adjusted for number of seizures (per month) and number of tonic clonic seizures (per year)

Table 8Clinical evidence summary: Over five seizures per month

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)
SUDEP - Male	No seizures as reference
SUDEP - Male	20 (1 study) 1 - 5 years	⊕⊝⊝⊝ VERY LOW¹^,²^,³^,⁴ due to risk of bias, indirectness, imprecision	OR 1.0 (0.1 to 10)
SUDEP – Female	No seizures as reference
SUDEP – Female	20 (1 study) 1 - 5 years	⊕⊕⊝⊝ LOW¹^,²^,³^,⁴ due to risk of bias, indirectness	OR 7.40 (1.3 to 42.12)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Outcomes adjusted for number of seizures (per month) and number of tonic clonic seizures (per year)

Table 9Clinical evidence summary: One to three tonic-clonic seizures per year

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)
SUDEP - Male	No tonic – clonic seizures as reference
SUDEP - Male	20 (1 study) 1 - 5 years	⊕⊝⊝⊝ VERY LOW¹^,²^,³ due to risk of bias, indirectness, imprecision	OR 4.30 (0.5 to 36.98)
SUDEP - Female	No tonic – clonic seizures as reference
SUDEP - Female	20 (1 study) 1 - 5 years	⊕⊕⊝⊝ LOW¹^,²^,³ due to risk of bias, indirectness	OR 11.20 (1.6 to 78.39)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Outcomes adjusted for number of seizures (per month) and number of tonic clonic seizures (per year)

Table 10Clinical evidence summary: Over three tonic-clonic seizures per year

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)
SUDEP – Male	No tonic – clonic seizures as reference
SUDEP – Male	20 (1 study) 1 - 5 years	⊕⊝⊝⊝ VERY LOW¹^,²^,³ due to risk of bias, indirectness, imprecision	OR 3.30 (0.5 to 21.78)
SUDEP - Female	No tonic – clonic seizures as reference
SUDEP - Female	20 (1 study) 1 - 5 years	⊕⊕⊝⊝ LOW¹^,²^,³ due to risk of bias, indirectness	OR 28.00 (3.8 to 206.31)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Outcomes adjusted for number of seizures (per month) and number of tonic clonic seizures (per year)

Table 11Clinical evidence summary: Seizure frequency

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One or less than one seizure compared to over one seizure per month

104

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

OR 2.50

(0.9 to 6.95)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Outcomes adjusted for Age at onset, Duration of disease, Aura, Family history of epilepsy, Psychiatric conditions, Epilepsy classification, Seizure frequency, Seizure related to lesion on MR imaging, Number of ASMs, Type of ASM

Table 12Clinical evidence summary: Number of anti-seizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Less ASM’s compared to more ASM’s

104

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^, ³

due to risk of bias, indirectness

OR 1.80

(1.1 to 2.95)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for Age at onset, Duration of disease, Aura, Family history of epilepsy, Psychiatric conditions, Epilepsy classification, Seizure frequency, Seizure related to lesion on MR imaging, Number of ASMs, Type of ASM

Table 13Clinical evidence summary: Adherence status: Nonadherence of medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Adherence to medication as reference

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 3.32

(3.11 to 3.54)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 14Clinical evidence summary: Adherence status: Untreated Epilepsy

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Adherence to medication as reference

33,658

(1 study)

>5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, imprecision

HR 0.92

(0.84 to 1.01)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed the null line

3: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 15Clinical evidence summary: Polytherapy

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No ASM polytherapy compared to ASM polytherapy

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 0.75

(0.69 to 0.82)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 16Clinical evidence summary: Alzheimer’s Disease

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No Neurological condition as reference

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 1.7

(1.54 to 1.88)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 17Clinical evidence summary: Brain tumour

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No Neurological condition as reference

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 1.58

(1.39 to 1.8)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 18Clinical evidence summary: Meningitis

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No Neurological condition as reference

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 1.34

(1.08 to 1.66)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 19Clinical evidence summary: Stroke

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No Neurological condition as reference

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 1.3

(1.22 to 1.39)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 20Clinical evidence summary: Charlson Comorbidity Index

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Lower CCI compared to higher CCI

33,658

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to risk of bias

HR 1.19

(1.18 to 1.2)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Outcomes adjusted for adherence status, gender, age, race, use of ASM polytherapy, epilepsy related comorbidities

Table 21Clinical evidence summary: CNS infections

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No CNS infection as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 6.10

(4.1 to 9.08)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 22Clinical evidence summary: Metastatic Cancer

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No metastatic cancer as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 3.70

(2.2 to 6.22)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 23Clinical evidence summary: Solid Tumour (no metastasis)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No solid tumour as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 2.0

(1.1 to 3.64)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 24Clinical evidence summary: Depression

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No depression as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 0.20 (0.1 to 0.4)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 25Clinical evidence summary: Diabetes (no complications)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No diabetes as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 1.40

(1 to 1.96)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 26Clinical evidence summary: Peripheral vascular disease

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No peripheral vascular disease as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 0.50

(0.3 to 0.83)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 27Clinical evidence summary: Traumatic brain and head injury

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No traumatic brain and head injury as reference

456

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, indirectness

OR 5.10

(2.8 to 9.29)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Outcomes adjusted for age, gender, CNS infections, metastatic cancer, renal disease, solid tumours without metastasis, anoxic brain injury, cardiac arrhythmias, encephalopathy, depression, paraplegia, diabetes without complications, peripheral vascular disease, traumatic brain and head injuries

Table 28Clinical evidence summary: Abnormal neurological examination

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Normal neurological examination as reference

467

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

HR 12.80

(1.4 to 116.96)

1: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

2: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

3: Adjusted for neurologic examination, cognitive function, previous status epilepticus, mode of onset, aetiology, usage of ≥ 2 ASM’s, seizure frequency, intractable at last follow up

Table 29Clinical evidence summary: Abnormal cognitive function

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Normal cognitive function as reference

467

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

HR 3.78

(0.42 to 34.02)

1: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

2: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

3: Adjusted for neurologic examination, cognitive function, previous status epilepticus, mode of onset, aetiology, usage of ≥ 2 ASM’s, seizure frequency, intractable at last follow up

4: Unclear which factors were adjusted for in the multivariate analysis

Table 30Clinical evidence summary: Status Epilepticus (ever)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No status epilepticus as reference

467

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

HR 1.34

(0.48 to 3.74)

1: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

2: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for neurologic examination, cognitive function, previous status epilepticus, mode of onset, aetiology, usage of ≥ 2 ASM’s, seizure frequency, intractable at last follow up

Table 31Clinical evidence summary: Metabolic / Structural Aetiology

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

No metabolic / structural aetiology as reference

467

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

HR 2.62

(0.69 to 9.95)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for neurologic examination, cognitive function, previous status epilepticus, mode of onset, aetiology, usage of ≥ 2 ASM’s, seizure frequency, intractable at last follow up

Table 32Clinical evidence summary: Tumour aetiology

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Cryptogenic aetiology as reference

263

(1 study)

1 - 5 years

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

HR 4.67

(1.76 to 12.39)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed the null line

3: Adjusted for age of onset, frequency, imaging, type of seizure, aetiology, medication, age, gender

Table 33Clinical evidence summary: Vascular lesion aetiology

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Cryptogenic aetiology as reference

263

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, imprecision

HR 1.37

(0.46 to 4.08)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed the null line

3: Adjusted for age of onset, frequency, imaging, type of seizure, aetiology, medication, age, gender

Table 34Clinical evidence summary: Trauma aetiology

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Cryptogenic aetiology as reference

263

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, imprecision

HR 0.81

(0.22 to 2.98)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed the null line

3: Adjusted for age of onset, frequency, imaging, type of seizure, aetiology, medication, age, gender

Table 35Clinical evidence summary: Infection aetiology

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Mortality

Cryptogenic aetiology as reference

263

(1 study)

1 - 5 years

⊕⊕⊝⊝

LOW¹^,²^,³

due to risk of bias, imprecision

HR 1.18

(0.15 to 9.28)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed the null line

3: Adjusted for age of onset, frequency, imaging, type of seizure, aetiology, medication, age, gender

Table 36Clinical evidence summary: Seizure frequency - >10 seizures per year (at baseline)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

probable SUDEP

≤Ten seizures per year as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, imprecision

OR 5.90

(2.2 to 15.82)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 37Clinical evidence summary: Seizures prior to SUDEP

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

probable SUDEP

Seizure free prior to SUDEP as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 9.50

(3 to 30.08)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 38Clinical evidence summary: Seizure frequency – (3 – 12 seizures past year)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

0 – 2 seizures as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

RR 4.47

(1.33 to 15.02)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year.

Table 39Clinical evidence summary: six to ten tonic-clonic seizures (previous 3 months)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

0 – 5 seizures as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

OR 0.70

(0.2 to 2.45)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for History of generalized tonic clonic seizures, No of tonic clonic seizures in previous 3 months, Total number of anti-seizure medications, Carbamazepine usage, Supervision, Asthma

Table 40Clinical evidence summary: eleven to twenty tonic-clonic seizures (previous 3 months)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

0 – 5 seizures as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 19.40

(1.7 to 221.4)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in the previous 3 months, number of ASMs, carbamazepine usage, supervision level, asthma

Table 41Clinical evidence summary: Twenty-one to fifty tonic-clonic seizures (previous 3 months)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

0 – 5 seizures as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 14.60

(1.3 to 163.96)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in the previous 3 months, number of ASMs, carbamazepine usage, supervision level, asthma

Table 42Clinical evidence summary: Over fifty tonic-clonic seizures (previous 3 months)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

0 – 5 seizures as reference

151

(1 study)

5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

OR 11.70

(0.3 to 456.31)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for history of GTCS, number of TCS in the previous 3 months, number of ASMs, carbamazepine usage, supervision level, asthma

Table 43Clinical evidence summary: History of generalized tonic-clonic seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No history of generalized tonic clonic seizures as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 13.80

(6.6 to 28.85)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in the previous 3 months, number of ASMs, carbamazepine usage, supervision level, asthma

Table 44Clinical evidence summary: Focal seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized seizures as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1.34

(0.77 to 2.33)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for age, sex, generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation, living conditions and antiepileptic drugs.

Table 45Clinical evidence summary: Focal and generalized seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized seizures as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1.42

(0.49 to 4.12)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for age, sex, generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation, living conditions and antiepileptic drugs.

Table 46Clinical evidence summary: Undetermined seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized seizures as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 3.51

(1.44 to 8.56)

1: Adjusted for age, sex, generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation, living conditions and antiepileptic drugs.

Table 47Clinical evidence summary: Substance abuse

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 2.07

(1.04 to 4.01)

1: Adjusted for age, sex, generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation, living conditions and antiepileptic drugs.

Table 48Clinical evidence summary: Alcohol dependence

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

OR 2.30

(1.02 to 5.21)

1: Adjusted for age, sex, generalized tonic-clonic seizures frequency and nocturnal generalized tonic-clonic seizures last year of observation, living conditions and antiepileptic drugs.

2: Downgraded by 1 increment if the confidence interval crossed the null line

Table 49Clinical evidence summary: Alcoholism

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized idiopathic seizures as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 1.42

(0.68 to 2.97)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 50Clinical evidence summary: Local symptomatic seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized idiopathic seizures as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 1.15

(0.18 to 7.35)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 51Clinical evidence summary: Local cryptogenic seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized idiopathic seizures as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 1.94

(0.27 to 13.94)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 52Clinical evidence summary: Undetermined seizures

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Generalized idiopathic seizures as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 1.17

(0.14 to 9.78)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 53Clinical evidence summary: Anti-seizure medication therapy - monotherapy

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.79

(0.44 to 1.42)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 54Clinical evidence summary: Anti-seizure medication therapy – Polytherapy (≥2 medications)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 0.48

(0.26 to 0.89)

1: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 55Clinical evidence summary: Anti-seizure medication therapy – Two anti-seizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.59

(0.31 to 1.12)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 56Clinical evidence summary: Two antiseizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One ASM as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 1.95

(0.65 to 5.58)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 57Clinical evidence summary: Three antiseizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One ASM as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

RR 10.23

(1.86 to 56.27)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 58Clinical evidence summary: Anti-seizure medication therapy – Polytherapy (> 3 anti-seizure medications)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 0.31

(0.14 to 0.69)

1: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 59Clinical evidence summary: three to four anti-seizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One to two ASM as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

OR 1.30

(0.6 to 2.82)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for history of GTCS, number of TCS in previous 3 months, total number of ASM, carbamazepine usage, supervision, asthma

Table 60Clinical evidence summary: Over four anti-seizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One to two ASM as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 3.10

(1.4 to 6.86)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in previous 3 months, total number of ASM, carbamazepine usage, supervision, asthma

Table 61Clinical evidence summary: No anti-seizure medications

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

One to two ASM as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 21.70

(4.4 to 107.03)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in previous 3 months, total number of ASM, carbamazepine usage, supervision, asthma

Table 62Clinical evidence summary: Monotherapy – Carbamazepine

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1

(0.48 to 2.08)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 63Clinical evidence summary: Monotherapy – Carbamazepine

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No carbamazepine use as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 2.00

(1.1 to 3.64)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of GTCS, number of TCS in previous 3 months, total number of ASM, carbamazepine usage, supervision, asthma

Table 64Clinical evidence summary: Monotherapy – Lamotrigine

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.93

(0.41 to 2.11)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 65Clinical evidence summary: Monotherapy – Valproic Acid

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.52

(0.2 to 1.35)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 66Clinical evidence summary: Monotherapy – Phenytoin

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.56

(0.17 to 1.84)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 67Clinical evidence summary: Monotherapy – Levetiracetam

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 0.1

(0.02 to 0.5)

1: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 68Clinical evidence summary: Monotherapy – Oxcarbazepine

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 0.58

(0.09 to 3.74)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 69Clinical evidence summary: Monotherapy – Topiramate

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 2.02

(0.29 to 14.07)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 70Clinical evidence summary: Monotherapy – Other anti-seizure medication

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No ASM as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1.32

(0.39 to 4.47)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 71Clinical evidence summary: Nonadherence

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Adherence as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 2.75

(1.58 to 4.79)

1: Adjusted for adjusted for matching variables (sex and calendar time), age, duration and type of epilepsy, living conditions (sharing bedroom), intellectual disability, substance abuse, alcohol dependence, and education level, history of GTCS, GTCS frequency in the last year and nocturnal GTCS last year

Table 72Clinical evidence summary: One to two changes in dose of antiseizure medication (per year)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No changes as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 0.69

(0.26 to 1.83)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 73Clinical evidence summary: Three to five changes in dose of antiseizure medication (per year)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No changes as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

RR 9.32

(1.95 to 44.54)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 74Clinical evidence summary: Antipsychotic medication

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No antipsychotic medication as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³^,⁴

due to risk of bias, indirectness, imprecision

RR 2.14

(0.90 to 5.09)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Downgraded by 1 increment if the confidence interval crossed the null line

4: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 75Clinical evidence summary: Anxiolytic medication

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No anxiolytic medication as reference

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

RR 3.00

(1.16 to 7.76)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for seizure frequency during last year, age in years at epilepsy onset, epilepsy type, number of ASM, changes in dose of ASM per year

Table 76Clinical evidence summary: Asthma

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No asthma as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 0.20

(0.1 to 0.4)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of TCS, number of TCS in previous 3 months, total number of anti-seizure medications, carbamazepine usage, supervision, asthma

Table 77Clinical evidence summary: Sharing household but not sharing a bedroom

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Sharing household and bedroom as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 2.28

(1.14 to 4.56)

1: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 78Clinical evidence summary: Living alone

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Sharing household and bedroom as reference

255

(1 study)

>5 years

⊕⊕⊕⊕

HIGH¹

OR 5.01

(2.93 to 8.57)

1: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 79Clinical evidence summary: Secondary education

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Post-secondary education as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1.59

(0.78 to 3.24)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 80Clinical evidence summary: Primary education

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

Post-secondary education as reference

255

(1 study)

>5 years

⊕⊕⊕⊝

MODERATE¹^,²

due to imprecision

OR 1.21

(0.58 to 2.52)

1: Downgraded by 1 increment if the confidence interval crossed the null line

2: Adjusted for age at onset, duration of epilepsy, type of epilepsy, causes of epilepsy, living conditions, highest education

Table 81Clinical evidence summary: Same room supervision at night

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No supervision at night as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 0.10

(0.03 to 0.3)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of TCS, number of TCS in previous 3 months, total number of anti-seizure medications, carbamazepine usage, supervision, asthma

Table 82Clinical evidence summary: Special supervision at night (regular checks throughout the night or the use of a listening device)

Outcomes

No of Participants

(studies)

Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

SUDEP

No special precautions for supervision at night as reference

151

(1 study)

>5 years

⊕⊝⊝⊝

VERY LOW¹^,²^,³

due to risk of bias, indirectness

OR 0.40 (0.2 to 0.8)

1: Downgraded by 1 increment if the majority of the evidence was at moderate risk of bias, and downgraded by 2 increments if the majority of the evidence was at high risk of bias

2: Downgraded for indirectness as analysis did not adjust for at least two of the non-modifiable confounders

3: Adjusted for history of TCS, number of TCS in previous 3 months, total number of anti-seizure medications, carbamazepine usage, supervision, asthma

Evidence review: Modifiable risk factors for epilepsy related mortality

Authors

1. Modifiable risk factors for epilepsy-related mortality, including SUDEP, and the magnitude of risk of those factors

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Prognostic evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the prognostic evidence

1.1.6. Summary of the prognostic evidence – Adults >18 years (follow up 1 – 5 years)

1.1.7. Summary of the prognostic evidence – Adults >18 years (follow up > 5 years)

1.1.8. Summary of the prognostic evidence – Children <18 years (follow up > 5 years)

1.1.9. Summary of the prognostic evidence – Mixed population of children <18 years and adults >18 years (follow up 1 – 5 years)

1.1.10. Summary of the prognostic evidence – Mixed population of children <18 years and adults >18 years (follow up >5 years)

1.1.11. Economic evidence

1.1.11.1. Included studies

1.1.11.2. Excluded studies

1.1.12. Economic model

1.1.13. Evidence statements

1.1.13.1. Effectiveness

1.1.13.2. Economic

1.1.14. The committee’s discussion and interpretation of the evidence

1.1.14.1. The outcomes that matter most

1.1.14.2. The quality of the evidence

1.1.14.3. Benefits and harms

1.1.15. Cost effectiveness and resource use

1.1.16. Other factors the committee took into account

1.1.17. Recommendations supported by this evidence review

References

1.1.17.1. 1.1.14.2. Economic evidence – included studies

Appendices

Appendix A. Review protocols

A.1. Review protocol for [add key area, for example, unplanned hospital admission]

A.2. Health economic review protocol

Appendix B. Literature search strategies

B.1. Clinical search literature search strategy

B.2. Health Economics literature search strategy

Appendix C. Prognostic evidence study selection

Appendix D. Prognostic evidence

Appendix E. Forest plots

E.1. Adults >18 years (follow up 1 – 5 years)

E.2. Adults >18 years (follow up >5 years)

E.3. Children <18 years (follow up >5 years)

E.4. Mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

E.5. Mixed population of children <18 years and adults >18 years (follow up > 5 years)

Appendix F. GRADE tables

F.1. Adults >18 years (follow up 1 – 5 years)

F.2. Adults >18 years (follow up >5 years)

F.3. Children <18 years (follow up >5 years)

F.4. Mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

F.5. Mixed population of children <18 years and adults >18 years (follow up > 5 years)

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Appendix I. Health economic model

Appendix J. Excluded studies

J.1. Clinical studies

J.2. Health Economic studies

Table 1PICO characteristics of review question

Table 2Summary of studies included in the evidence review - Adults >18 years (follow up 1 – 5 years)

Table 3Summary of studies included in the evidence review - Adults >18 years (follow up >5 years)

Table 4Summary of studies included in the evidence review – Children <18 years (follow up > 5 years)

Table 5Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up 1 - 5 years)

Table 6Summary of studies included in the evidence review - mixed population of children <18 years and adults >18 years (follow up >5 years)

Table 7Clinical evidence summary: one to five seizures per month

Table 8Clinical evidence summary: Over five seizures per month

Table 9Clinical evidence summary: One to three tonic-clonic seizures per year