Corinn Cross, MD (Host): The Neonatal Seizure Registry estimates that about one to four per 1,000 live born babies experience seizures and most seizures occur within the first few days to first week of life. While some babies will have visible symptoms, like body twitching or random eye movements, other babies may not exhibit any signs at all.

In some cases, congenital seizures can lead to the development of epilepsy later in life. This makes diagnosis and early detection crucial for the best outcomes. This is Pediatric Insights, Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Cori Cross. Today we have with us Dr. Alison Dolce, Pediatric Neurologist and Epileptologist at Children's Health, an Associate Professor of Pediatrics and Neurology at UT Southwestern. She is part of the Neurological Neonatal Intensive Care Unit and Fetal and Neonatal Neurology Program at UT Southwestern with a particular interest in neonatal seizures and early infantile developmental epileptic encephalopathies. Today she is here to discuss neonatal seizures and the expert care being used to improve outcomes for neonates.

Welcome, Dr. Dolce, and thank you so much for being here today.

Alison Dolce: Thank you so much for having me.

Host: So neonatal seizures can be challenging to diagnose and treat. Can you share a bit about the expertise of the different specialists involved in caring for this patient population?

Alison Dolce: Yes, you're right that seizures in this very vulnerable age group can be especially challenging. So it really does take a team of experts to appropriately diagnose and treat these babies. This obviously includes not only the bedside nurses and the neonatologists who really need a high degree of clinical suspicion for seizures based upon certain risk factors, but also pediatric neurologists and epileptologists who really recognize these challenges and who are aware of the various causes of seizures and how they can present so differently.

At Children's, I really can confidently say that we're pretty much at the forefront of understanding and treating neonatal seizures.

Host: In the intro, we talked a little bit about how these seizures can present differently in different babies. Some have body twitching, some have random eye movements. Other babies may not exhibit any signs at all. We also know that early detection and intervention improve outcomes and increase the chances of a seizure free future for these infants. Talk to us a little bit about how important it is to use fetal imaging to identify abnormalities that may cause seizures before the baby is born in the sense that after the baby's born, we may not have those indications that you would think of to tip us off that there's something going on underneath the surface.

Alison Dolce: Sure. Yeah, I think before I talk about fetal imaging, the reason I can better explain why seizures are so subtle in neonates. We have to remember that seizures manifest themselves depending on what part of the brain the seizures are originating from. So in an older child, if they're having a seizure from, say, the occipital lobe, which is really intimately involved in vision, they may be able to say, Hey, I'm having visual symptoms.

Obviously a baby is not going to be able to tell us if they're having any kind of funny sensation. So more commonly than not, there aren't any clearly overt physical manifestations. It's really about 80 to 90% of seizures in neonates that are subclinical or meaning they don't have any obvious clinical symptoms, and the only way we can identify them is by EEG.

Now, you mentioned the fetal imaging, so part of that is kind of preemptively thinking about babies that are really at risk for seizure. So, at Children's, we often have the ability to identify malformations of the brain in utero, which really can allow for rapid transition to treatment, such as epilepsy surgery whenever that might be necessary.

And it's those really early interventions that enhance our outcomes and increase the chance of seizure freedom for these infants. Typically, if there's any fetal abnormality identified on prenatal imaging, our fetal center at Children's, quickly gets our Neuro NICU team involved. We then are able to visit with the family prior to delivery, and we discuss all the imaging findings and implications.

And really, an important concept behind all of this is that the success of our treatments, especially when we start talking about epilepsy surgery, it's often significantly better the earlier it's implemented. There's really good data showing that earlier epilepsy surgery not only leads to better seizure outcomes, but improved neurodevelopmental outcomes, which is what we really care about. So we have this unique ability at Children's to develop this early relationship with families and then be able to follow them through infancy and childhood.

Host: That's amazing. And that's a lot in part to your multidisciplinary team and the way that you're able to plug the children in quite early.

Alison Dolce: Yes, absolutely. You know, the imaging is not just prenatal. Then we have postnatal imaging, right? So once the baby is born we are already aware of this child because we've done a prenatal consult and we're able to follow them in the NICU and kind of continue that relationship.

And we utilize postnatal MRI and things like MR spectroscopy that really can give us a better snapshot of what might be going on. Is it something structural? Or like the MR spectroscopy helps us to determine, is there some abnormal metabolic state within the brain that could aid us in kind of what we think our diagnosis might be that's causing seizures?

Host: Let me back up for a second. So you have the children who maybe have structural anomalies that you can see and you say, okay, this is a child that might also have seizures, we should plug them in and make sure we know what's going on when these babies are born. Then you have the children who might have comorbid conditions, which might give them an increased risk of having epilepsy or neonatal seizures. What about, you said there was a lot of children who have, they're just subclinical. How do you find those children?

Alison Dolce: Yes. So that is really where we rely heavily on kind of this multidisciplinary approach and excellent neonatologists and excellent neurologists that are able to kind of understand those babies are at high risk. So there are certain neonates that we know are just at a high risk of seizures. And just some examples are babies who have had a hypoxic ischemic injury or a preterm baby where they've had intraventricular hemorrhage. Or a baby who's got meningitis, those are children that are at very high risk of seizure. So even if you don't see clinical manifestations, those are babies who really do deserve having an EEG hooked up for monitoring to kind of screen for seizures, since so many babies, again, will have subclinical events.

Host: That makes sense. Now some babies do well on medications while you alluded to others needing a more invasive care. Can you discuss with us epilepsy surgery and when it's necessary as well as the risks of medication?

Alison Dolce: Yeah so when we talk about epilepsy surgery, this is usually for children who have really what we call medically refractory or intractable epilepsy. So they've been tried on at least two or more anti-seizure medicines and they continue to have seizures.

 But sometimes we know, based upon that very early imaging that they have a malformation of their brain that really predisposes them to, to very severe seizures. And so again, those are the children that we really try to expedite, follow closely, and move them to surgery you know, in an expedited fashion if necessary. Something though, I mean, when we think about seizures in babies, most babies actually have what's called acute symptomatic seizures. So, they're caused by some acute brain injury.

So, again, those are things that I mentioned earlier. Hypoxia, infection, hemorrhage. And those babies actually will typically stop seizing after several days. We can say about 25 percent of those survivors of acute symptomatic seizures, like in the NICU, they will go on to have a post neonatal epilepsy. And so some of those kids down the road, again, may end up having refractory epilepsy and needing a surgical workup.

And so that's where that early relationship that we develop with these families is so important. And another thing, and you asked about the risks of medication. So we really have to weigh the risk of brain injury from ongoing seizure activity against the risk of all these medication side effects.

So those side effects can be simple things like hypotension or respiratory depression, but it could be something more serious like organ dysfunction and lab abnormalities. And then we really worry about the long term effects. So, so there are animal models that suggest some of our medications that we use in the neonates, can cause neuronal death or neuronal apoptosis and then lead to adverse neurodevelopmental outcomes. So, with the risk of medication, we are really shifting kind of our frame of thought and trying to get these babies off of anti-seizure medicines before they even go home from the NICU, if we can.

Now, historically, most babies would go home on anti-seizure medicines if they had seizures in the NICU. Now, again, we try to get them off but there are always you know, exceptions to that story. If a child has an obvious malformation of their brain or some underlying genetic cause to have a neonatal epilepsy, then those children would of course be going home on a medicine.

Host: That makes sense. So are there any other diagnostics and treatments Children's Health offers for neonatal seizures that you'd like to share?

Alison Dolce: When we think about diagnosis for seizures in neonates, the key really does remain the EEG. You absolutely have to have it to diagnose seizures in this age group because so many are subclinical. So I think what's great about Children's Health is our group really offers 24/7 EEG monitoring for babies in the NICU, so we really can readily identify seizures.

Another thing is that it's really important we complete that kind of diagnostic workup very expeditiously. So outside of imaging, if imaging doesn't show us anything and we're seeing seizures, we often utilize metabolic and genetic tests to help differentiate those babies that may have some true underlying genetic or neonatal epilepsy versus those that have acute symptomatic seizures.

And regards to like, you asked about any other treatments that we offer. I mean, in regards to that, we're pretty vividly aware that if seizures aren't responding to our standard anti seizure medicines, that we need to be considering Neonatal Genetic Epilepsy Syndromes. The reason is, even though it's a small number, about 10 percent of those cases of seizures in neonates are going to be due to something genetic or metabolic.

And we want to think about that early because now there really are several what we would call precision kind of therapeutic approaches or medicines that really aim at addressing the underlying pathogenesis of the disorder, not just like a band aid of an anti-seizure medicine. The other thing is really the ketogenic diet.

So the ketogenic diet is something that is well known to be very helpful for refractory seizures, and we do utilize that at times in the NICU. And it's even considered a precision therapy for some genetic syndromes. So there are other therapies that we can utilize other than just our standard anti-seizure medicine.

Host: And do we know why the ketogenic diet is so successful at times?

Alison Dolce: Oh boy, that's like the age old question. I mean, we know from like literally the time of Hippocrates that like fasting and dietary things can help with seizures and very smart people have looked at this and it's still not perfectly clear. We know that it has something to do with ketosis, but not everything.

And so, it's not really clear, but it is something that we utilize in those circumstances of refractory seizures. Now, sometimes I said it's used as a precision therapy. If a child, for example, can't utilize glucose within their brain for energy like we normally do; the ketogenic diet kind of bypasses that, and we, and it utilizes fat for energy within the brain.

Host: Right, you're giving them an alternative fuel.

Alison Dolce: Exactly.

Host: It's so interesting. I mean, amazing. And to your point, it's amazing that they've known that this has been somewhat successful for a very long time. And it sort of shows how much we know when you think about the gene therapy and genetics and how far we're, getting with science, but then also how far we have to go. So it's, I just find it fascinating. Thank you for explaining to us.

Alison Dolce: Yeah.

Host: So Dr. Dolce, could you tell us a little bit more about the gene therapies and what's going on at Children's Health now and how you see that maybe progressing in the future?

Alison Dolce: Yes, I would love to. This is where I get really excited about things because historically, so many of these disorders really didn't have a cure. We were just kind of treating them symptomatically. So, I think because our team is really involved in these pretty groundbreaking cases of neonatal seizures; we will hopefully be on the forefront of some of the gene therapies that are coming. Specifically in the neonatal age group, there's a lot of common, they're called monogenic epilepsies, meaning there's like, they're a single gene mutation. And there's been success in treating other monogenic neurologic disorders.

For example one is spinal muscular atrophy. So there's a lot of optimism about gene editing in these monogenic epilepsies. And the reason it pertains so much to neonatal seizures is because they typically present themselves in the neonatal period. So those gene mutations really play a role in those developmental, what we call developmental epileptic encephalopathies.

Host: That's amazing because what you're talking about doing is being able to get in there and actually change it before really the effects happen to the brain and what leads to so many things down the line. That's just game changing.

Alison Dolce: Yes, it really is.

Host: As we wrap up, is there one thing that you would love other neurologists to know about neonatal seizures?

Alison Dolce: Yeah, absolutely. So kind of a real quick summary is that first you have to have a high degree of clinical suspicion in those high risk babies. We know that seizures aren't easily identifiable at the bedside. So you really, if you can, you want to get an EEG to help really diagnose and confirm seizures.

And then I think another thing that has become really very important and we're more aware of now is how, how the semiology of seizure really matters and it helps us when we're coming up with our differential diagnosis or what the etiology might be. So what I mean by that is how does the seizure present itself?

The International League Against Epilepsy recently provided some recommendations and guidelines on how we classify neonatal seizures and how we treat them. And so we know now that different types of seizures, again, mean different potential etiologies. So an example would be if a baby's having a myoclonic or a tonic seizure, that should make us start thinking of could there be an underlying metabolic or genetic etiology versus a baby who's having, like rhythmic jerking of an arm or a leg or some part of their body, a focal clonic seizure, that should make us immediately think of something cerebrovascular, like, did the baby have a stroke?

Host: Got it. And I'm assuming that if parents are at home and they're witnessing something like this, of course they want to get medical attention, but also a video would be helpful.

Alison Dolce: Oh yes, that is absolutely something we talk with all of our families about before they leave the NICU. And we, I mean, we counsel them on what seizures could look like. Again, realizing that seizures look so very different in neonates than they do in older children. But we always encourage them if you're worried at all, grab your phone. Everybody has cell phones now. Grab your phone. Take a video of it so that we can see it and hopefully help kind of guide them on what needs to be done.

Host: Thank you so much for taking the time to share your expertise with us today. This has been such an educational discussion. We really appreciate you being here.

Alison Dolce: Thank you so much for having me.

Host: To learn more about Children's Health's Pediatric Epilepsy Center, visit childrens.com/epilepsy. Thank you so much for your time with us today and to our audience for listening to Pediatric Insights Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research.

You can find more information at childrens.com. And if you found this podcast helpful, please rate, review, and share this episode. And please follow Children's Health on your social channels.