Living with Epilepsy-Treatment Strategies and Outcomes of Epilepsy Among Older People

Video Transcription

So, my task is to, I guess, bring us back to looking at epilepsy onset in this population  on a broader sense, at a more kind of population level, if you like, and touch back on a more, if you like, a system level and how do we approach, you know, having listened to two,  I think, really wonderful talk from basic science to clinical immunology, to some extent, and how they intersect with epilepsy.  So I've been given the title to talk about treatment strategies, how do we look at, you know, what are the treatment strategies and outcomes, and so these are my disclosures,  and like all people getting old, we like to do things backwards. So I'm going to talk about outcomes first, and this is some work that we've done and  look at the long-standing, standing call from Glasgow, and then I'll wind back to, you know,  what are the kind of approaches just to treating older people with epilepsy and see where we go from there.  So this is, Vanessa asked me to talk about this particular study that we've done, published  a couple of years ago, in which we specifically looked at the older population who developed new onset epilepsy in the ongoing, you know, Glasgow cohort over the last 30 years.  So we wanted to ask three specific questions. First, you know, are the treatment outcomes of, what are the treatment outcomes in this population?  And secondly, what are the factors associated with different outcomes? And thirdly, given that we have the opportunity to look at patients treated, diagnosed in  this setting over, you know, quite an extended period, have outcomes change over time? So for those of you who have not been to Glasgow, this is the tip of this little island, you  know, off the Atlanta or North Sea somewhere, and this, we're at Glasgow, but it's a major town or city in the west of Scotland.  It's beautiful, where I had the privilege to spend a number of years there, and still able to continue to look at this population.  So at the time we did the analysis, we were able to extend the study period over a 30-year period from the 80s to the 2012, so anyone treated and diagnosed at this, over this time  could be included. And we, I guess, took the old, the proper old, if you like, you know, over 65, so you look at the literature, the older age cutoff does vary.  Sometimes you see 50, 55, but we decided to go to the proper old, what we call, so over 65 to be included.  And patients were followed up until 2016 or death, and we make sure that all patients had at least a two-year follow-up.  So this is a larger, rather, at least we've got some decent follow-up for these patients. At the clinic, the practice was to see them quite regularly, and we asked the patient  or the carers to help keep a diary. And so we had a total population of close to 1,800 patients who were newly diagnosed  and treated over this period of time, that's including all patients. And of these, 201 were, at the time of treatment, 65 years or older.  So a relatively small population, if you like, because the youngest age was down to nine years old, so the vast majority were in the younger adult age, but we did have 201, and  this is already, I think, one of the largest population for new-onset epilepsy at this age. This is the kind of breakdown for the demographics.  There were slightly more male than female, similar to the entire total cohort. The age at initial treatment, the median was 73 years, and the interquartile range, as  you can see there, 66 to 79, and the median follow-up was more than seven years. So we had a decent follow-up, as I said.  Some interesting kind of baseline factors to highlight, found history of epilepsy only found in 6%, compared to the whole total cohort, it was closer to somewhere between 15 to 20%,  which is what you expect in the general epilepsy population. Only a very minority had this history of febrile seizure, where you see a bit more in the overall  population, and interestingly, or not surprisingly, cerebrovascular disease was common, a third  of patients had a history, either as a contributing factor, or it could be just a comorbidity.  And as many studies have found, there was a high proportion of patients taking concomitant medication, and in fact, the median number was at least three drugs, and going on from  interquartile range from two to four, and some had far more than four medications. I'll come back to the aspirin story later on.  Some other demographics here, and you notice that many patients had quite a lot of seizures before they started treatment, and in fact, more than 40% of seizure had already had more  than five seizures by the time they start treatment, and we've found in a few studies that more than five seizures is a risk factor for poorer treatment outcomes, and some patients  even had more than 20 seizures by the time they started treatment, and this is consistent in line with the duration of treatment, so the median duration from the first seizures  to being treated was as long as eight months. So 50% of patients were only treated after eight months of having had their first seizures,  and some even more than that, more than a number of years before, and this is likely reflecting what we've often heard, the more subtle presentation of seizures in this age  group, so as you can see, many patients, more than a third, would only have focal seizures, either focal aware, focal unimpaired awareness seizures, which are very subtle and often  missed by the patients and their carers, and many patients in this age group also, they may be living by themselves, so there are really no witness to help confirm the diagnosis,  and as you would expect, most patients were classified, at least based on the semi-history  and investigations to a focal epilepsy type, but we did have one patient who were classified  to have IgE with absence and bilateral tonic-clonic seizures, and that's been reported old age  onset, they could still develop IgE or recognize IgE, although it's debatable whether they had sometimes had more subtle seizures in the past. What about investigation results?  So EEG findings, about a third, we can find epileptiform abnormalities, so this is probably  a bit lower than the general epilepsy population, we often, I often carry the figure about 50%, you can find epileptiform abnormality on an indirect or EEG.  What I think is important to highlight is that abnormal but nonspecific, you know, non-epileptiform  abnormalities are common, more than a third of patients, again, and imaging findings also vary, you do find a lot of things, as you would expect in this population, but there  were epileptogenic abnormalities in around 20%, and not surprisingly, again, most of these were related to, you know, stroke, gliosis, acanthopilumalacia, there was one,  a total one patient found that, the famous mesotemporal sclerosis, so you could find  it, but very, very rare, and the overall population in our cohort, less than 10% new onset patient  had MTS, and that's similar to many other studies that looked at new onset epilepsy, and I think that, again, reflects in, you know, in centers, surgical centers, we used  to see a lot of MTS, now less common, of course, but in the general new onset epilepsy population, in fact, MTS is the exception rather than the norm.  But again, like EEG, many people display non-epileptogenic abnormalities, very common, more than 50%,  and these relate to atrophy, small vessel disease, and it's important to realize this and not to make the wrong, erroneous assumption that this could be epileptogenic, and so I  think there is, and also which will mean that these are often just coincidental findings and you still need to hunt for the underlying cause. What about outcomes?  So when we looked at the last seizure outcome, the last follow-up, nearly 80% were seizure-free for at least the past 12 months at the last follow-up.  Vast majority was taking just the monotherapy. Very few were taking combination therapy.  In the overall cohort, you might recall that's around two-thirds, you know, were 64% seizure-free  on the overall cohort, but so comparative speaking, it does appear that they seem to have a better outcome measured by this last follow-up.  And this table shows you how many patients were treated with the first drug, how did they respond, and what's the percentage in terms of the patient achieving seizure freedom  and the total cohort. So what's interesting is that about, you know, 201 patients, you know, tried the first drug and 6% were seizure-free on this drug.  And once you failed two medications, again, in the population level, very few became seizure-free. But not many people, sometimes they didn't want to try more medications.  You see that, you know, of these 120 seizure-free, left you about 80 patients not seizure-free, only 55 would want to try the second drug. And then I think that's clinical reality.  You know, often there's a risk and balance how, what is the price to pay in pursuing your perfect, you know, seizure freedom and how do you balance the potential side effects.  But overall, I think this shows that there is, when you prognosticate, when you counsel the patients, I think it's fair to counsel that, you know, most of the time for the first  couple of drugs, we should be able to bring the epilepsy under control. And these are the most commonly prescribed drugs at the unit.  Just remembering that this does span 30 years, you know, from the 80s. So some of these usage may be reflecting to the older practice, in the more recent days.  I think we're pretty much stealing away from the enzyme-inducing drugs such as carbamazepine. What are the risk factors?  So we looked at the usual risk factors, and these are a few risk factors that went into a multivariable model.  Interestingly, the only one that turned out still to be significant was whether the patient was taking aspirin.  So having a history of cardiovascular disease and or cerebrovascular disease and taking aspirin, these patients had a lower probability of achieving terminal seizure freedom, you  know, compared to the other patients. And I'll leave it to the clever basic scientists to work out the reason. Our theory was maybe has some enzyme-induction effect.  If you look at some of the animal models, aspirin was said to have some enzyme-inducing effect. It's not been really well studied.  And obviously, we now have other antiplatelet treatment, so aspirin may not be as commonly used as in the past, but it probably would be simple enough to sprinkle a bit in your  mice and find out whether it does anything. Well, has the outcome changed over time? Now that we've got so many new drugs and we are using them more and more often,  so there's no doubt that these what we call second-generation antidrugs, we classify them as developed after 1980s, as we said in this analysis,  and there's no doubt these drugs have been used more increasingly often, and if you look at the first, we divided them into two time epochs in this trim period from 1982 to 1999,  and then from 2000 to 2016, you can see the proportion of patients given the second-generation drug as the first monotherapy increased or more than doubled  within this space of time, over 70%, and now given the newer drugs. But has that helped the overall outcomes? And the answer is unfortunately no. So if you look at whether you look  at the seizure freedom rate, so the probability of achieving seizure freedom, as you can see in this top panel on the right-hand side here,  and also patients who needed to withdraw their treatment due to intolerable side effects, and this is looking at first drug, the two lines overlapped for this two-time epochs.  So meaning that even though we're using more and more of the newer drugs, the overall outcomes where they look at seizure freedom, probability,  or intolerable side effects has not really changed. And you might feel a bit disappointed by this, and you feel that often some of the new drugs seem to be better tolerated,  and what we've found is that, as you would find in your practice, the new drugs do come with the newer side effects. They get rid of the skin rashes,  then you come the newer psychiatric problems. So when everything balances out, it does seem to be, if you look at the population level, and we haven't seen much more advances.  Mind you, this is up until 2016, so there are newer therapies more increasingly used that may be better tolerated, and at some point, I think we need to redo the analysis.  With the remaining 10 minutes, I'd like to move on to related, in some way, what are the, how should we approach treating epilepsy in this population at this age,  in 20, what is it, 2023 now, almost 2023. And this is a recent commissioned work by the International League Against Epilepsy in the Medical Therapies Commission  established a task force on epilepsy in the elderly, and the task force was asked to do various things, and one of which was to critically review  the management of epilepsy in older adults. And this is a work just published a couple of months ago in Epilepsia, and I want to hear, and these are all the task force members  in this particular work. I want to give a big shout out to Ed Fort, who was the chair of the task force and kept us along, and a lot of, and some of the heavy lifting  was done by Loretta Pichena and my group, Rebecca Dwyer at Rush, and Ilo, of course, at University of Minnesota. And what we aim to do in this review,  if you haven't looked at it yet, is to critically review the evidence pertinent to the management of epilepsy in the older adults. We included not just pharmacological,  but also some non-pharmacological treatments, mostly around diets and surgery, and studies that looked at prognosis. And what we like to do is to,  aim to do was to provide a map of these key studies, and you'll find various references to the key studies.  We highlighted the current gaps and pitfalls in research, and we wanted to make some recommendations on what are the model of care, and how do we move forward in the future.  And here, I'll just highlight a few of the important points we touched on. And in any review of management, you have to look at, there's no escape, look at the treatment outcomes.  And there are very few head-to-head comparisons, as you will know. And there was a, he highlighted a penta-analysis of five comparative monotherapy studies  in the old age onset epilepsy, and this is all you found. These high level one evidence are really very limited. Overall, there was no difference  in either six or 12 months seizure freedom rate, between these drugs, carbamazepine, control release, immediate release,  lamotrin, levotriazetam, valproate, and lacosamide. These are the only drugs that have been looked at in the literature. There was, we did, some studies did find  that the immediate control release carbamazepine had a high withdrawal rate, and the control release, but the control release also had a high withdrawal rate than in some studies,  compared to levotriazetam and valproate. So it seems that carbamazepine does have a high withdrawal rate, compared with other medications. We also touched on, about an Alzheimer's,  you've heard in the first talk, this relationship,  what is often now called a bi-directional relationship between Alzheimer's and epilepsy, because we know that people with Alzheimer's have increased risk, and some literature  mentions up to 10 times, often can be at the beginning of the onset of their neurodegenerative disease. And so, this particular study randomized patients  in open label to levotriazetam, phenobarbital, or lamotrigine, don't ask me why this choice, and what is interesting, though, is they use patients with Alzheimer's disease  only as controls, and what they found was that in a relatively small sample size, there was no difference in seizure control, but interestingly, cognition measures improved  in the group randomized to receive levotriazetam, whereas patients randomized to the phenobarbital in the lamotrigine group declined. Again, maybe you said not surprisingly.  And a talk like this, we have to mention, I think the really nice work by Keith Vossel's group, and very, I admire them. It was a difficult study to do,  a number of years at the end,  hard to recruit patients, but nonetheless, there were some very interesting findings, and these studies randomized in a crossover way patients with cognitive impairment,  with Alzheimer's disease, but without clinical epilepsy, and looked at how they respond to levotriazetam over this crossover period, and looked at their cognition measures,  and segregating patients to with or without epileptiform abnormality, detect on EG or LMAG, and what's interesting was that in patients without any epileptical activity,  there was no change in their cognition, whereas those with underlying epileptical activity, they showed an improvement in some cognitive measures in patients given levotriazetam,  and these are just a couple of examples, they look nice graphs, but notice the sample size was relatively small, but it does seem to show some signal,  and perhaps consistent with at least the animal work, and whether it's consistent in larger population clinical practice, I think would be very interesting to look at.  In the review, we also looked at beyond seizure control of a quarter of life, and we could only find 10 studies, and most of them used the quality 31,  and you could argue whether some of the questions are relevant for this age group as well, and there's some inconsistent findings  whether elderly with epilepsy had a poorer quarter of life compared to the quote-unquote more general epilepsy population, the younger population,  but there are some domains, subdomains seem to be particularly affected, like energy, fatigue level, and particular factors that contribute to quarter of life,  in particular the physical health, the social relationships often change by this age, the level of independence, and the factors such as even the personal relief, self-esteem,  and psychological well-being are really very important for this age group, not to say not important by other age group, but maybe more so for these age groups,  and what we think is we need to develop a more specific scale for these older adults for quarter of life measures.  We had some practical considerations in the article, you know, how we choose drugs, and given that the efficacy is similar between different drugs, and adverse effects  is really what's driving drug choices, and we need to, this all look at particular cognitive side effects, effects on memory, cognition, the mood, even coordination  and balance and sedation, and these become very important for treating patients at this age group, and this, the age of start low, go slow, cannot be more true for this population  than any of the others, and these are the side effects you need to actually inquire the patient, sometimes, I don't know your practice,  but in Australia even, people are still pretty reserved, they don't tell you, you have to really actively ask them, have you got these side effects,  and it's, you know, sometimes even up to the five or six visits, the spouse will tell you that, you know, their loved one is developing irritability  due to nivotracetam, but they don't use the word, you know, they don't come and say, oh, my husband's become irritable, you know, they say something else,  so you have to really actively inquire them, there's some sort of, there's a lot of cultural, I think, aspect as well in how people disclose  these kind of side effects at this age group, there's lots of stigmatization, they feel almost ashamed, you know, to tell you something don't work,  you know, they still look at the medical fraternity, you know, differently, I guess, in that age, and some, I think, for some, I think this population  will also need to look at other, another criteria, look at the comorbidities, and often these are age-related, so some Alzheimer's, you might be more tempted,  you know, to give, you know, nivotracetam a shot, based on some of these animal and human studies,  and the motrigine has benefits for mood and depression, so that might be something to try, and in people with Parkinson's disease, it's long been known that fire break can cause  a Parkinsonian tremor, so that should be avoided, if you can.  I think another important factor is drug interactions, we know that in enzyme-induced, it should really be avoided, and, you know, these days, we tend,  you know, we don't really use carbamazepine much, but although it can still be the only one that works, for some patients, and some very practical things,  you know, big tablets, and complex regimen, they need to take this one, and 200 milligrams more, a sick eight o'clock, and 400 milligrams,  300 milligrams, it's just very confusing for them.  We propose that, you know, the management should really extend beyond just seizure control, and needs to look into the whole transition, you know, of life for this, at this age,  because it is a transitioning stage, it's almost like in teenagers, in adults, so you have transitional clinic for teenagers, you know, why don't we have transitional clinic  for people going into older age? And now, this emphasis on aging in place really needs integration of primary and secondary care, and there's a recent study,  I don't know whether you had a chance, look at Ilo's and Becky's abstract, presented, it is eight years when they surveyed nursing homes across the US,  and found that only a little over half of these nursing homes have any seizure management protocol, so most of the nursing homes don't know what to do,  you know, when one of the residents develop a seizure, and we definitely need better education, and this is sort of the framework we propose  how to transition in a close collaboration between the community care and the hospital care system, involving multidisciplinary with not just epileptologists,  or maybe more so beyond epileptologists, involving primary care physicians, pharmacists in the community, and the emergency and geriatricians in the hospital,  so that there can be a seamless transition between the two. So just to conclude, I think we're hammering home, and maybe speaking to the converted,  managing epilepsy in this age really face unique challenges, and you have to look at more evidence and treatment beyond self-seizure control,  and we're calling for international collaboration to promote further research and develop practical solutions to tackle these challenges, so watch this space. Thank you very much.

Video Summary

The talk focuses on understanding epilepsy treatment strategies and outcomes in older adults, particularly those 65 years and above, using data from a 30-year study in Glasgow, Scotland. The study included 1,800 newly diagnosed epilepsy patients, with 201 of them aged 65 and older. It identified cerebrovascular disease as a common comorbidity and discussed the impact of factors like aspirin use on treatment outcomes. Surprisingly, newer antiepileptic drugs have not significantly improved seizure control over time. The talk also emphasizes the need for managing epilepsy beyond just seizure control to consider quality of life, psychiatric effects, and drug interactions in the elderly. Recent findings suggest novel antiepileptic drugs may improve cognition in Alzheimer's patients with epileptiform activity. The speaker calls for international collaboration to enhance research and create integrated care approaches for older adults with epilepsy, stressing the importance of multidisciplinary efforts to address the unique challenges posed by aging-related transitions.

Asset Subtitle

Presenter:

Patrick Kwan, MD, PhD, is Professor of Neurology and Co-Director of the Monash Institute of Medical Engineering, a unique cross-faculty platform of Monash University that aims to accelerate innovation, commercialization and manufacture of medical technologies to improve health. He is also Head of Epilepsy at the Alfred Hospital in Melbourne, the largest comprehensive adult epilepsy program in Australia. He has particular research interest in the outcomes, clinical pharmacology, genetics and pharmacogenetics of epilepsy, and the application of medical technologies for Precision and Personalized Medicine. He has published more than 300 peer-reviewed articles. He led an ILAE task force to establish the currently accepted definition of drug-resistant epilepsy and later served as Chair of the ILAE Medical Therapies Commission (2013-2017), and is currently a member of the ILAE Big Data Commission.

Keywords

epilepsy treatment

older adults

cerebrovascular disease

antiepileptic drugs

quality of life

international collaboration