Epileptic seizures are a common occurrence, with a lifetime prevalence of around 5%, and around two-thirds of these being unprovoked seizures, namely not a manifestation of some underlying pathology such as a metabolic insult, brain injury or structural brain lesion. Uncertainty remains over whether one should treat an unprovoked seizure with the aim of preventing a recurrent seizure.

This subject was discussed in a previous journal post, but since it was based on a study from around 2006 and another from the 1990’s, it seemed worthwhile to revisit the topic in the light of recent Cochrane reviews. It is interesting to compare our “wish-list” compiled in 2013 of what a more definitive study would look like, versus what has actually happened in the intervening decade.

The main issue remains the same: if we don’t know what the recurrence risk is after a single unprovoked seizure, and the level of reduction of risk by taking antiepileptic drugs (AEDs), how can patients make an informed choice on whether to embark on such long term treatment?

I will first discuss a related Cochane review that looked at risk factors for a recurrent seizure as it highlights the limitations of pooling information from disparate studies. This review took 5918 patients across 23 studies; only one was an RCT and in only seven were AEDs investigated. A major issue was that not even the statistical calcuation was standardised; some used relative risk, sone odd ratios and some hazard ratios. While broadly measuring the same thing, they can give widely different values and it is worth for the sake of this journal club about critically appraising studies to explain what the measures are.

Risk, statistically, is the number of times an event occurred divided by the number of times it could have occurred, so 1/6 chance to get a 1 on a six-sided die.

Odds is the number of times an event occurred divided by the number of times it didn’t occur, so 1/5 in the same example. The difference is not quibbling when the risk is high; a 0.5 risk becomes 1.0 odds.

Relative risk is simply one risk value divided by another, and the odds ratio is analogous.

There are not hard and fast rules but, generally, an odds ratio should be used in a case-control study, with two separate populations (the haves versus the have-nots, or the “1”s on a die roll versus the “non-1″s).  A classic example is the proportion of smokers in lung cancer cases versus the proportion of smokers in non cancer controls. Performing linear regression gives an odd ratio result.

Relative risk should be used for a cohort study, where there is one population and some are exposed to some factor, or in the case of a randomised controlled trial, the exposure is a controlled intervention. An equivalent example would be taking a cohort and following up if they developed lung cancer while seeing if they had started smoking; the calculations would be the rate of cancer in the smokers versus the overall rate, and the rate in the non-smokers versus the overall rate.

An aside, with which this journal club is relatively or absolutely obsessed, is the difference between absolute differences versus relative differences. An intervention that changes a risk from 2% to 1% could be quoted as 50% improvement or 1% improvement depending on what case the authors wish to make.

The statistical hazard specifically refers to a time to event analysis, namely cox proportional hazard regression analysis. A typical Kaplan- Meier plot can give a relative risk looking at the difference in survival rates at a certain time point, when the start values were obviously 100%. The hazard ratio is the instantaneous risk at a certain time point given they had already survived to that point, not the total risk from time zero to that point. It is more like the slope of the graph at that point, in fact specifically the slope of the graph at that point divided by the survival probability at that point.

So the Cochrane review produced a mix of relative risks, hazard rations and odd ratios. For example family history in a first degree relative gave a relative risk of 1.47 (1.16 to 1.85 confidence interval) and a hazard ratio of 1.35 (1.03 to 1.76). The only other ones that reached significance were abnormal imaging, abnormal EEG, Todds paresis (just), and noctural seizures. Perhaps surprisingly, status at presentation was not a risk. Child versus adult age gave conflicting significant results for odds ratio versus relative risk in different studies.

That all being said, the main subject of this journal club, Prognosis of adults and children following a first unprovoked seizure by Neligan et al (2023) had even more patient numbers – 12160 across 58 studies, most being cohort studies (relative risks anyone?)

They included status and a cluster within 24 hours, as standard, and usually excluded myoclonic jerks and infantile spasms as they are rather obviously part of ongoing epileptic syndromes. In adults the 6 month risk was 25%, at 12 months 35%, at 24 months 41%. These closely match the rates of the FIRST study of 1993 from the previous journal club and higher than the subsequent MESS study.

The study looked at a number of other parameters, but these were more based on individual studies and did not necessarily show the effect of AEDs. Delaying treatment in the FIRST study until after second seizure did not increase mortality eg at 5 years, 97% (95 to 99%) in immediate versus 98% (95 to 100%) delayed, but there is more to treatment than avoiding mortality and it simply shows that the risk of SUDEP is thankfully low and so it is difficult to tease out differences.

High risk subgroups were as expected: traumatic brain injury gave 82% risk at 12 months if the first seizure was after 7 days following the injury, and there was a high risk after stroke. There was a somewhat higher risk in patients with Alzheimer’s dementia and lower in Lewy body dementia.

In the very long term NGPSE study, if a patient was seizure free for 5 years after single seizure, their risk of subsequent seizure at 10 years was still 10%, but if free for 10 years, the risk at 20 years was 1%. There are not clear data on the effects of AEDs on this risk.

In conclusion, the Cochrane reviews support the 40% 2 year risk quoted figure for seizure recurrence after a first unprovoked seizure, but there is no clearer information on treatment strategies. It would take a study with the design of the wish list of the previous journal club to answer those questions rather than another Cochrane review pooling existing data.