We discuss the presentation, evaluation, and management of neonatal seizures. We are joined by Alison Dolce, MD, Assistant Professor of Pediatrics and Neurology at UT Southwestern and Children’s Health Dallas.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern newborn nursery. Welcome back to the podcast. In today's episode, we will be discussing neonatal seizures. We are recording remotely due to the ongoing COVID pandemic. We are joined today by Dr. Alison Dolce Assistant Professor of Pediatrics and Neurology at UT Southwestern and Children's Health Dallas, who is the neonatal neurologist and epileptologist within UT Southwestern's Neurological NICU program.
Dr. Alison Dolce:
Hello.
Dr. Neeta Goli:
Hi Dr. Dolce, thanks for joining us today.
Dr. Alison Dolce:
Hi, thank you so much for having me.
Dr. Neeta Goli:
Neonatal seizures, if noted, require immediate evaluation and intervention, which will typically require transfer from the regular newborn nursery to a higher level of care, typically, the neonatal intensive care unit or NICU. How common are seizures during the neonatal period?
Dr. Alison Dolce:
Seizures are very prevalent in our newborn population. It's honestly, probably one of the most common reasons that we are consulted in the NICU. Worldwide incidence for neonatal seizures is about 1-3.5 per every 1,000 live births. But really the important thing to know is that the incidence of seizures is just highest in the neonatal age group, more so than any other age group, including the elderly.
Dr. Neeta Goli:
What are some reasons that newborns can have seizures?
Dr. Alison Dolce:
So newborns that are really going to be at the highest risk for having seizures or those that have had some suspected or confirmed acute brain injury. So when I think of neonatal seizures, I really think of it as it's a symptom of something. It's indicating to me that there's some underlying brain abnormality. And so we'll often refer to seizures in the newborn as acute symptomatic seizures. So by far, the most common cause of seizures in our full-term newborns is going to be hypoxic ischemic encephalopathy, or HIE. But I would say that the etiology really does depend on the age of the child. So for example, a premature infant, the most common risk factor for them is going to be intraventricular hemorrhage. So again, most common cause is HIE in a term baby, and then IVH in a preterm baby.
Dr. Alison Dolce:
And then beyond that, things that we think about that are causes are things like stroke or electrolyte abnormalities, certainly any kind of central nervous system infection, meningitis, encephalitis. Those babies that are born with a brain malformation, a congenital brain malformation, or some structural abnormality are at high risk. And then, once you've thought about those acute symptomatic causes for seizures, then you're really left with, could it be an inborn error of metabolism or something genetic? And so about one in 10 or about 10% of seizures in our newborns are going to be due to something metabolic or genetic. But again, the most common causes are going to be those acute symptomatic things that I mentioned previously.
Dr. Neeta Goli:
What kind of syndromes or potentially metabolic disorders would increase the baby's risk of seizures?
Dr. Alison Dolce:
I think when we think about risk factors, we first consider starting with the mom. So we know that babies that are born to mothers that are over the age of 40, or those mothers who have preexisting or say gestational diabetes. Those babies are just going to be at a higher risk of having seizures. And then we have intrapartum factors like placental abnormalities that put a baby at higher risk. And then we know that preterm babies and babies of very low birth weight and also babies that are post-term, beyond 42 weeks, there is really much higher risk of having seizures. And then the risk factors are a lot about what I was just talking about with causes. So we're thinking about those acute symptomatic things, so core provoking factors. But once you get beyond that, you're really getting to more of the neonatal epilepsies or what we call early infantile epileptic encephalopathy syndromes.
Dr. Alison Dolce:
So we can have babies that might be born again with malformations of cortical development or some structural brain abnormality that they're obviously going to be at high risk of seizures. But what's interesting is a lot of these babies don't necessarily start seizing when they're in the NICU. They tend to declare themselves within the first year of life, but they don't always present right in that NICU period. And really contrary to previous assumptions, a lot of these malformations of cortical development are now thought to have some genetic basis. So when we talk about syndromes increasing your risk for baby seizures, it really kind of boils down to, are there potential inborn errors of metabolism or genetic things? So an example would be: we have babies that have vitamin responsive epilepsies, or for example, pyridoxine-dependent seizures where they aren't responding to our standard anti-seizure medications and we have to treat them with a vitamin, with B6.
Dr. Alison Dolce:
And then in this neonatal age group, there are several, what I would say are the more common genetic epilepsies. So these are going to be caused by typically a single gene mutation. And I think to me, these are what are really fascinating and what are so interesting because they can present along this spectrum. So when you have a baby having seizures in the NICU, you're going to ask about family history. And so you may have a baby, say presenting with seizures around the fifth day of life, and you talk to the family and grandma comes in and she's like, "Oh yeah, mom or dad did this when they were babies."
Dr. Alison Dolce:
And so this would sit with a diagnosis of benign familial neonatal seizures, and it's most commonly going to be caused by a mutation in a potassium channel gene, KCNQ2. What's so fascinating is that we can have babies that have a mutation in this exact same gene, but they present with a much more severe clinical phenotype. They present as that early infantile epileptic encephalopathy. And so, again, it's the spectrum. So historically, those babies that have this benign form, where we expect that they outgrow the seizures, they're not going to have epilepsy later on in life, that's usually going to be passed on as an autosomal dominant condition.
Dr. Alison Dolce:
And then we have the more severe forms, those tend to be de novo mutations. And this is where I get really excited because knowing the genetic defect is now leading us to precision medicine. So if we know what the genetic defect is, we know that there are certain medications that may be more helpful or not helpful. And we have a lot of ongoing trials right now with gene-modifying therapies for several of these neonatal epilepsies. So I think there's a lot of hope on the horizon and it makes what I do very exciting.
Dr. Neeta Goli:
Yeah. That's exciting and I bet comforting to the families too, to kind of have an answer.
Dr. Alison Dolce:
Absolutely. I think historically, people think about neurology as being this field where you can just diagnose and there's not a whole lot that can be done and that's just not the case anymore.
Dr. Neeta Goli:
That's great. And about some of the other risk factors you mentioned in terms of advanced maternal age, post-term gestational age, things like that, is the physiology or pathophysiology of that understood in terms of why that increases the risk of neonatal seizures, or is it not clear?
Dr. Alison Dolce:
I would say for the most part, it's not clear. I think the biggest thing is that we're dealing with an immature brain and the way the immature brain works is so very different from an older child. It boils down to neurotransmitters and channels and different things where babies in that early period of development actually respond differently than an older child.
Dr. Neeta Goli:
Okay. So lots of research to be done then.
Dr. Alison Dolce:
Absolutely.
Dr. Neeta Goli:
So when we are caring for these babies, in the newborn nursery, seizure activity can be very subtle and often difficult to identify in newborns when compared to seizure activity in older children and adolescents. So in a newborn, how might we expect seizures to present?
Dr. Alison Dolce:
So you're absolutely right that seizures in the newborn can be very, very hard to identify. I think in general, the way a seizure presents itself really depends on where in the brain the seizure's coming from. So if you have an older child, who's having a seizure from the occipital lobe, just as an example, they may have visual symptoms. Obviously, a baby is not going to be able to tell us, "I have a funny sensation" or "I have a funny feeling." And so more commonly than not, there's actually not going to be a clearly overt physical manifestation. And it's really impressive, greater than 50%, probably more like 80-90% of seizures in newborns are going to be subclinical. So that means, again, there's no outward manifestation whatsoever. You would never know they're seizing unless they were hooked up to an EEG.
Dr. Alison Dolce:
The most common type of seizure that we actually correctly do identify at the bedside is a clonic seizure. And so this is something that you're going to see a very rhythmic twitching of an extremity. And typically, if you put your hand on it and try gentle restraint, that twitching will persist despite you putting your hand there. And so that would give you a high degree, it should give you a high degree of suspicion that this is a clonic seizure. And really that's the most common type to present itself because that tells me that the seizure's originating, or at least propagating along the primary motor cortex of the brain and that's why we see a clinical manifestation because the baby can move. They may not be able to tell us things, but they can move.
Dr. Alison Dolce:
Another thing that I think is really important to keep in mind is that we're dealing with a newborn brain. So again, it all boils down to that immaturity. Because their brains are not fully developed and myelinated, they're absolutely not capable of generating a generalized tonic clonic seizure, like an older child might be able to do. So in a neonate, seizures are focal. So I think that's a really key point.
Dr. Alison Dolce:
And then I think I've been asked a lot, are there certain pathognomonic seizure types that would tell me it's a certain etiology, and really there isn't. I would say that if I see a baby that's having asymmetric tonic seizures where they've got sustained stiffness in a limb, or they're having repetitive myoclonic seizures, which is just a very rapid sudden jerk. It's not rhythmic jerking like a clonic seizure. That's when I worry about the possibility of it being genetic or metabolic. So the presentation, again, it all boils down to most of them are going to be subclinical or not easy to identify. And so this year in fact, the International League Against Epilepsy just did a modification of how we classify seizures in neonates and really broadly classified it in two categories. They're either going to be electrographic only, or subclinical seizures, versus electroclinical seizures. And those can present in various different ways.
Dr. Neeta Goli:
Would you mind saying that again? Electrographic versus what was the second?
Dr. Alison Dolce:
The second is electroclinical. So you have a clinical manifestation along with an EEG seizure.
Dr. Neeta Goli:
Okay. So if we get called to the bedside to evaluate a baby for abnormal movements, what kind of things can we do in our physical exam to try to help distinguish whether this is a seizure? I know you mentioned trying to suppress the movement.
Dr. Alison Dolce:
Yeah. So the only real potential beneficial things to try to do is to see if with gentle restraint, does the movement stop? Otherwise, to be able to confirm a seizure, you really do need an EEG.
Dr. Neeta Goli:
Okay. So then if we do have abnormal movements we're not sure about, in addition to the EEG, what would the initial evaluation be for these babies?
Dr. Alison Dolce:
So I think, again, that approach is exactly what you said. We want to ask ourselves, am I even sure that this is in fact a seizure? Because we know that some of our treatments are not benign, so we don't want to be inappropriately treating them, but we also don't want to miss the diagnosis because if we do, then the baby's undertreated and it can lead to this “kindling phenomenon” where you have preexisting brain injury and add seizures on top of that and it can permanently potentially alter that seizure threshold. So I like to think of it as the seizures are essentially teaching that young brain how to become very good at epilepsy. And so the key really when you're questioning “is it seizure or not,” is to get an EEG if you can.
Dr. Alison Dolce:
Now, I understand that the ability to call up an EEG may not always be possible depending on where you are. So if it's not, usually I would say to treat if your suspicion for that clinical event is high, because we know that untreated seizures can contribute to worsened outcomes. But once you've decided, you say, "Well, I'm pretty sure that the baby's seizing," or you've confirmed it on EEG. The way we evaluate that baby then, really there's some kind of knee jerk tests. And that includes simple things like let's look at electrolytes, let's get a CBC. We should check CSF for signs of infection. And then again, obviously neuroimaging. If those tests don't reveal anything, that's when we tend to broaden our workup and include additional tests, like metabolic things like plasma amino acids, urine organic acids, we'll sometimes send CSF neurotransmitters, and then we may do an MRS or an MR spectroscopy of the brain, or send an epilepsy gene panel, again, looking for some of those gene mutations that are commonly associated with neonatal seizures.
Dr. Neeta Goli:
So while that workup is ongoing, in terms of management, if the EEG does confirm seizure activity and there is no immediately correctable cause such as hypoglycemia, something like that, what would be your typical management in the acute period?
Dr. Alison Dolce:
Can I just say one more thing about the confirmation of the seizure activity? Because you were asking me about that. You may say to yourself, "I'm pretty good at the bedside. I think I can differentiate what is a seizure, what's not a seizure." You'd be quite surprised how inaccurate we actually are at differentiating that. There have been really good studies that have looked at this and they have essentially shown videos of paroxysmal events in newborns to bedside nurses, doctors. And some of these videos were seizures, some of them were not. And they asked them, "Do you think this is a seizure or not?" And what they found is that seizures were correctly identified in only about 50% of cases. And there's a really broad range. And impressively, doctors were no better at discriminating between these different events than any other healthcare professionals. So that's again why I'm emphasizing that the EEG is so important if you can get it. And then, like you were saying, I'll get to the management. I'm sorry, I didn't mean to go over important questions.
Dr. Neeta Goli:
No, go ahead.
Dr. Alison Dolce:
That's where it gets really tough here because there's so much that we need to do. There aren't any FDA indicated treatments for neonatal seizures. And so our arsenal's really limited. We have medications like barbital, which has been around for over 100 years and phenytoin which has been around for over 80 years. But all the data that we have so far really shows that our medications aren't very great. They're pretty equally incompletely effective. So they have little over maybe 40% success rate. And for those babies that have more severe seizure severity, our medications are even less effective. So when we think about how to manage these babies, we're obviously trying to weigh risks of brain injury from the ongoing seizures and then the risk of the medication side effects.
Dr. Alison Dolce:
There's a lot of studies in rats, for example, that have shown that our medications like phenobarbital, phenytoin lead to neuronal apoptosis, or cell death. Well these are the medications that we have available to use in our babies. So that's a problem, right? There had been really high hopes of Keppra being better from a safety standpoint, but a recent trial last year was really important because what they did is they compared Keppra to phenobarbital in neonates and hands down, they showed that phenobarbital had a much, much higher success rate. So really, first line, as it stands now, should be phenobarbital. We shouldn't be using Keppra as a first-line agent for babies that are having seizures. And then, if the seizures persist, that's even more difficult because there's no head-to-head trials on second-line medications for these babies. And so it's often based on individual preference, but the most common medications you'll see us use are Keppra or Fosphenytoin as a second line drug.
Dr. Neeta Goli:
There's a very broad spectrum of causes and etiologies that we discussed earlier. So obviously, the prognosis for these babies is going to vary based on their etiology. But can you speak in general regarding the long-term prognosis for a neonate with seizures, maybe with some of the most common etiologies that you would see?
Dr. Alison Dolce:
Yeah. So you're right that the neurodevelopmental outcome really depends primarily on what the cause of the seizures is. So if we know the etiology, it's much easier to potentially predict what the prognosis may be. So if you have a baby that has a very extensive cerebral brain malformation, we know that they're likely going to have a poorer outcome. But then you have the cases of infection or various degrees of HIE, those are going to be more variable. The parents usually want to know number one, "What's the risk that my kid is going to have epilepsy down the road?" And we can say pretty confidently that about 25% of those babies that had those acute symptomatic seizures are going to go on to have a post-neonatal epilepsy.
Dr. Alison Dolce:
However, I think that brings up a really important point, if it's okay if I say it quickly? It's about medication duration. So historically, we used to keep babies on medications and then possibly wean them off about three to six months from discharge. And I think that was really because of this fear of postnatal epilepsy. But we have to remember that most seizures in the neonatal period are these acute symptomatic seizures. And they tend to persist for 48 or 96 hours, somewhere around there, and then they really subside. And there's now really good evidence that supports discontinuing these medications for babies who've had these acute symptomatic seizures before they even go home from the hospital. And so we have to keep in mind that there's really not a benefit to their neurodevelopmental outcomes in staying on these medications and potentially prolong the exposure to the harmful effects of the drugs.
Dr. Alison Dolce:
And then, speaking again along the lines of prognosis, staying on these medications does not in any way seem to prevent the development of epilepsy or prevent or delay the onset of epilepsy. And another important thing is that some of those early-onset epilepsies tend to occur despite kids that have been sent home on medications. About a third of those early epilepsies are going to be a seizure type that's called infantile spasms. And this is a type of seizure that doesn't even respond to say a phenobarbital or a Keppra. So from a prognostic standpoint with post-neonatal epilepsy, most kids don't need to go home on anti-seizure medications. Obviously, if you had a child who had a very high seizure burden or they required multiple medications to get seizures to stop, we're more concerned about their outcomes.
Dr. Alison Dolce:
I think too, another thing when I get asked about prognosis is that this is where the EEG is like my best friend and it can be so helpful. We obviously rely on imaging to tell us how bad the injury has been. But prognosis is honestly going to be more dependent on what the background of the EEG looks like rather than whether or not the baby has seizures or not. So for example, you can have a baby that had seizures, but if they have a really relatively normal looking EEG background, I feel pretty comfortable telling the family that we likely have a much better prognosis than if the baby had a horrible EEG background and they were having seizures.
Dr. Alison Dolce:
And then another thing I think that families want to know about is not just will they have epilepsy down the road, but "How is my baby going to be, cognitively?" or "What's their motor function going to be like?" And we don't have perfect numbers here, but I would say about 50% of those babies that have seizures are going to have some degree of developmental delay. But it could be really mild. And then about a third of our babies may have cerebral palsy down the road, that's going to be diagnosed. But I think that makes sense again, because we think about the causes and the most common causes are things like hypoxic injury or stroke, which are going to put you at risk for having CP.
Dr. Neeta Goli:
And what about the babies who, since you mentioned that so many of the neonatal seizures can be subclinical without any presenting physical exam findings, do they typically resolve as well at 48, 96 hours without intervention? How do we know that subclinical seizures would even be presenting?
Dr. Alison Dolce:
That's a great question. So we think of subclinical seizures with the same sort of burden on prognosis as a clinical seizure. So we treat them the same. We don't want babies having them. And so usually, part of the whole evaluation and management of seizures is that the baby is hooked up to an EEG. And what we try to do is we keep the EEG up for at least 24 hours after the last seizure, to be sure that seizures have in fact resolved, because we know again that after that kind of initial insult, most seizures tend to subside after several days. So again, it's important to treat those just like we would a clinical seizure.
Dr. Neeta Goli:
Are the subclinical seizures typically seen in babies who are being monitored via EEG for other things, for example, for HIE or IVH?
Dr. Alison Dolce:
Yeah, definitely. For babies that have HIE, most of those babies now, especially in big centers, are going to be monitored because they're put on cooling. And part of the cooling protocol is often to get an EEG because there's a potential risk of seizures upon rewarming. And so we very commonly see subclinical seizures with babies of HIE. With babies that have IVH, this is a little bit more challenging to answer because that's going to be more common in the preterm babies, and we tend to monitor the preterm babies less frequently for several reasons. One is they may not present with any clinical concerning signs of seizures, so an EEG never gets ordered. But also because they're so fragile. Their skin is so fragile, we worry about skin breakdown if the electrodes are on there too long. And so there's a lot we still don't know about the seizure burden in these extreme preemies.
Dr. Neeta Goli:
Is there any literature on prevalence of subclinical seizures in healthy term newborns without any of these risk factors?
Dr. Alison Dolce:
So the answer to that is that yes, there is literature. The reason that you're going to get an EEG usually is because you have some clinical suspicion. There's not really data looking at prospectively having babies that are monitored if they don't already have some underlying risk factor, if that makes sense.
Dr. Neeta Goli:
Yeah, yeah. So no universal EEG screening program study.
Dr. Alison Dolce:
Exactly, yeah.
Dr. Neeta Goli:
And one thing, when we're talking to families about this, every parent who has a baby who has seizures, you mentioned is worried about cognitive status, developmental delay, but just in general layman's terms, a lot of times they'll ask, "Will it damage my baby’s brain?" And you did mention brain injury or the kindling phenomenon, if you will. Is that based on duration, after a certain duration of having untreated seizures or is there a certain quality of the seizure that would make it more likely to lead to a long-term worsened outcome?
Dr. Alison Dolce:
That's a great question. I think we really try to think of seizures and looking at it as an overall seizure burden. So we don't just count the seizures, we absolutely look at the duration of them, how long they're lasting. I think just in general, those babies that have that higher seizure burden, where the percentage of time they're seizing is quite high, whether it's because they're having frequent short ones or prolonged ones, those babies tend to have a worse outcome. And those are the babies that we absolutely worry about, this epileptogenesis. So you have this peak where you have these seizures in that early couple of days, and then seizures do tend to subside, and there's this latent period. And that's where there's this potential for epileptogenesis and this kindling, because there was already an insult and then you're kind of adding insult to injury with seizures on top of that, there's this concern for this kindling phenomenon and it sets the baby's brain up for just being at risk for seizures and epilepsy in the future.
Dr. Neeta Goli:
How do you usually counsel these parents while the evaluation is ongoing?
Dr. Alison Dolce:
Yeah. I think it really depends obviously on each patient's individual clinical picture. So for some infants, we know really quickly, like okay, this is the etiology, this is the prognosis. An example would be what we were talking about earlier, is a benign familial neonatal seizure, but those kids, we know they have excellent outcomes. And so it's easy to counsel the family on that. For other children, it may not always be so simple and I know that it makes for such an uncomfortable waiting game for the parents. I would say that it's important to correctly state the facts and what you can be certain of. So we want to be really careful about prognosticating without all the available information. When I talk to residents and fellows about meeting the families, I always tell them to try and always lead your conversation with some sense of hope.
Dr. Alison Dolce:
Obviously, we want to be realistic and we don't want to provide false hope, but we also want to avoid forecasting something that we can't be sure of. You never want to be that doctor that the family remembers years from now that told them, "Oh, your child's never going to walk," or "They're never going to talk" because a lot of times, we'll be wrong. Babies, I like to emphasize brain plasticity in this age, that if something like this happened to you or I, an older person, we may not recover in the same way that your child might be able to do. And so I think it's all about providing as clear and consistent communication is possible, but not providing a false sense of hope either. And then I guess the other thing that I do when I'm counseling families, especially if I think that they're going to be at high risk of future seizures, is to talk to them about what seizures may look like in a baby.
Dr. Alison Dolce:
And again, in the neonatal period, we know that the majority are going to be subclinical. But I want to counsel them on other potential feature types, so like the chronic type of seizures. And then another really big one that is becoming, I feel more important and we know more now, is to counsel families on infantile spasms, which is a seizure type that tends to present a little bit later around three to six months of life, not in that neonatal period. Because that's a seizure type that we feel that it's sort of like, not necessarily a neurological emergency, but a neurological urgency where the earlier we treat, there's a potential benefit for the neurodevelopmental outcome.
Dr. Neeta Goli:
And for our listeners, could you describe the typical movements you would expect to see for infantile spasms?
Dr. Alison Dolce:
Yeah, absolutely. So for infantile spasms, there's a couple of key characteristics. So it can sort of mimic what a Moro may look like, or a startle, where there is a sudden jerk or extension of the upper extremities, where the arms go out stiffly. Often there may be something more subtle where just the eyes get wide suddenly. The key to these is that they are very brief, but they're a little bit longer in duration than a myoclonic seizure. So when we think about myoclonic seizures it's a muscle twitch. It's like you got shocked by something. For a spasm, it's kind of in between a myoclonic seizure and a tonic seizure.
Dr. Alison Dolce:
So a tonic seizure is where you have sustained muscle contraction, you're very stiff, you have increased tone. So in infantile spasms, they have this sudden jerk that's a little bit longer than a myoclonic twitch where the arms kind of tend to go out. They tend to have some flexion at the waist as well. And the key thing is honestly the clustering of these. These are events that tend to occur in clusters. So we'll have a spasm, it'll be a few seconds, they'll have another one, it'll be a few seconds. And they do this repetitively over minutes in duration. The other thing that would be a clue that the baby's maybe having an infantile spasm is that it happens most commonly in that sleep-wake transition. So the baby's asleep and as they're waking up, they start having this cluster of events.
Dr. Neeta Goli:
Okay. Good for our listeners to know. And that is probably ripe for another separate episode in and of itself.
Dr. Alison Dolce:
Yeah, absolutely.
Dr. Neeta Goli:
To end the episode today, what advice do you have for our listeners while they care for newborns?
Dr. Alison Dolce:
Well, I think for me, as it pertains from a neurologic standpoint, I think it's the awareness of how the immature brain is at risk of having seizures and that these seizures, number one, because of that immature brain, don't present the way seizures would present in an older child. They're commonly going to be subclinical with no clinical signs. And then the other thing is that they can't be generalized, seizures would be focal in these babies. So I think being vigilant and knowing those babies are high risk, those are the babies that you should be really heavily considering getting an EEG, if your clinical suspicion is high.
Dr. Neeta Goli:
Thanks again for joining us today, Dr. Dolce.
Dr. Alison Dolce:
Yeah, absolutely. It was my pleasure.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@UTSouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.