Evidence review: Modifiable risk factors for a second seizure

1. Modifiable risk factors for a further seizure after a first seizure

1.1. Review question

What are the modifiable risk factors for a further seizure after a first seizure, and what is the magnitude of risk of those factors?

1.1.1. Introduction

The likelihood of having a further seizure following a first seizure differs between individuals. Understanding and quantifying the magnitude or risk associated with different factors may help people to manage that risk and influence the impact on their lives as well as informing their shared decision to start long term antiseizure medication. This review area examines modifiable risk factors for a further seizure after a first seizure and what the magnitude of risk is for those factors.

Assessing modifiable risk factors for a second seizure is different from the prediction of a second seizure. Prediction is assessing if a tool can accurately predict a second seizure using all, or most of, the known risk factors for a second seizure. This will provide a risk score based on an individual’s risk factors. So, this identifies who is at risk of a second seizure. In comparison, analysing potential modifiable risk factors looks for individual modifiable risk factors which may have an impact on second seizures. This informs us which risk factors may be modified in people who are identified to be at risk of a second seizure.

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: Included studies

Six cohort studies were found investigating the modifiable risk factors for a second seizure after having a first seizure and were included in the review.^{2, 4, 5, 12, 31, 33}

Within the six studies included within the review, the risk factors considered were psychological factors, health conditions (e.g., diabetes and hypertension), infection or raised temperature and types of seizures. No evidence was found for the other risk factors considered:

• Blood pressure
• Activity/exercise levels
• Alcohol/ recreational drugs
• Psychosocial factors
• Sleep deprivation
• AED use
• Other drugs that reduce seizure thresholds
• Tumours
• Drugs affecting sleep

Of the included studies, two^{2, 4} cohort studies investigated adult participants who were followed up from 1 – 5 years; one³¹ study assessed adults, followed up for more than 5 years; and three^{5, 12, 33} studies reviewed children (under 18) who were followed up for 1 – 5 years after their first seizure. No studies were found for other stratifications or those who had a mixed adult and child population.

Evidence from these studies is summarised in the clinical evidence summary below (Table 5).

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.

1.1.4.1. 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 (follow up > 5 years).

Table 4

Summary of studies included in the evidence review – Children <18 years (follow up 1 – 5 years).

See Appendix D for full evidence tables.

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

Table 5

Clinical evidence summary: Lifetime generalized anxiety disorder.

Table 6

Clinical evidence summary: Lifetime mood disorder.

Table 7

Clinical evidence summary: Psychiatric Disorders.

Table 8

Clinical evidence summary: Sepsis.

1.1.5.2. Summary of the prognostic evidence: Adults >18 years (follow up >5 years)

Table 9

Clinical evidence summary: Partial seizures.

Table 10

Clinical evidence summary: Status Epilepticus.

Table 11

Clinical evidence summary: Diabetes Mellitus.

Table 12

Clinical evidence summary: Hypertension.

Table 13

Clinical evidence summary: Atrial Fibrillation.

Table 14

Clinical evidence summary: Functional disability – severe.

Table 15

Clinical evidence summary: Functional disability – moderate.

1.1.5.3. Summary of the prognostic evidence: Children <18 years (follow up 1-5 years)

Table 16

Clinical evidence summary: Unprovoked Seizures.

Table 17

Clinical evidence summary: Temperature ≥38 degrees.

Table 18

Clinical evidence summary: Temperature (per F increase).

Table 19

Clinical evidence summary: Temperature (per F increase).

See Appendix F for full GRADE tables.

1.1.6. Economic evidence

1.1.7. Included studies

No health economic studies were included.

1.1.8. 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.

1.1.9. Economic model

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

1.1.10. Evidence statements

1.1.10.1. Clinical evidence statements

• None

1.1.10.2. Economic

• No relevant economic evaluations were identified.

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

1.1.11.1. The outcomes that matter most

The only outcome for this review question was a second seizure, as this review question was designed to evaluate the modifiable risk factors for second seizure in people who have had a first seizure.

1.1.11.2. The quality of the evidence

The evidence concerning the modifiable risk factors for second seizure was of low or very low quality. The main reasons were the risk of bias and indirectness. As all the studies were observational studies, they had to show adjustment was made for potential confounders, and one of the main reasons for downgrading was the failure of studies to adjust for at least two of the modifiable risk factors specified. Appropriate statistical adjustment for confounding variables should lead to the results that would be observed if the confounding variables are the same across the risk factor and no-risk factor groups, which should increase our confidence that the results are not confounded. Where the confidence interval of the odds, hazard or risk crosses the null line, this signifies that the result is consistent with the possibility of no effect from the risk factor in the population. The committee took note of these different elements in the quality assessment of the evidence in order to decide on recommendations.

1.1.11.3. Benefits and harms

The evidence showed that in adults who are followed up between one to five years, the presence of psychiatric disorders leads to almost three times the odds of a second seizure as no psychiatric disorders. In addition, people with sepsis have an odds of a second seizure that is almost five times greater than the odds in people who do not have sepsis. In adults followed up for over five years, vascular risk factors such as diabetes, hypertension and atrial fibrillation do not show significant effects in relation to a second seizure. However, the committee noted that vascular risk factors can predispose to late onset epilepsy. The committee, therefore, considered it good practice to assess these areas of a person’s health when they are assessed following a seizure.

The evidence showed that in children followed up for one to five years, unprovoked seizures result in 3.5 times the risk of a second seizure as no unprovoked seizures. One study showed that a temperature of over 38 degrees carries an odds of a second seizure that is double the odds observed with a temperature below 38 degrees. However, two studies also showed that a higher temperature can be a protective factor against premature mortality. They showed that people with higher temperatures have 0.3 to 0.8 times the risk of a second seizure, compared to lower temperatures.

No evidence was found in relation to other factors that the committee considered modifiable risk factors such as alcohol and recreational drug use and sleep deprivation. There are good pathophysiological reasons why these may cause seizures, and this is seen in clinical practice.

The committee agreed to emphasize that a comprehensive assessment of potential psychological, biological, and social risk factors should be carried out after a person’s first seizure and that these risks, and advice on how they may be modified, should be discussed with the person, their family, or carers.

1.1.11.4. Cost effectiveness and resource use

No economic evidence was identified for this review question.

The committee discussed the clinical evidence noting the low quality of the evidence presented for determining risk factors of a second seizure for both adults and a paediatric population. The committee noted that in adults, underlying psychiatric disorders and sepsis are non-modifiable risk factors that may increase a person’s risk of a second seizure. Therefore, the committee made a recommendation to assess the presence of these risk factors when presenting with an initial seizure.

The committee also discussed the clinical evidence presented for children, noting that children presenting with an initial afebrile seizure may be at increased risk of a second seizure.

The committee agreed that the recommendations made for adults are current best practice, but noted current practice varies. The committee estimated that only 25% of people presenting with an initial seizure are fully assessed for modifiable risk factors. In addition, the committee acknowledged that in current practice, biological risk factors are more likely to be reviewed than psychosocial risk factors.

The committee also acknowledged that in current practice, children presenting with an initial seizure will always be assessed to try and determine if they experienced an afebrile seizure. The committee noted that for those children presenting with an afebrile seizure, appropriate safety advice will be provided to the child’s parent or carer, and urgent referral advice will be provided, which can be used if a child experiences a second seizure.

The committee noted that if people are not appropriately assessed for risk of a second seizure, this could have a negative impact on a person’s quality of life in the long-term for those people who experience a second seizure. A first seizure may significantly impact a person’s life (for example, through social interactions or driving privileges), but the committee also noted experiencing a second seizure can result in a more severe negative impact on a person’s QoL compared to those people only experiencing one initial seizure. The committee also noted people who were appropriately assessed for risk of a second seizure are less likely to experience such a significant impact on their overall QoL if they experience a second seizure compared to those who were not assessed. This is because making people aware of the risks of second seizure enables them to understand these risks and manage the future impact seizures may have on their lives. Conversely, people who are not aware of these risks may be unaware they are at risk of a second seizure. In addition, people who experience a second seizure and have not been informed of these risks may feel annoyed they were not appropriately informed when they presented with an initial seizure. An epilepsy diagnosis can significantly impact a person’s daily living (for example, driving restrictions). Therefore, some people may perceive not being fully informed at the early stages of diagnosis pathway as ‘lost time’ in coming to terms with their diagnosis if they are later diagnosed with epilepsy.

The committee also acknowledged that not appropriately assessing a person’s risk factors when presenting with initial seizure may result in some people experiencing increased anxiety. For example, a person presenting with an initial seizure may be at low risk of a second seizure but if this is not appropriately assessed and conveyed to the person presenting with an initial seizure, they may seek information on the internet that does not necessarily apply to them.

Overall, the committee concluded there will likely be a change in clinical practice for how a large proportion of adults are managed after their first seizure resulting in additional costs for the NHS. However, the recommendations are not expected to lead to a substantial resource impact because the assessment of risk factors does not take long and can be discussed and assessed with the clinician when a person presents with an initial seizure. This will not constitute an additional visit with a health care professional but may require some additional time with a clinician assessing the person who has presented with an initial seizure. The additional costs incurred by the NHS observed in the form of additional staff time will likely be offset by the QoL gains observed from providing people with the appropriate information regarding their individualised risk of a second seizure.

There is not expected to be a substantial resource impact associated with the recommendation made for children as this recommendation reflects current practice.

1.1.11.5. Other factors the committee took into account

The committee agreed it was important to highlight that modifying risk factors to prevent second seizures is a multifactorial process. This is because the exact reason why some of these risk factors have a direct impact on seizure occurrence is not completely understood.

The committee discussed that after a person has had a seizure it is important to provide information to the person, and their families or carers on how to recognise a further seizure and to give advice on first aid and any measures they could take to reduce their risk of another seizure, as well as who they should contact if they experience a further seizure before their first appointment with the epilepsy service.

1.1.12. Recommendations supported by this evidence review

This evidence review supports recommendations 1.1.1 to 1.1.9 in the NICE guideline.

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Appendices