Do Autism & Intellectual Disability Come With Epilepsy? - Vaishnav Krishnan, Baylor College of Medicine Medical Center, USA
Do Autism & Intellectual Disability Come With Epilepsy? Learn of the Epilepsy, Autism, and Intellectual Disability “triad” - studied by clinician scientist, and epileptologist; Vaishnav Krishnan.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Vaishnav Krishnan
”If you have a history of psychiatric illness, you're more likely to have a side effect to a commonly prescribed Anti-Seizure Medication. And, if you have a history of psychiatric illness you're more likely to have medically refractory seizures. And that means that you've got fewer and fewer medicines to work with and there's a higher and higher likelihood of needing to have a surgical treatment.”00:22 Torie Robinson
Fellow homo sapiens! Welcome back to Epilepsy Sparks Insights.
So, it’s amazing if a person with a refractory epilepsy can get hold of an epileptologist. But then, it’s even more impressive when, if you need one, you can find an epileptologist who works on and researches the “triad” of epilepsy, intellectual disability, and autism. And I say that because these diagnoses all too often do come hand in hand and often needed (as a result) is a clinician who understands all three!
That’s why I’m delighted to, this week, bring to you the exciting clinician scientist, epileptologist Vaishnav Krishnan, from the Laboratory of Epilepsy and Emotional Behavior at the Baylor College of Medicine. And,, he ticks all of the aforementioned boxes of knowledge!01:13 Vaishnav Krishnan
My name is Vaishnav Krishnan. I'm an epileptologist for adults at the Baylor College of Medicine here in Houston, Texas, in the Texas Medical Center. As a clinician and as a neuroscientist, I'm interested in studying more generally the problem of mental health disorders in patients with epilepsy. And so, to get at that, I run a small lab that uses digital technologies to study behaviour in mouse models of epilepsy and mouse models of epilepsy treatment. And simultaneously, we're studying wearable technologies in humans with epilepsy to ask “How can we align the measurements across species?” and do a better job of coming up with better treatments that are holistic and address both not just the seizures but also other neuropsychiatric comorbidities that come with epilepsy.02:02 Torie Robinson
And so, I think, well, many of us know, many of us don't know that humans and rodents are so similar in many ways, especially when it comes to the epilepsy, correct?02:12 Vaishnav Krishnan
I think that's a weighted question. How much time do I have?02:13 Torie Robinson
Hahaha02:14 Vaishnav Krishnan
It proved that both species have the circuitry to display seizures. Unlike other neurologic diseases, we can induce seizures in both rodents and humans and we had shared the same neurochemistry, shared the same neurotransmitters. Obviously, there's differences in lifespan, differences in behavioural repertoires, but yes, in general rodents are a good model to study both the seizures and the non-seizure aspects of epilepsy.02:48 Torie Robinson
Keeping in conversation then, seizures (epileptic seizures), autism, and intellectual disability, which often like a bit of a threesome to put it politely. Can you tell us about the correlation between all three and what you've discovered in your research about those, please?03:07 Vaishnav Krishnan
So yes, I like the way you put it. I like to call it a triad. Seizures, intellectual disability, and autism. There's been a lot of epidemiological work to look at the link between these three syndrome symptoms. It turns out that epilepsy increases the risk for autism. Autism increases the risk for epilepsy. And so, it doesn't really matter which one comes first. They both tend to go together. And the link that seems to connect them is intellectual disability, which is a broad term to basically denote someone that has difficulty learning and has difficulty functioning independently. So, what does that mean at a very practical level? It means that many genes that we think of as “epilepsy genes” in humans may not cause seizures but may simply cause autism and intellectual disability. And what it also means is that in mouse models of epilepsy, we may be able to find evidence of autistic behaviours and changes in intellectual function. At the end of the day, you have a single underlying lesion /problem and what you're measuring are the symptoms of that lesion.04:28 Torie Robinson
And you say “lesion”, so is it that type of epilepsy that you tend to focus on or a bit of genetics as well? Which, well, they can come hand in hand, obviously, but...04:36 Vaishnav Krishnan
Yeah, great question. So, the triad: autism, intellectual disability, and epilepsy - often is manifested with early onset seizures that begin in childhood. And if you ask more generally “What are the causes of childhood onset epilepsy?”, they can be broadly divided into genetic causes and also structural causes, like for example, changes in brain shape, malformations, as well as other environmental causes, such as for example, perinatal hypoxia (basically not enough oxygen at the time of birth). So, of those three, the ones that are easiest to recapitulate in the lab are the genetic causes. Thanks to the technologies that we have today, any genetic mutation in a human subject that's associated with epilepsy can be recapitulated in a mouse. And you can ask a simple question “Does that mouse, in comparison to its genetically normal counterparts have a higher risk of displaying seizures, or intellectual disability or autistic features?”. So, yes, I would say that the mouse models that have had the most success in epilepsy have been genetic ones, but there's tricky stuff involved. Many of the mice that are designed to recapitulate those mutations actually don't have seizures. So, what do you do then? And what does that mean? So, these are some issues that we deal with.06:02 Torie Robinson
I've heard about, sometimes, people having, on paper, the same genetic epilepsy, but they will have different traits. So, some… ones I've come across, there might be one person who doesn't have any degree of intellectual disability. In fact, one person I met, he was a scientist himself, but he had the same genetic disease or genetic epilepsy as the multiple relatively young children that I saw around me. It's totally varied, correct?06:27 Vaishnav Krishnan
Very, very varied. We call that phenotypic heterogeneity. And that boils down to several different factors. Obviously, the genetic background is hugely important. That's why the same mutation in one line of mice may not be seizure-prone, but in another line of mice, another genetic background may be seizure-prone. There's also environmental differences that come about from sociodemographic factors, environmental exposures, that all play a role in deciding not just whether a patient will have seizures, but also when their first seizure will be. And that's what makes human research messy. And that's what drives researchers to go towards simple animal models to ask very basic questions.07:19 Torie Robinson
At least first of all, I guess, and hopefully...07:20 Vaishnav Krishnan
Right, the challenge is how do you bring those insights back to the humans? And these are the million-dollar questions that we're working on.07:27 Torie Robinson
And I guess that's why the roles (plural) that you hold are of benefit, right? We were talking about this before. So, you're, you're an epileptologist so you work with patients, but you're also in the lab. And we were also saying how (or I think you implied) that perhaps sometimes the way that you look at things, having patient and family insight can be a bit different to people who don't have exposure to families.07:50 Vaishnav Krishnan
Being able to connect with patients and families and learning their experiences and prescribing the poisons that we have to treat these seizures and recognising the successes and failures is, I think, indispensable for me personally as a clinician-scientist. But at the same time, I think transforming those big picture clinical questions into animal experiments is difficult. And many labs do it in different ways. And so, yes, I think I have a unique perspective from both angles. But as I said, the challenge is always how best to translate across these fields.08:36 Torie Robinson
Well, at least right now you're giving lots of people hope which is great. But actually, gosh, do you know what coincidentally, I don't know if we'll include this Pete, but I was reading a comment from somebody on LinkedIn and which I reposted and they were talking about how certain publications which tend to be more sort of mainstream science promoters if you like will give some kind of “tabloid-y” title to results from a study which makes people pick up or read the piece but actually leads them down the wrong path, is completely misleading, and encourages people to think “Well, none of this science works.”. Or, they found out this something… this particular thing was about a study into some kind of cancer but using rodents and… but the title didn't reflect that - they thought it was about humans straight away. And then they're told in the piece “Oh, well, it worked in this type of rodent we don't know about humans.”. And it's really, really frustrating. And I find that amongst many people who aren't familiar with epilepsy research, they'll come into that a lot.09:40 Vaishnav Krishnan
Yeah, I think you hit upon many important points. We have an epidemic of issues with rigor and reproducibility within the basic science community. And, there's also the urge to publicise exciting results that come from a simple animal model as being able to hold the potential for treatment for patients today. I get questions like this from my patients as well. Stem cell treatments, brain transplants, gene therapy, CRISPR-Cas9. And the truth is I think we're closer to some of those technologies than others (in terms of implementing them in patients right away). But, at the end of the day (and again, this is where my knowledge as a clinician comes), to be very frank, you know, the first line of seizure prevention in human beings all over the world, for as long as we can see, will be Anti-Seizure Medications. Drugs that are taken every day as pills or liquids, what have you. And how can we make those safer and more effective? And how can we better implement those more advanced technologies in patients that fail those drugs is one approach to think about it.11:19 Torie Robinson
Do you ever speak to your patients and consider, no doubt in your research, how sometimes adjustments in lifestyle can impact a patient's quality of life? Whether we're looking at seizure control or whether we're looking at psychiatric issues and that would include many people with autism like the stress from such and such, you know. Sometimes you can make changes in your lifestyle, right?11:43 Vaishnav Krishnan
Yes, I think that what I tell my patients is that there are some things that I don't have a prescription for! Like, there are things that you can do in your life to manage your stress better. Get a dog, walk the dog, yoga, meditation, deep breathing, go and join a cooking class, be a part of a church group, do something spiritual as a part of a team. And that's hard, because the depression and anxiety that comes with their epilepsy or the changes in social drive that come with the autism and their epilepsy can preclude some of those very same activities. Even something as simple as engaging in therapy for a short period of time, just a few sessions, is very difficult sometimes for patients to wrap their heads around. And, it often… they accuse me of calling them crazy, which is not the case! I never said that word! It's just that, you know, these are neighbouring signs that come with seizure risk. So, I only have so many medicines that I have available. There are things that are better left treated without medicines. So, diet is one of them. Obviously…you’ve probably had sessions on the ketogenic diet (the modified Atkins diet). Sleep and sleep hygiene is obviously crucial. And then there's this other stuff that's difficult to measure… that is probably a key part of the resilience that we see in some patients that are seemingly unaffected by depression and absent in those that are affected.13:27 Torie Robinson
I think relationships, personal relationships often can't be changed overnight. Or if you're in a remote area, how can you get closer to a city? Well, often you don't have a job, or you don't have the energy to do it. And there are so many factors, right?13:39 Vaishnav Krishnan
Definitely. I have patients that say “My seizures only ever come when my family visits me during Thanksgiving or Christmas!”. And I tell them once again “I don't have a medicine for that!13:50 Torie Robinson
Hahaha13:51 Vaishnav Krishnan
I don't have a treatment for the psychosocial stressors, ongoing stressors, that can promote seizures or other stress issues at the time that you see your family.”.14:04 Torie Robinson
What would you say, if you could predict, you know, the next two, five, even ten years of your research? And we want people to…’cause I want people… because a huge thing here is to manage people's expectations, right? And science is we don't know. But if you could, are there any expectations or predictions that you have in your work?14:21 Vaishnav Krishnan
One of the things that my lab is focused on now is how to remotely monitor the well-being of patients with epilepsy. And this borrows from a large body of science in the wearable community, looking at how patterns of rest and movement and activity can encode symptoms of depression and anxiety and seizure exacerbations. And so, my goal is, from my own research, that over time, we use some of these technologies to watch how patients are doing, live, in their own worlds. And have, sort of a dashboard, if you will, and watch a community of patients over time and monitor not just their seizures but also some of these other aspects of their syndrome that are equally disabling. And this is moving towards a field that is more data-driven…12:17 Torie Robinson
Mm-hmm.12:18 Vaishnav Krishnan
…that's more digital, and so, you know, in the old way (which is the current way, sadly): you meet your doctor every three or six months. He or she says “How have you been? How's your sleep? How's your mood? How many seizures have you had?”. And recalling that information is tricky. It's prone to bias, and it's not very often very accurate. But what if you could collect that data every day, automatically and objectively? And what would you do with that data? How could you use it to predict the likelihood of symptom worsening? How could you integrate it into how we measure the success of our Anti-Seizure Medication trials, and so on and so forth. So, that's the, that’s the type of scientific effect that I'd like my research to have moving over time.
Now, obviously, just like humans have a circadian rhythm and have sleep that's interrupted by wakefulness, we can measure a lot of those same properties in mice and rats. And the advantage of studying these diseases in mice and rats is that you can study the illness without the confounds of the treatment - which is a luxury that we don't have in human subjects. By the way, in mice and rats you can also study the treatment in the absence of the illness. You can take normal mice and rats and give them these drugs and ask how does that change your mood, how does that change your movement patterns, wheel running, so on and so forth, and in a manner that's unrelated to whether you have seizures or not. So that’s, that’s the long-term goal of our labs work.17:03 Torie Robinson
I have to say, I like that last bit you said, using rodents to measure the impact, say for instance of drugs on people who don't have or rodents that don’t have epilepsy, because sometimes I’ve found in other people that I've spoken to - and no doubt with your patients - it's like sometimes we don't know how affected we are. Because our senses can feel so diminished and you're so used to things, it’s like “Meh, I don't really know how I'm affected now, I just feel rubbish”.17:27 Vaishnav Krishnan
I like how you put that. Sort of this feeling of just blah/numbness. You're not excited about things. You're not upset by things. It's just almost a state of dullness, if you will. How can we measure that in humans? How can we measure that in mice? And, you know, as I tell my patients, these drugs that we use; they don't just act on the parts of your brain that are causing seizures. They act on all of it. And so, it's not surprising that many of these drugs are associated with changes in sleep, in mood, in memory, in personality, rage... And, the sad part is, if you look at, there's one study that I often quote, where they looked at thousands of new medication trials and they asked how many of them stayed on that new medicine and how many of them had to come off of it. Well, some drugs were better than others. But at the end of the day, the patients that had the highest likelihood of developing an intolerable side effect were the ones that had a history of psychiatric illness to begin with. So, these two things are compounding each other in a way that's really terrible. If you have a history of psychiatric illness, you're more likely to have a side effect to a commonly prescribed Anti-Seizure Medication. And if you have a history of psychiatric illness, you're more likely to have medically refractory seizures. And that means that you've got fewer and fewer medicines to work with, and there's a higher and higher likelihood of needing to have a surgical treatment.
And I have nothing against surgical treatments. I advocate for it all the time. I'm involved in surgical treatment strategies here at Baylor. And I think that while some treatments like resection are permanent and irreversible and can lead to an irreversible deficit or a change in behaviour, other treatments are not permanent, like, for example: neuromodulation or neurostimulation, where you put an electrode in, but if you don't like how you're feeling with those set of stimulation parameters, you can stop it, turn it off, change it to something else…19:42 Torie Robinson
Mm-hmm.19:43 Vaishnav Krishnan
…and learn from what works and what doesn't work. And clearly, the one message that you get from working with neurostimulation is that not every patient is the same. And so, in the search for generalisable knowledge, which is research using mouse or rats, can we really develop generalisable knowledge that's generalisable to all patients? I don't know. We'll see. That’s the challenge.20:09 Torie Robinson
We've spoken largely about seizures, and, and, depression, and anxiety. Do you think there is a role for, um, or would you say there's a need for neuropsychiatrists and people who have relatively deep insight into both psychiatry and epileptology?20:27 Vaishnav Krishnan
Of course, please. I wish I could have a psychiatrist with me during all of my visits. And we could sit together and think about the two sides of the coin. From a practical sense, I think that that's probably very difficult to institute in any medical system, whether it's national or not national. At the end of the day, it's important that one person is changing one drug at a time. And so, if you have a psychiatrist who wants to change drug A, make sure the neurologist knows about it. There are some drugs that should be avoided by the psychiatrist because they can make seizures worse. And similarly, there are some Anti-Seizure Medications that can impair mood, thought, and sleep. So, this is the problem at the end of the day. So, we need to be better integrated. We need to have a more collaborative environment to provide the comprehensive care that we claim to provide. ‘Cause if you look at most epilepsy clinics in the United States at least, they're labelled the comprehensive epilepsy centre. But are they really that comprehensive, you wonder? Because they're, for the most part, mostly focused on seizure prevention.21:42 Torie Robinson
And which is like… is so silly when you stand back from it, because if you're only looking at seizure prevention and you're not addressing other issues, say mental health or the stress that somebody, whether they have autism or not, is experiencing, you're actually missing common seizure triggers. So, it's silly!21:59 Vaishnav Krishnan
Yeah, I think patients figure that out too. And I hope that there are more epileptologists in the future that are minded in this way.22:09 Torie Robinson
A massive thanks to Vaishnav for sharing with us his knowledge of the intricacies of the epilepsies, or autism, and/or intellectual disability as well - and having his clinical work compliment the scientific work - and vice versa!
If you’ve enjoyed this episode and would like to help us spread awareness and understanding of the epilepsies around the world, if you haven’t already, please just press the like and subscribe buttons! And, see you next week! -
00:00 Intro
01:13 Meet Vaishnav Krishnan
02:48 The Triad: epilepsy, autism, and intellectual disability (ID)
06:02 Same genetic mutation but different symptoms: phenotypic heterogeneity
07:33 Being a clinician and scientist: benefits
08:45 Misleading science articles
11:19 Lifestyle adjustments for epilepsy, autism, and ID
14:04 Next 10 years for Vaishnav’s research
17:14 When patients feel numb
20:18 Need for neuropsychiatrists
22:09 Conclusion and thanks
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Vaishnav Krishnan is a physician-scientist at the Baylor College of Medicine’s Comprehensive Epilepsy Center and the Peter Kellaway Section of Clinical Neurophysiology. In the clinical domain, he is an adult neurologist with subspecialty expertise in the treatment of epilepsy and related disorders (such as functional/psychogenic seizures). As a board-certified clinical neurophysiologist, he reads and interprets clinical electroencephalographies (EEGs) and other intraoperative neurophysiological monitoring studies. His clinical interests focus on caring for patients with epilepsy who are affected by one or more psychiatric comorbidities (including depression, psychogenic nonepileptic seizures (PNES/NEAD), schizophrenia, anxiety disorders and autism); a neurobiological niche that is the scientific focus of his basic science lab. In addition to bedside and EEG lab-side teaching, Vaishnav formally participates in didactic education for medical, graduate and undergraduate students.
Vaishnav’s prior research focused on applying systems neuroscience to study mouse models of neuropsychiatric disease.
For his PhD at the UTSouthwestern Medical Scientist Training Program, Vaishnav examined how specific molecular changes in mesolimbic dopamine neurons underlie whether a mouse may display a vulnerable or resilient behavioural profile following repeated social stress. During and after residency/fellowship training at the Beth Israel Deaconess Medical Center, he returned to the bench to explore how recurrent seizures induce cascades of neuroplasticity that function to impede sociability/social drive. Today, his lab research program combines multimodal behavioural telemetry in mice and wearable technologies in patient volunteers to study how seizures, seizure risk (epilepsy) and antiseizure treatments impact spontaneous behaviour. This work seeks to improve on treatments for epilepsy spectrum disorders by devising new, translationally fluid behavioural endpoints designed to tease out the determinants of interictal behaviour. In doing so, his research defines a new quantitative and objective approach to ascertain the mental status of a mouse. -
LinkedIn: vaishnav-krishnan
Baylor College of Medicine: vaishnav-krishnan
ResearchGate: Vaishnav-Krishnan