First seizure from sleep - What is the risk of recurrence? Dr. Elaine Pang

Are people who have their first seizure during sleep at greater or lesser risk for future seizures, compared with people who have their first seizure when they're awake? Dr. Laurent Sheybani interviews Dr. Elaine Pang, author of a 2023 paper in Epilepsia that analyzed data from 1,312 adults visiting a first-seizure clinic.

This episode also discusses a 2015 evidence-based guideline on managing a first unprovoked seizure in adults. The guideline was developed by the American Academy of Neurology and the American Epilepsy Society.

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

[00:00:00] Dr. Laurent Sheybani: Hello, everyone. Today I am with Elaine Pang to discuss a recent paper that she published in Epilepsia this year. The title is "First seizure from sleep: Clinical features and prognosis." This is a very interesting paper on the risk of recurrence after a first seizure during sleep, and I am very much looking forward to discuss her results.

To start with, I suggest that you introduce yourself, Elaine.

[00:00:28] Dr. Elaine Pang: Hi. I'm Elaine Pang.

I'm an epilepsy fellow currently working in the University of Calgary at Foothills Medical Centre. And I'm originally from Perth, Western Australia, working at Charles Gardner Hospital and Fiona Stanley Hospital. 

[00:00:44] Dr. Laurent Sheybani: Thank you. Would you mind introducing the background and the question that you wanted to answer with this paper?

[00:00:51] Dr. Elaine Pang: So we know that patients that present with a first seizure really want to know their risk of recurrence. And it's important to kind of identify any prognostic factors that we can find to counsel our patients about that risk. And there's some things that we already know about, such as epileptic abnormalities and EEG and remote symptomatic kind of etiologies that increase the patient's risk of developing seizure recurrence after a first seizure.

And there have been some smaller studies that have suggested that seizures from sleep also conferred an increased risk of seizure recurrence. But they were small, they had a variable diagnosis of how they made the diagnosis of seizure from sleep, and a couple of studies included a pediatric population, which included childhood epilepsy syndromes that were more prone to have seizures from sleep and had their own prognostic kind of predictions.

So what we wanted to see was in an adult population with a first seizure from sleep, what was the risk of recurrence? And what was the degree of that risk as well? And with that, were those recurrences more likely to be from sleep or from wakefulness? And what were the possible associated complications of seizures such as injury associated with that?

[00:02:03] Dr. Laurent Sheybani: I think it was a very nice study, very systematic in the way that you presented the methods, but also the results afterwards. Can you tell us what were the main results of your paper? 

[00:02:16] Dr. Elaine Pang: So of 1,312 adult patients who presented with a first seizure, 23 percent of them presented the first seizure from sleep. So just under a quarter. Compared to those that had seizures from wakefulness, this population had a higher rate of seizure recurrence, with a one-year risk of 57 percent and a 10-year risk of 77.5 percent, so quite substantial. Seizures from sleep were a strong predictor of seizure recurrence with a hazard ratio of 1.44, and this actually on par with other known risk factors, such as epileptiform abnormalities and remote symptomatic etiologies.

Those patients that had seizures from sleep were more likely to be older and more likely to present with tonic-clonic seizures from the description, nd were only slightly more likely to have focal abnormalities. Of note, they were markedly less likely to have generalized epileptic abnormalities.

Of those that had recurrence, the majority had them from sleep and were their second and third seizure. And they were actually surprisingly less likely to sustain any injuries from their initial seizure from sleep or from their recurrences, apart from oral lingual trauma. 

[00:03:33] Dr. Laurent Sheybani: Based on the current definition of epilepsy, why is that so important, to know that the risk of recurrence is that high?

[00:03:43] Dr. Elaine Pang: So I think it's important to know that the risk of recurrence is high for multiple reasons. For one, it's important to counsel our patients about that risk, so that they know what to look for in the future. And it might influence the way that we manage our patients. But of course, a few years ago there were the recommendations to consider patients after a first seizure who have a risk of recurrence of more than 60 percent in the next 10 years to be considered as having epilepsy. 

I think this is still a bit of a gray area in terms of nocturnal seizures. So I think that paper was from 2015, and even then they raised the possibility that nocturnal seizures was associated with increased risk of seizure recurrence and whether they should be considered in that kind of criteria.

That study's recommendations were based on two prior older studies from the 80s and 90s that had a very different definition of seizures, of nighttime seizures. Rather than looking at seizures from sleep, they looked at nocturnal seizures and defined it as between midnight and 9 a.m. So that could have easily included patients who had seizures from wakefulness soon after waking up. So it's a bit of a different population. So what I'll say, does it add to that kind of discussion saying actually, when we have a much more defined definition of seizures from sleep, there is still this conferred increased risk of seizure recurrence more than that 60 percent cut off at 10 years. 

That paper kind of raised the possibility of treating patients after a first seizure to decrease their risk of recurrence, but they were quite guarded as well when they discussed it. They said it should be an individualized approach. And our study kind of is in line with that. We showed that 26 percent of patients who had seizures from sleep or from wakefulness were on anti-seizure medication after their first seizure for various reasons at the clinician's discretion. And that was not associated with a decreased rate of recurrence in our study.

We also agree with an individualized approach to whether we treat a patient after a first seizure from sleep. It depends. So we know that they are at a lower risk of having injury from recurrences and those recurrences are more likely to occur from sleep. And for example, driving, which is a massive issue for lots of our patients with epilepsy, is maybe less of an issue in those with pure sleep epilepsy, as many jurisdictions allow our patients to drive. So there's pros and cons to starting treatment after a first seizure from sleep. And this just adds to the conversation.

[00:06:20] Dr. Laurent Sheybani: Regarding the risk of recurrence of seizures when they occur during wakefulness, the overall risk of recurrence after 10 years is about 65 percent in the paper. But if we remove patients that had an EEG abnormality or an MRI or an epileptogenic lesion on the MRI, I suppose that this risk is much lower than the 65 patients. What would be the risk of recurrence in your cohort? 

[00:06:49] Dr. Elaine Pang: So in patients with a first seizure from sleep who do not have all of those factors, so do not, a non lesional MRI, have a normal EEG, do not have a past history of a CNS insult, the risk of recurrence at 10 years is still 78.5 percent. So it's actually surprisingly high. Which kind of demonstrates that this is a significant predictor of seizure recurrence on its own. So even in what we would have said is a traditionally very low-risk patient for seizure recurrence compared to other patients, they still have a substantial risk of recurrence purely from having a seizure from sleep alone.

[00:07:31] Dr. Laurent Sheybani: You also showed that patients with a first seizure during sleep were older. What is your interpretation  of this? Is it just that people need to be witnessed when they have a seizure during sleep, and so it takes more time to be actually identified, or is it something else?

[00:07:49] Dr. Elaine Pang: So I think this is kind of an interesting finding of this study. And it's not 100 percent clear why this was the case. We do know that adults in the older population are more likely to have focal epilepsy. And we know that focal epilepsy is associated with increased recurrence from other studies.

But in our population, there were more focal epileptiform abnormalities in those that had seizures from sleep. There was no real significant difference in remote symptomatic etiologies or epileptogenic lesions on imaging. So not 100 percent sure why this is the case. The majority of our patients, independent of age, had witnessed events. So that's definitely going to factor into the identification of their sleep seizure.

[00:08:34] Dr. Laurent Sheybani: You already partially addressed this question, but how are your results comparable with the study by Krumholtz and colleague in 2015 in Neurology? They also looked at the risk of recurrence based on each abnormality, epileptogenic lesion on the MRI, and other factors.

[00:08:53] Dr. Elaine Pang: Yeah, so I think our study contributes to that discussion. So in that paper they demonstrated that there was level A evidence that remote symptomatic etiologies and epileptiform abnormalities on EEG were associated with seizure recurrence after a first seizure and that there was level B evidence for nocturnal seizures specifically, so seizures between midnight and 9 a.m., not necessarily sleep seizures, having a risk, comparing also a risk of recurrence. Those studies were much, were smaller and older and they had kind of variable inclusion exclusion criteria. So for example, one study included provoked events and the other study excluded focal seizures.

So it was a bit of a different population. Which I think is why that study from 2015 had a relatively guarded approach when it came to discussing what to do after a patient presents with a first seizure from sleep. So this study contributes to that, and it confirms that we definitely do have an increased risk of seizure recurrence after first seizure from sleep that is significant and over that 60 percent mark at 10 years. But whether treatment is appropriate straight after a first seizure from sleep is debatable, and it should be individualized, which is what they said as well in their paper.

[00:10:19] Dr. Laurent Sheybani: An interesting finding also in in your paper is that when people who suffer the first seizure during sleep have a recurrence, it usually occurs in, let's say, the late part of the night, the second part of the night, which is kind of surprising because the second part of the night is really made of more rapid eye movement sleep, which is supposed to be resistant against epileptic seizure. So how would you interpret? How would you reconcile these two presumably opposable views?

[00:10:52] Dr. Elaine Pang: This was definitely a surprising finding. We're not sure of the exact physiological mechanism of it. We did raise the possibility that given the sleep cycle being 90 minutes, are there periods of non-REM sleep during that time that predisposes patients to have seizures during that time period? But we're not 100 percent sure. And it's definitely something for more research.

[00:11:16] Dr. Laurent Sheybani: I was about to ask. In general, what do you think is the mechanism that makes seizures occurring during sleep more likely to recure than seizures occurring during wakefulness. Do you have any hypothesis on that? 

[00:11:31] Dr. Elaine Pang: This is also kind of a big question mark still. Is it, as you've raised, something to do with the underlying physiology of the sleep state and the relationship with epilepsy? Could it be the fact that a lot of these patients were more likely to have focal seizures and this is just kind of a manifestation of vocal seizures, more likely to have recurrences?

One thing is that one of the limitations of all studies of first seizure patients is you're never 100 percent sure whether it's really their first seizure. When a patient comes to clinic, and maybe particularly for sleep seizures, it's even harder to make that diagnosis.

So maybe these patients who present to clinic with their first seizure from sleep may have had previous seizures in the past. And therefore, these are already patients that are having seizure recurrence. And that's why we're getting more recurrence in this population.

[00:12:24] Dr. Laurent Sheybani: If I were a patient that suffered from a first seizure during sleep, what would be the discussion that you would have with that patient regarding the diagnosis of epilepsy and regarding the introduction of a treatment?

[00:12:37] Dr. Elaine Pang: So, I would discuss with them that they would have an increased risk of recurrence. You wouldn't quote the general 50 percent chance of having a recurrence. You would quote a much higher percent chance of having a recurrence. But I would also reassure them that this is most likely going to reoccur from sleep. It is less likely to be associated with injury. And that recurrence has an impact on their long-term prognosis and quality of life, but so does treatment as well.

And so adding up those pros and cons for that individual patient to see whether they would like, whether the treatment is appropriate for them after first seizure from sleep, or whether we wait for that recurrence and then act. And in addition, looking at all those other standard predictors of seizure occurrence, such as remote symptomatic etiology, lesions on imaging, EEG abnormalities, may further sway our opinion one way or the other as to whether to treat.

[00:13:35] Dr. Laurent Sheybani: Since both seizure during sleep and EEG abnormality, for example, are both independent factors for seizure recurrence, what is your attitude regarding these two independent factors? Are you more inclined to start a treatment when someone has a seizure during sleep or when someone has EEG abnormality, or do you need both to start a treatment, or what's your attitude with this?

[00:14:00] Dr. Elaine Pang: I think this is always kind of the million-dollar question when you're in a first seizure clinic. And I don't necessarily say every time a patient has a seizure from sleep, I will start them on treatment. And same with epileptic abnormalities on EEG. And it just depends on the situation, honestly, is a lot of it. You very much individualize it to the patient. 

[00:14:19] Dr. Laurent Sheybani: Maybe a last question. Do you see any limitations in your in your work or anything that you would have made different or a follow up study that could improve your current results?

[00:14:31] Dr. Elaine Pang: So as previously said, one of the limitations of all first seizure studies is whether it's truly a first seizure that we're capturing. And that's probably more so for patients with first seizure from sleep, because there may be delays in diagnosis or misdiagnosis as parasomnias and whatnot that may affect it, that may have affected our results.

And with that, It's very hard for people to identify focal seizures from sleep. So, as you can see from the paper, the majority of the seizure types was labeled as bilateral tonic-clonic seizures, but a good portion of them could have easily been hyperkinetic seizures from frontal lobe epilepsy, for example, that were misinterpreted by the bystander or the patient as a bilateral tonic-clonic seizure. So, semiology is a lot harder to interpret in this population inherently. 

And probably the only other major limiting factor, or kind of interesting point of the study, was we had a relatively low percentage of patients that had epileptiform abnormalities: only 17 percent. Probably one of the limitations of the study is we only used the first EEG to make the diagnosis of epileptiform abnormalities; we didn't look at repeat studies. And as a routine, we would normally use a routine study as a first line, and sleep deprived and subsequent repeat studies. And in this population of sleep-only seizures, or seizures from sleep, a sleep-deprived study will probably pick up more epileptiform abnormalities. So probably our study underestimates that to some degree.

[00:16:02] Dr. Laurent Sheybani: Okay. Thank you very much for all your answers. Do you have anything that you would like to add regarding your study or regarding epilepsy and sleep? 

[00:16:14] Dr. Elaine Pang: So I think all I want to say is for clinicians just to be aware that there is an increased risk of recurrence in this population and that needs to be discussed and considered in their management and assessment of patients.

[00:16:26] Dr. Laurent Sheybani: Thank you very much for your time. It was very interesting.

[00:16:29] Dr. Elaine Pang: Thank you very much. Thanks for your time today.