The Menopause Transition and Epilepsy

Dr. Katie Krulisky talks with Dr. Kelsey Smith about the impact of menopause on women with epilepsy, including therapeutics and clinical management during midlife.

Read the related article in Neurology^®Clinical Practice. 

Disclosures can be found at Neurology.org. 

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Podcast Transcript: 

Dr. Jose Merino:
This is Jose Merino, Editor-in-Chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Katie Krulisky:
Hello, and welcome to this episode of the Neurology Podcast. This is Katie Kruliski from the VA and University of Utah in Salt Lake City, Utah. Today, I have the pleasure of talking with Kelsey Smith. She's a neurologist and epileptologist at Mayo Clinic in Rochester, Minnesota. We will be discussing her recent paper published in the Neurology Clinical Practice Journal titled The Menopause Transition and Epilepsy: A Focus on Therapeutics. Welcome, Kelsey, and thank you for joining us.

Dr. Kelsey Smith:
Thank you so much for having me. I'm really excited to be here today to talk about this paper and this really important topic.

Dr. Katie Krulisky:
Yes. Your paper highlighted a staggering statistic, that women spend approximately 40% of their lives post-menopause. That shook me when I was reading this for a presentation on management of women in epilepsy. Being a woman, I felt totally blindsided by the statistic. I've never thought about it this way. I feel like so much of the emphasis of our clinical practice in epilepsy is choosing the right medications for pregnancy. And there is a lack of information and focus on women in perimenopause and post-menopause, even though a much larger percentage of the lifespan is spent in this phase. Let's go ahead and start with the clinical scenario. A 45-year-old woman with focal epilepsy is having some symptoms attributed to perimenopause and is interested in pursuing hormonal treatments. As her epileptologist, what is your approach to counseling her based on the current available data?

Dr. Kelsey Smith:
And when it comes to patients like this, it's a very important topic. And the first thing is that it really requires both an individualized and multidisciplinary approach. So I think first as an epileptologist, I want to understand all I can about her epilepsy, what the current seizure control is, what the current therapy is, what the epilepsy's been like over other life stages if she's had epilepsy no earlier, to understand how seizures may have been during menstrual cycles to know if there's kind of a hormonal driver of seizures that's been noticed through the lifespan. And then also I really want to understand about her menopause symptoms. What are the symptoms that are really bothering her that she's hoping to start the hormonal therapy for? And are those symptoms things like vasomotor symptoms or sleep disturbances? And are those actually also influencing her current seizure control? If the vasomotor symptoms are waking her up at night and she's not getting good rest, is this lowering the seizure threshold and actually driving worse seizure control?
Understanding all of this background's really important. And then to discuss with her what the data is about menopausal hormonal therapy and how it's related to epilepsy, how that data is really limited. And so we don't have a lot of data to go off of to provide counseling in this scenario. And all the studies that have really looked at this topic are really quite old, over 20 years old and have not used the same formulations of menopause hormonal therapy we use nowadays. And a lot of these studies didn't even use the anti-seizure medicines that we use nowadays. It's important to work with a patient like this and really let her know that despite the limited data, that epilepsy itself should not be a strict contraindication to considering menopausal hormonal therapy, but there are special considerations that we would need to think about, especially interactions between the hormones and anti-seizure medications and that she would probably require close following throughout using menopause hormonal therapy. I would also collaborate closely with a women's health expert so they can help us decide what the best hormonal therapy may be if it's indicated to treat her symptoms.

Dr. Katie Krulisky:
So a lot of these patients will ask, "When looking at hormones, I want to know where my hormonal levels are at now." Are you ordering their hormone levels?

Dr. Kelsey Smith:
Yeah, this is a common question that patients ask and I've also been working some with the women's health experts here at Mayo. And as we've worked on papers and things, it's not standard of care to draw these levels even throughout perimenopause and into menopause because of the fact that menopause is a clinical diagnosis. And also during perimenopause, there can be such wide fluctuations in hormonal levels. And so it's difficult to know what to make of different values and how that would influence clinical care. So overall, I'm typically not ordering hormonal levels, but would work with a women's health expert and if they though it would be helpful in a specific scenario, then definitely would consider it.

Dr. Katie Krulisky:
So on a very basic level, I've come to understand that in general, estrogen can make you more likely to have a seizure. Progesterone is protective. With that in mind, it sounds like you're not saying completely no to addition of estrogen in the hormone replacement therapy. Is that accurate?

Dr. Kelsey Smith:
Yeah, that is accurate. One of the things I learned by putting this paper together is that although some direct comparison of estrogen levels is difficult, but overall, usually actually estrogen that's used in menopausal hormonal therapy, the estrogen is less than the estrogen in oral contraceptive pills. And we don't see epilepsy as a contraindication to considering oral contraceptive pills, although obviously we need to take into consideration interactions with anti-seizure medications and things like that. But I don't think overall it should be a broad contraindication to considering the hormonal therapy. During perimenopause, the endogenous hormonal levels can fluctuate very significantly and there could potentially be an influence of seizure control based on those fluctuations. At least in theory, even menopausal hormonal therapy could potentially help with some of those fluctuations and could potentially be helpful, especially if some of the symptoms associated with menopause, like the sleep disturbances, like the vasomotor symptoms are actually making seizure control worse by reducing the seizure threshold.

Dr. Katie Krulisky:
That's a really good thing to keep in mind because there's a lot of fear-based decision-making surrounding women's health and seizure medications because a lot of that, we see a lot of that in pregnancy, right? We also see a lot of that in perimenopause and menopause. I think historically we've though, oh, estrogen is dangerous. You shouldn't have any exogenous estrogen. And then it seems like women are suffering the consequences from exactly like you've pointed out, very limited actual data. So just for review, what is the actual data that we're extrapolating this from?

Dr. Kelsey Smith:
Yeah. So there's a few older studies from the late 1990s and then early 2000s that are mostly observational studies asking women with epilepsy how did their seizures change with menopause hormonal therapy and things like that. And then there's one randomized controlled trial. It was published I believe around 2006, but it had very limited numbers, less than 25 patients. And that study said that with menopausal hormonal therapy, with the higher doses, there was a dose dependent relationship where seizures worsened with that therapy, the menopausal hormonal therapy. However, this study was using formulations that aren't typically in clinical practice anymore for menopausal symptoms as they're using more like estrogen patches and things like that. And so we really don't have data that looks at our currently used treatments in women's health and how it influences seizure control.

Dr. Katie Krulisky:
So I'll just say that the available data is extremely outdated and not even necessarily applicable to our current treatment standards in that area.

Dr. Kelsey Smith:
I would agree with that statement. I think we need more research, more data. And that was one of the motivations of putting this paper together, is just highlighting some of the gaps, but also using some of what we know from other life stages to highlight some of those interactions with anti-seizure meds, some of those things that we can at least talk to our patients about and we can try and improve clinical care.

Dr. Katie Krulisky:
And when you're selecting an anti-seizure medication for women, how heavily are you considering its association with osteoporosis?

Dr. Kelsey Smith:
Yeah, this was another very important topic when we're thinking about epilepsy and the menopause transition is osteoporosis. It's never too early to consider this and what anti-seizure medications are better for bone health because we know that there's many anti-seizure medications like enzyme inducing anti-seizure medications that can negatively impact bone health. And then there's even data that epilepsy itself can negatively impact bone health. So I don't think there's ever a time where it's too early to consider it and we should probably be considering it over the lifespan because if you get someone on an anti-seizure medicine that's really controlling their seizures, it's more difficult to switch them off to something else. But I do think that as people are reaching perimenopause age 40 or so, really reconsidering looking at that anti-seizure medication and how it could impact bone health.
And also just considering bone health in general is important for us epilepsy doctors. And so thinking about both recommending lifestyle modifications that are good for bones, but then also thinking about things like vitamin D calcium or when they should have screening. And really as they reach menopause and estrogen levels drop significantly, that's when we know that bone mineral density is really impacted and this is a time where we really need to be thinking about this and considering it.

Dr. Katie Krulisky:
The medication that always sneaks up on me is clobazam because I always think of it as a newer medication, but it can make you more likely to have osteoporosis, right?

Dr. Kelsey Smith:
Yeah. Some of the newer medicines, there's still less data out there, but most of the anti-seizure medicines or even some of the newer medicines suggest some newer data that they can negatively impact bone health. And then also interestingly, some newer studies that suggest even epilepsy itself, taking populations of patients with epilepsy that for different reasons may not be on anti-seizure medicines may have impacted bone health. And all these things are so important to consider when we have patients who are having seizures, who are at higher likelihood of having falls related to seizures, or as they're aging and they're on anti-seizure medicines that can make them dizzy and predisposed to falls as well.

Dr. Katie Krulisky:
That's so true. It's in addition to the epilepsy that can make you more likely to fall, all these other factors, the seizure medication, the sodium channel side effects, we have to keep in mind. When it comes to the screening tests, are you yourself ordering the DEXA scans or are you partnering with primary care? I've done it a little bit of both ways depending on the patient situation.

Dr. Kelsey Smith:
I've done it a few different ways. Sometimes it's easier if they have that close primary care and I'm going to rely on primary care to help me out if the DEXA is really abnormal anyway. So if I can, I'd probably collaborate with their primary care provider, but in some scenarios I have ordered the DEXA scans.

Dr. Katie Krulisky:
Because I know we both had these patients where it's like, if you don't order it, you know it's not going to happen.

Dr. Kelsey Smith:
Yeah. Yeah. And then, yeah, if I get the result and it's very abnormal, then I can work with other folks or even refer to endocrinology to consider treatment.

Dr. Katie Krulisky:
And we've touched on this a tiny bit, but overall, how do sex hormones impact seizure control?

Dr. Kelsey Smith:
Really simplifying a very complicated relationship we don't completely understand. So overall, it's felt that estrogen is to be pro-convulsive, can reduce the seizure threshold and make seizures more likely to occur. While progesterone, especially through its metabolite allopregnanolone, is more kind of anti-convulsant in nature. But like I said, it's simplifying something that we don't completely understand, but there's some basic science data that supports some of that.

Dr. Katie Krulisky:
When I do my presentation on this topic, I say exactly that, is that this is a gross oversimplification of the available information, but something that I always find interesting is that those GnRH cell populations themselves are vulnerable to injury from seizures themselves. So I wonder if that ties into the whole... Anyways, there's a lot more to learn. We can-

Dr. Kelsey Smith:
Yes, I totally agree with that statement. I think there's a lot more to learn.

Dr. Katie Krulisky:
So what's a practical approach to balancing the lamotrigine and estrogen interaction in midlife women?

Dr. Kelsey Smith:
It's just really something we need to anticipate the interaction as opposed to saying, "Oh, you're on lamotrigine, you can't be on anything with estrogen in it." And we need to be prepared for it. And so if menopause hormonal therapy is indicated and is being started, we need to know that baseline serum concentration of lamotrigine and need to recheck levels within two to four weeks of starting something with estrogen in it and adjust the dose as needed based on those serum concentration levels. So also if they've had epilepsy throughout their lifespan and have had changes in estrogen earlier in life, like during pregnancy, for example, or with oral contraceptives, we may have some idea by their history if they're more likely to have that drop in the lamotrigine level.

Dr. Katie Krulisky:
And when you're ordering lamotrigine levels, are you really going for a trough or are you more trying to get a consistent time of day? What's your approach with that?

Dr. Kelsey Smith:
Yeah, as much as possible, a trough. You need at least a consistent time of the day, but I do prefer trough levels, just because that's what a lot of the reference range is based on. And then if it's a true trough level, it will be a consistent time of the day.

Dr. Katie Krulisky:
What inspired you to put this review together?

Dr. Kelsey Smith:
This review was a lot of fun to put together and I really learned a lot about menopause and menopausal hormonal therapy. This was an effort though that was actually initiated through the Epilepsy from Childbearing Age to Menopause Consortium. This was from the menopause committee of this consortium, and so got to work with a lot of great co-authors on this paper to put it together, really learned a lot and really excited to see what this consortium can do over time to really advance care for women with epilepsy.

Dr. Katie Krulisky:
That is so cool. Can you say the name of this consortium again?

Dr. Kelsey Smith:
Yeah. So it's ECAM for short, and it's Epilepsy from Childbearing Age to Menopause Consortium. And it's only been around for a few years. I joined it a couple years ago, but it's really got a lot of wonderful people involved and different committees looking at care for women with epilepsy really across the lifespan.

Dr. Katie Krulisky:
I want to be a part of this group. That's so exciting.

Dr. Kelsey Smith:
Yeah, you should be. There's a website and everything. So yeah, if you Google it, you'll find it.

Dr. Katie Krulisky:
I feel like I have been somewhat radicalized by the process of having a child because all of just the things that women go through with the hormone fluctuation and truly the lack of available information on the impact of those hormone fluctuations is crazy. It is such a wild experience and to be in such a modern society and have so many blind spots within women's health is incredible in not a good way.

Dr. Kelsey Smith:
I totally agree with that statement and some of that sentiment as well, is that once I had children myself, then you really start looking at some of these things in different ways. And it's not something that us as epileptologists need to overlook or shy away from in clinic. Our patients a lot of times want to talk to us about these things, especially if they think it's influencing seizure control. And now trying to work on some research studies in the area and stuff, menopause is so hard to find in the chart. We're not always bringing it up. We're not addressing it. It's a topic that we really need to be thinking about because it definitely can impact our patients. And we do know some about the best ways to manage things over this life stage, especially based on some of the data we have from other life stages.

Dr. Katie Krulisky:
In general, what age range is menopause usually happening?

Dr. Kelsey Smith:
Yeah. So the average age of menopause in the United States is around 51 to 52. There's some earlier data from those other studies I already mentioned about menopause and epilepsy that suggests the age may even be younger for women with epilepsy, especially with uncontrolled seizures. We need to be thinking about this really between the ages of 40 to 55 or so.

Dr. Katie Krulisky:
So maybe even, considering I'm always asking women about childbearing potential, but maybe even including it in that discussion of are you still having a menstrual cycle?

Dr. Kelsey Smith:
Yeah, I think so. Are you still having a menstrual cycle? Is there association with your seizures? And if we get more comfortable with this topic, even understanding eventually menopause symptoms and how they could influence seizures. The other thing that's a little interesting in terms of epilepsy and menopause is vasomotor symptoms. People get these hot flashes. They just last a few minutes. They can happen any time of the day. And so I could even see how clinically it could be somewhat difficult for some patients to maybe differentiate from focal seizures and things. So it's just interesting in that scenario. They could not be clear, are those seizures, what are these new symptoms? So important for us as epileptologists to recognize.

Dr. Katie Krulisky:
It's important in epilepsy and I also think it's important, because I do some general neurology. I do general neurology and epilepsy as my practice, and I see it actually pervasively in neurology. I've had people come to me with symptoms of difficulty swallowing and just really broad symptoms. And then I remember one case specifically that they came back to me and said, "Oh, I was just going through menopause. I feel much better now."

Dr. Kelsey Smith:
Yeah. And the brain fog and other things that can come with menopause obviously can span different potential neurologic diagnoses.

Dr. Katie Krulisky:
Totally. And I have to say somewhat embarrassingly that I feel like I myself am not the most comfortable with discussing vasomotor symptoms associated with menopause. What topics are you screening for or what symptoms are you screening for?

Dr. Kelsey Smith:
When you see someone in this midlife stage just asking, "Are you still having menstrual cycles? Do you feel like you've gone through menopause?" Because it's difficult to get that information or impossible to get that information without just asking about it. And then just asking if they're having symptoms they think that have changed with fluctuations in menstrual cycles as well to suggest they're in perimenopause and if they're having vasomotor symptoms or new sleep disturbances, what those could be like.

Dr. Katie Krulisky:
I know the sleep thing comes up a lot with our patients. Do you have a first step of approaching that with the sleep issues or are you referring, trying to manage it yourself?

Dr. Kelsey Smith:
I try and understand what the sleep disturbance is. Is it falling asleep? Is it frequently waking up? If there's any chance there could be potential sleep apnea playing a role, then I usually do an overnight oximetry and consider referral to look for that because sleep disturbance from sleep apnea, which can obviously start at any age, but mostly in older adults, if they're having problems with sleep apnea, then that needs to be managed first.

Dr. Katie Krulisky:
Thank you so much, Kelsey, for taking the time to discuss your review on management of epilepsy in midlife women. The paper is titled The Menopause Transition in Epilepsy: A Focus on Therapeutics, and you can read all the details in the Neurology Clinical Practice Journal.

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