Pediatric epilepsy is a complex condition that affects countless children, but advancements in treatment are paving the way for brighter futures. Join us as Dr. Juliet Knowles, Assistant Professor of Neurology at Stanford University, sheds light on the multifaceted nature of epilepsy in children. In this enlightening discussion, we’ll explore the critical differences between seizures and epilepsy, the profound impact of early intervention on neonatal brain development, and the exciting advancements in genetics that promise to transform treatment options.
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Episode Transcript
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(00:00):
(upbeat music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify, or YouTube
(00:22):
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adewuya.
In this episode, I will bechatting with Dr. Juliet Knowles.
Dr. Knowles is an assistantprofessor of neurology
and neurological sciencesand of pediatrics
at Stanford University.
She is a physician-scientist
specializing in pediatric epilepsy,
(00:42):
providing clinical careand leading a research team
focused on basic, translational,and clinical research.
Dr. Knowles completed herMD and PhD in neurosciences
at Stanford University,followed by a residency training
in pediatrics and childneurology at Stanford
where she also served as chief resident.
She further pursued a clinical fellowship
(01:02):
in pediatric epilepsyand postdoctoral research
on myelin plasticity and epilepsy
under the mentorship ofdoctors Michelle Monje
and John Huguenard.
Dr. Knowles has received several honors,
including the Stroup Awardfor Rising Star in Epilepsy
from Johns Hopkins University in 2021
and the Elterman Research Award
(01:24):
from the Pediatric EpilepsyResearch Foundation in 2020.
She serves on theScientific Program Committee
of the American Epilepsy Society
and the Research Committee ofthe Child Neurology Society.
Thank you so much forbeing here with me today.
- Thank you so much for having me, Ruth.
It's a real privilege to be here.
- I'm really excited to havethis conversation with you
about epilepsy, especiallypediatric epilepsy.
(01:47):
It's a topic that sparksa lot of discussion
and it's a privilege to hearfrom an expert like you.
When most people think of epilepsy,
they often picture dramatic seizures
with uncontrollable muscle contractions.
While that is one form,
epilepsy is actually a broad condition
with many different types ofseizures and presentations.
(02:08):
Can you start by defining whatepilepsy and seizures are?
And then could you expand onthe different types of seizures
and walk us through the key criteria
for diagnosing epilepsy?
- It's helpful to firststart with some definitions
and to distinguish betweenseizures and epilepsy.
Seizures are transient events.
(02:29):
In general, seizures are defined
in terms of their brainactivity component,
which we can visualize with an EEG,
and this involves abnormally synchronous
or excessive activity.
Then there's also the outwardmanifestation of the seizures,
what we call the seizure semiology.
And as you had mentioned,
this can involve tonic-clonic shaking
(02:51):
of all four extremities,a dramatic presentation
which we would call ageneralized tonic-clonic seizure.
But there can be much moresubtle seizure semiology,
such as the brief behavioral arrest
that occurs in absence seizures.
We conceptualize seizuresin two basic categories:
focal and generalized.
Focal seizures are thosethat begin in one region
(03:12):
and one hemisphere of the brain,
whereas generalized seizuresare those that begin
in both sides of the brain at once.
These two types of seizureshave different causes
and they also have different treatments.
Just as there are twodifferent seizure types,
there are different epilepsy types.
But first, let's define what is epilepsy.
What the diagnosis of epilepsy means
(03:33):
is that the person's brainhas an enduring predisposition
or tendency to have unprovokedseizures if left untreated.
And the diagnosis can be made
under a few different conditions.
One, if someone hastwo unprovoked seizures
generally 24 hours or more apart,
then that is oftenconsidered to be sufficient
(03:54):
for the diagnosis of epilepsy.
Or the person might have a single seizure
with a greater than 60%of having another seizure.
In many cases, thatwould also be sufficient.
Finally, there are epilepsy syndromes
where recurrent seizures go together
with certain patternsof activity on the EEG
and at certain ages.
When we see those factors co-occur,
(04:16):
that is also sufficient tomake the diagnosis of epilepsy.
The type of epilepsy thatsomeone has is determined
by the type of seizures that they have.
For example, there are focal epilepsies
which involve focal seizures only,
generalized epilepsies
that involve generalized seizures only,
and mixed forms of epilepsy
involving a mix of generalizedand focal seizures.
(04:37):
In some cases, the diagnosisof epilepsy is made,
but we don't know wherethe seizures begin,
so we just say onset unknown.
- That's a really helpful distinction
between seizures and epilepsy,
especially in terms of understanding
the brain activity component
versus the outward manifestations.
The way you broke down focalversus generalized seizures
(04:58):
and how they not only present differently
but also have differentcauses and treatments
really underscores the complexity
of epilepsy as a condition.
I appreciated your commentthat an epilepsy diagnosis
isn't just about the number of seizures,
but also factors like risk,prediction, and EEG patterns
that can point to specificepilepsy syndromes.
(05:21):
Given that complexity, I imagineearly detection is crucial.
That brings me to imaging.
Are there any earlywarning signs in imaging
that could allow clinicians to intervene
before seizures worsen?
- Brain MRI and EEG are standard tools
in the diagnostic investigationof seizures and epilepsy.
(05:43):
They play an important partboth in diagnosing the epilepsy
and its cause and guiding treatment.
It's particularly importantto get a brain MRI
when the epilepsy involves focal seizures.
That suggests that there maybe a focal structural area
of abnormality that's causingthe epilepsy to occur.
When we obtain the brain MRI,
we sometimes do findactionable structural changes
(06:05):
that would influence our approachto treating the epilepsy.
Some examples that wouldimmediately influence our treatment
might include multiplebenign hematomas in the brain
that occur in a conditioncalled tuberous sclerosis
that might influence thetype of epilepsy treatment,
including medications that we give.
Sometimes seizures can comefrom a focal cortical dysplasia,
(06:27):
which is just a small, limited area
of disrupted development, butthat can lead to rapid onset
and severe forms of epilepsy.
A common finding is hippocampal sclerosis
in the case of temporal lobe epilepsy,
which is the most common type of epilepsy.
These findings might influence our choice
of medication for the seizures
or they might encourageus to consider surgery
(06:50):
earlier in the course of treatment.
- I think that's really compelling,
especially how imagingdoesn't just confirm
an epilepsy diagnosis
but can actually shape treatmentstrategies from the start.
It makes me think aboutthe importance of timing
in epilepsy care.
If an MRI reveals a structuralabnormality early enough,
(07:11):
it could open the door formore targeted interventions
before seizures becomemore difficult to manage.
And I think that question oftiming is even more critical
when we look at neonatal epilepsy.
What challenges do neonatalepilepsies present,
and how do they differ from epilepsy
that develops later in childhood?
(07:33):
- Neonatal seizures andepilepsy often occur
in the setting of acute significant issues
that arise in the perinatal period.
Those things need to beaddressed immediately.
Some examples include
perinatal hypoxic-ischemic encephalopathy,
the condition resultingfrom lack of adequate oxygen
during the perinatal period.
(07:55):
Brain hemorrhages or ischemicstrokes can occur in infants.
Sepsis, meningitis, encephalitis,so infectious causes.
Then genetic metabolicetiologies tend to present
in the neonatal period.
So, many types of geneticepilepsy as well tend to manifest
during this time of life.
This list of causes requiresus to take action immediately
(08:18):
to address those problems.
So you're right, when aneonate has a seizure,
it's an emergency and weaggressively investigate that
with EEG and MRI.
- You've highlighted how neonatal seizures
often stem from acute medical events
that require immediate attention.
With that in mind, how do thecauses, diagnostic approaches,
(08:38):
and treatment strategies differ
when managing epilepsy in neonates
versus epilepsy thatdevelops later in childhood?
- The same categoriesstill apply in childhood,
sort of structural changes in the brain,
including acquired structuralchanges like brain injuries
or congenital malformations of the brain
as well as infection, but thelikelihood of causes shifts
(09:02):
as you think about older children.
For example, some epilepsy syndromes,
such as childhood absence epilepsy,
which is something thatwe study in my lab,
tends to present in middle childhood
between ages four and eight.
We think about thesecauses a bit differently
in older children.
- The challenges of neonatalepilepsy really highlight
(09:22):
the need to understandthe broader mechanisms
driving epilepsy progression.
As you mentioned,
while the underlying causesmight shift with age,
there's still a continuum of factors
influencing how epilepsydevelops over time.
One area that plays a key role
in that progression is myelination.
Your research specifically explores
(09:44):
how maladaptive myelinationcontributes to epilepsy.
Could you explain whatmaladaptive myelination is
and why it plays such acritical role in epilepsy?
- It's important to provide some context
for the work that we didon maladaptive myelination.
This work began when I was a resident
(10:04):
in neurology here at Stanford.
Around that time, thelab of Michelle Monje
published a really important study
in which they used atool called optogenetics
to demonstrate that recurrentpatterns of neuronal activity
in the brain can influencestructural changes in myelin
in the same circuits
that are having this recurrent activity.
(10:26):
This was a paradigm shift
because prior to that ourunderstanding of brain myelination
is that it occurs early inlife as our brains are forming.
And in a stereotyped progression,
we understood thatmyelin was fixed or inert
as the brain adapted.
What the study from Dr.Monje's lab demonstrated
was that this is not the case.
(10:48):
Actually, even after this process
of developmental myelination is complete,
recurrent patterns of neuronal activity
can, in fact, alter myelin structure
in a circuit-specific manner.
Moreover, those myelinchanges subsequently influence
the activity of that brain circuit.
It's a form of brainplasticity and adaptation
(11:11):
analogous to synaptic plasticity.
Where did my work come in?
I remember learning about this discovery,
which they called adaptive myelination.
At that time, I was thinkinga lot about pediatric epilepsy
as I took care of children with seizures
that had these recurrentpatterns of unhealthy behavior
in the form of seizures.
This prompted me to wonder
(11:32):
whether recurrent patternsof unhelpful brain activity
could also influence myelin structure.
If that were the case,
what impact might thatunhealthy myelin plasticity have
on the brain subsequently?
To study that question, Idid a postdoctoral fellowship
with Michelle and Dr. John Huguenard,
(11:52):
who is an epilepsy researcherand expert here at Stanford.
We looked in mouse and ratmodels of generalized epilepsy,
and what we found
is that seizures inducedmyelin structural change.
We found thicker myelin sheaths
and increased numbers of myelinated axons
in the seizure network of these animals.
(12:14):
We then did further experiments
where we genetically engineered mice
so that we could block myelin plasticity
during this period of seizures.
What we found is thatmice that have seizures
and normal myelin plasticityhave a progressive course
where the seizures become moreand more frequent over time,
and this is reminiscent of children
(12:35):
with severe forms of epilepsy,
especially generalized epilepsy
that have this progressive course.
By contrast, in the same type of mouse
when we blocked theactivity-dependent myelination
during the period of seizure progression,
we found that theseizures did not progress
to nearly the same degree.
They persisted at a very low level.
What this information indicated to us
(12:57):
is that seizures are infact inducing myelination
in an activity-dependent manner.
This seizure-inducedmyelination in turn reinforces
the same seizure pattern
and makes it easier forthe brain to have seizures.
We termed this phenomenon ofseizure-induced myelination
that reinforces seizuresmaladaptive myelination
(13:19):
to contrast it from theadaptive myelination
that was described byMichelle's group earlier
in which patterns of activity
that underlie learning induce myelination
that helps retune thenetwork to that same pattern
of sort of helpful activity.
- That's really exciting,
thinking about epilepsy notjust as a disorder of neurons
(13:40):
but as a condition influencedby this broader ecosystem
of neuron glial interactions.
It opens up so many newpossibilities for intervention,
especially if we can targetthese supporting cells
to disrupt the cycle of seizure.
- You hit the nail on the head.
These glial supporting cells,
(14:01):
like oligodendroglialcells and astrocytes,
are a part of this complexecosystem in the brain
and they play a underappreciated role
in sculpting brain network activity.
That is a new frontier
that we're just beginning to understand,
to understand the role ofneuron glial interactions
in health and diseases like epilepsy.
(14:22):
- That brings me to your 2022 study
on generalized epilepsy progression.
In that study, youdiscussed how myelin changes
may worsen seizures.
What does this mean fordeveloping treatments
that address both seizuresand their underlying causes?
- That is an open question thatmy independent research lab
(14:43):
started about threeyears ago is working on.
One lead that we stumbled on
in the course of our earlier work
is that we wanted topharmacologically block
myelin plasticity during the seizures
in complementary studiesto the genetic blockade
that I told you about a few minutes ago.
When the same mice
that have the progressivegeneralized seizures,
(15:04):
we treated them with a drug
that is a histone deacetylase inhibitor.
This drug prevents epigenetic changes
that are required foroligodendroglial cells to mature
so that they can form myelin sheath.
The type of HDAC inhibitor that we used
for our study in mice is not a drug
that we could likely use in children
because of its toxicity profile,
(15:25):
but there are otherFDA-approved HDAC inhibitors,
including one called phenylbutyrate
that's already being studiedfor children with epilepsy.
That's one interesting lead.
But we still have a lot more work to do
to understand the molecularand cellular mechanisms
that are going on inneurons and oligodendroglia
during this process ofmaladaptive myelination.
(15:46):
That's something thatmy lab is working on now
is identifying those specific pathways
that get activated in oligodendroglia
during maladaptive myelination.
And a key aspect of this work
is trying to identify mechanisms
that are relatively specific
to maladaptive myelination in seizures
compared to adaptivemyelination during learning.
(16:07):
Because we're talkingabout treating children,
we don't wanna give a drug
that would impair healthy plasticity
that's needed for learning.
- That's such a critical balance,
finding ways to disruptmaladaptive myelination
without interfering withthe healthy plasticity
that's essential forlearning and development.
It's really exciting that your work
is not just identifyingpotential drug targets
(16:30):
but also thinking abouthow to refine treatments
so that they can be botheffective and safe for children.
That also makes me wonderabout myelin plasticity
more broadly though,especially how it might change
across different age groups.
How does myelin plasticitydiffer in children
compared to adults?
And why is this difference important
(16:52):
for understanding pediatric epilepsy?
- Animal studies have shown us
that the brain has this capacity
for neuron activity-regulatedmyelin plasticity
well after the initialdevelopmental myelination
of the brain is complete.
However, that capacity doesdecline with older age.
The capacity for myelinplasticity peaks when we're young.
(17:14):
What that means for us whenwe think about children
with seizures and epilepsy
is that their brains are susceptible
to heightened plasticity that may result
from either healthy adaptivepatterns of neuronal activity
or maladaptive patterns ofneural activity like seizures.
- That is a compelling insight
since myelin plasticity isat its peak in childhood,
(17:37):
both healthy and maladaptivepatterns of brain activity
can have an outsized impact,
and it really underscoreswhat you mentioned earlier
that early intervention is so important
not just to stop seizures,but to potentially reshape
how these neuronalnetworks develop over time.
With that in mind, your work suggests
that myelin plasticity couldbe a novel therapeutic target.
(18:01):
What potential treatments ortherapies are on the horizon
based on your findings?
- I mentioned the HDAC inhibitor
that's being studiedin kids phenylbutyrate,
that's still in clinical trials.
My lab is actively investigatingtargeting specific pathways
that we know get activatedduring maladaptive myelination.
We don't as yet have a specific compound
(18:23):
that we're ready to sendto a clinical trial yet,
but I think that will come eventually.
One really exciting direction
for pediatric epilepsycare is neuromodulation.
This is a category of treatments
that includes vagus nerve stimulation
where peripheral repeatedlyprovides stimulation
to the vagus nerve that thentransmits that information
(18:44):
to the brainstem and thenthe rest of the brain.
Other forms of neurostimulation
include deep brainstimulators that are implanted
in the deep nuclei of the brain
and that are very interconnected
with other parts of the brain,
as well as more focal stimulators
such as responsive neural stimulators.
An open question is whetherthese types of treatments
(19:04):
that introduce new patternsof neuronal activity
into the brain can reversemaladaptive myelination
that has already occurred.
- Since these approachesare already being explored
in clinical trials, howclose are these therapies,
both neuromodulation andpharmacological interventions,
to actual deployment in practice?
- In the case of phenylbutyrate,
(19:25):
we're already in clinical trials.
In the case of theneuromodulation techniques
that I mentioned, VNSis already widely used
in children with refractory epilepsy.
DBS and RNS, the two other approaches,
are approved relativelyrecently for use in adults
and beginning to be used in children.
This is an exciting time to understand
(19:47):
how to optimize those approaches
to help kids with refractoryforms of epilepsy.
In terms of the other directions,
we're still in the reallybasic preclinical stages
of understanding mechanismsand how to target them.
That's a bit further out,but we're persistent.
- It's encouraging to hearthat some of these approaches
are already making a difference
in children with refractory epilepsy
(20:09):
and that the others like DBS and RNS
are starting to bridge the gapfrom adult to pediatric care.
As you mentioned, even though
some of the molecular targeted therapies
are still in the early stages,
it sounds like the progress in this field
is really promising.
That brings me to a questionabout the connection
between research and patient care.
How do you integrate thefindings from your research
(20:32):
into your everyday experiencesin the clinic with patients?
- I'm fortunate in thatmy work as a clinician
is really synergistic withwhat we do in the lab.
Working with kids thatare affected by epilepsy
and their families is the inspiration
for the hard work that we do in the lab.
It's my why.
It keeps me going in the labno matter what hurdles we face.
(20:53):
There is a lot of overlapin what we do in the lab
and what I do in the clinic.
My lab has two main focus areas.
We're interested, firstof all, in understanding
what leads to and what perpetuatessevere forms of epilepsy.
One example of that is themaladaptive myelination mechanism
that we discovered.
Then the other focus area
is that we study differentforms of genetic epilepsy
(21:15):
with a specific goal ofdeveloping precision treatments
that address the geneticcause of the epilepsy.
This work is intertwinedwith what we do in clinic.
I spend a good deal of my time
working in our genetic epilepsy clinic
where pediatric epileptologists like me
work alongside a genetic counselor
and a neurogenomics specialist
to identify genetic causes for epilepsy.
(21:37):
And genetic diagnosis canreally be a game changer.
It can open up new opportunities
for a child and theirfamily, like the opportunity
to try a precision therapyif one is available
or participate in a clinical trial.
It can help us to connect thefamily with support systems.
Sometimes there are foundations
for specific genetic disorders.
(21:59):
And it can also mark the end
of what we call the diagnostic odyssey
where we're doing lots of testing
to try to understand what'scausing the epilepsy.
It can also help us predict the future
and help the family plan
for what lies ahead for their child.
- I loved hearing about the synergy
between your research and clinical work.
Your unique perspective as botha scientist and a clinician
(22:22):
allows you to play such an important role
in advancing epilepsy research and care,
and it's truly inspiring to see
how your work not only helpsuncover mechanisms in the lab,
but also provides real solutions
for families navigating epilepsy.
Looking ahead, with allthe advances happening
in epilepsy research,
what are the most exciting breakthroughs
(22:43):
that you foresee in pediatric epilepsy
over the next 5 to 10 years?
- We're in a new genomic era of epilepsy.
We're increasingly ableto obtain genetic testing
and to identify a change in a single gene
as a cause of epilepsy.
The diagnosis of a specificgenetic cause for the epilepsy
(23:03):
opens up new lines of investigation
as to whether we can treat that epilepsy
with a precision therapy
that targets the underlyingroot genetic cause.
Some of the existing precision therapies
for these genetic forms of epilepsy
include already FDA-approved drugs
or gene-based approaches likeantisense oligonucleotides
(23:25):
or gene therapy.
These are precision therapies,
and some of them may turn out to be cures.
We are in a period of revolution.
Many of these precision treatments
are still in preclinical stages
or just beginning to betested in clinical trials.
We're just at the beginning of this,
but it's a really exciting time
to be practicing pediatric epilepsy.
- It truly sounds likewe are at the forefront
(23:47):
of a major shift in epilepsy care.
The idea that we're movingbeyond just managing seizures
to potentially curingcertain forms of epilepsy
through precision therapiesis groundbreaking.
And even though many of these treatments
are still in early stages,
the fact that we are in a genomic era
where targeting the root genetic cause
(24:09):
is becoming a real possibility
is incredibly exciting to hear.
I know we could keep thisconversation going for a long time
because there's so much more to explore,
but what really stands outto me from our discussion
is a complexity and diversity of epilepsy,
especially in children,
and how research in myelinplasticity is opening up
(24:30):
entirely new avenues for treatment.
I've also been so inspired
by how your work isn'tjust pushing the boundaries
of scientific discovery,
but also shaping the futureof how we care for patients.
The breakthroughs thatyou mentioned happening
in pediatric epilepsy giveus so much to anticipate,
and I really appreciateyou sharing your expertise
(24:50):
and your insights with us today.
Thank you for helping us understand
not just where the field isnow, but where it's headed
and what it means forpatients and families.
- Thank you, Ruth. It wasa pleasure to talk to you.
- This episode was broughtto you by Stanford CME.
To claim CME forlistening to this episode,
click on the Claim CME link below
(25:11):
or visit medcast.stanford.edu.
Check back for new episodes
by subscribing to "Stanford Medcast"
wherever you listen to podcasts.
(gentle music)
(upbeat music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify, or YouTube
(00:22):
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adewuya.
In this episode, I will bechatting with Dr. Juliet Knowles.
Dr. Knowles is an assistantprofessor of neurology
and neurological sciencesand of pediatrics
at Stanford University.
She is a physician-scientist
specializing in pediatric epilepsy,
(00:42):
providing clinical careand leading a research team
focused on basic, translational,and clinical research.
Dr. Knowles completed herMD and PhD in neurosciences
at Stanford University,followed by a residency training
in pediatrics and childneurology at Stanford
where she also served as chief resident.
She further pursued a clinical fellowship
(01:02):
in pediatric epilepsyand postdoctoral research
on myelin plasticity and epilepsy
under the mentorship ofdoctors Michelle Monje
and John Huguenard.
Dr. Knowles has received several honors,
including the Stroup Awardfor Rising Star in Epilepsy
from Johns Hopkins University in 2021
and the Elterman Research Award
(01:24):
from the Pediatric EpilepsyResearch Foundation in 2020.
She serves on theScientific Program Committee
of the American Epilepsy Society
and the Research Committee ofthe Child Neurology Society.
Thank you so much forbeing here with me today.
- Thank you so much for having me, Ruth.
It's a real privilege to be here.
- I'm really excited to havethis conversation with you
about epilepsy, especiallypediatric epilepsy.
(01:47):
It's a topic that sparksa lot of discussion
and it's a privilege to hearfrom an expert like you.
When most people think of epilepsy,
they often picture dramatic seizures
with uncontrollable muscle contractions.
While that is one form,
epilepsy is actually a broad condition
with many different types ofseizures and presentations.
(02:08):
Can you start by defining whatepilepsy and seizures are?
And then could you expand onthe different types of seizures
and walk us through the key criteria
for diagnosing epilepsy?
- It's helpful to firststart with some definitions
and to distinguish betweenseizures and epilepsy.
Seizures are transient events.
(02:29):
In general, seizures are defined
in terms of their brainactivity component,
which we can visualize with an EEG,
and this involves abnormally synchronous
or excessive activity.
Then there's also the outwardmanifestation of the seizures,
what we call the seizure semiology.
And as you had mentioned,
this can involve tonic-clonic shaking
(02:51):
of all four extremities,a dramatic presentation
which we would call ageneralized tonic-clonic seizure.
But there can be much moresubtle seizure semiology,
such as the brief behavioral arrest
that occurs in absence seizures.
We conceptualize seizuresin two basic categories:
focal and generalized.
Focal seizures are thosethat begin in one region
(03:12):
and one hemisphere of the brain,
whereas generalized seizuresare those that begin
in both sides of the brain at once.
These two types of seizureshave different causes
and they also have different treatments.
Just as there are twodifferent seizure types,
there are different epilepsy types.
But first, let's define what is epilepsy.
What the diagnosis of epilepsy means
(03:33):
is that the person's brainhas an enduring predisposition
or tendency to have unprovokedseizures if left untreated.
And the diagnosis can be made
under a few different conditions.
One, if someone hastwo unprovoked seizures
generally 24 hours or more apart,
then that is oftenconsidered to be sufficient
(03:54):
for the diagnosis of epilepsy.
Or the person might have a single seizure
with a greater than 60%of having another seizure.
In many cases, thatwould also be sufficient.
Finally, there are epilepsy syndromes
where recurrent seizures go together
with certain patternsof activity on the EEG
and at certain ages.
When we see those factors co-occur,
(04:16):
that is also sufficient tomake the diagnosis of epilepsy.
The type of epilepsy thatsomeone has is determined
by the type of seizures that they have.
For example, there are focal epilepsies
which involve focal seizures only,
generalized epilepsies
that involve generalized seizures only,
and mixed forms of epilepsy
involving a mix of generalizedand focal seizures.
(04:37):
In some cases, the diagnosisof epilepsy is made,
but we don't know wherethe seizures begin,
so we just say onset unknown.
- That's a really helpful distinction
between seizures and epilepsy,
especially in terms of understanding
the brain activity component
versus the outward manifestations.
The way you broke down focalversus generalized seizures
(04:58):
and how they not only present differently
but also have differentcauses and treatments
really underscores the complexity
of epilepsy as a condition.
I appreciated your commentthat an epilepsy diagnosis
isn't just about the number of seizures,
but also factors like risk,prediction, and EEG patterns
that can point to specificepilepsy syndromes.
(05:21):
Given that complexity, I imagineearly detection is crucial.
That brings me to imaging.
Are there any earlywarning signs in imaging
that could allow clinicians to intervene
before seizures worsen?
- Brain MRI and EEG are standard tools
in the diagnostic investigationof seizures and epilepsy.
(05:43):
They play an important partboth in diagnosing the epilepsy
and its cause and guiding treatment.
It's particularly importantto get a brain MRI
when the epilepsy involves focal seizures.
That suggests that there maybe a focal structural area
of abnormality that's causingthe epilepsy to occur.
When we obtain the brain MRI,
we sometimes do findactionable structural changes
(06:05):
that would influence our approachto treating the epilepsy.
Some examples that wouldimmediately influence our treatment
might include multiplebenign hematomas in the brain
that occur in a conditioncalled tuberous sclerosis
that might influence thetype of epilepsy treatment,
including medications that we give.
Sometimes seizures can comefrom a focal cortical dysplasia,
(06:27):
which is just a small, limited area
of disrupted development, butthat can lead to rapid onset
and severe forms of epilepsy.
A common finding is hippocampal sclerosis
in the case of temporal lobe epilepsy,
which is the most common type of epilepsy.
These findings might influence our choice
of medication for the seizures
or they might encourageus to consider surgery
(06:50):
earlier in the course of treatment.
- I think that's really compelling,
especially how imagingdoesn't just confirm
an epilepsy diagnosis
but can actually shape treatmentstrategies from the start.
It makes me think aboutthe importance of timing
in epilepsy care.
If an MRI reveals a structuralabnormality early enough,
(07:11):
it could open the door formore targeted interventions
before seizures becomemore difficult to manage.
And I think that question oftiming is even more critical
when we look at neonatal epilepsy.
What challenges do neonatalepilepsies present,
and how do they differ from epilepsy
that develops later in childhood?
(07:33):
- Neonatal seizures andepilepsy often occur
in the setting of acute significant issues
that arise in the perinatal period.
Those things need to beaddressed immediately.
Some examples include
perinatal hypoxic-ischemic encephalopathy,
the condition resultingfrom lack of adequate oxygen
during the perinatal period.
(07:55):
Brain hemorrhages or ischemicstrokes can occur in infants.
Sepsis, meningitis, encephalitis,so infectious causes.
Then genetic metabolicetiologies tend to present
in the neonatal period.
So, many types of geneticepilepsy as well tend to manifest
during this time of life.
This list of causes requiresus to take action immediately
(08:18):
to address those problems.
So you're right, when aneonate has a seizure,
it's an emergency and weaggressively investigate that
with EEG and MRI.
- You've highlighted how neonatal seizures
often stem from acute medical events
that require immediate attention.
With that in mind, how do thecauses, diagnostic approaches,
(08:38):
and treatment strategies differ
when managing epilepsy in neonates
versus epilepsy thatdevelops later in childhood?
- The same categoriesstill apply in childhood,
sort of structural changes in the brain,
including acquired structuralchanges like brain injuries
or congenital malformations of the brain
as well as infection, but thelikelihood of causes shifts
(09:02):
as you think about older children.
For example, some epilepsy syndromes,
such as childhood absence epilepsy,
which is something thatwe study in my lab,
tends to present in middle childhood
between ages four and eight.
We think about thesecauses a bit differently
in older children.
- The challenges of neonatalepilepsy really highlight
(09:22):
the need to understandthe broader mechanisms
driving epilepsy progression.
As you mentioned,
while the underlying causesmight shift with age,
there's still a continuum of factors
influencing how epilepsydevelops over time.
One area that plays a key role
in that progression is myelination.
Your research specifically explores
(09:44):
how maladaptive myelinationcontributes to epilepsy.
Could you explain whatmaladaptive myelination is
and why it plays such acritical role in epilepsy?
- It's important to provide some context
for the work that we didon maladaptive myelination.
This work began when I was a resident
(10:04):
in neurology here at Stanford.
Around that time, thelab of Michelle Monje
published a really important study
in which they used atool called optogenetics
to demonstrate that recurrentpatterns of neuronal activity
in the brain can influencestructural changes in myelin
in the same circuits
that are having this recurrent activity.
(10:26):
This was a paradigm shift
because prior to that ourunderstanding of brain myelination
is that it occurs early inlife as our brains are forming.
And in a stereotyped progression,
we understood thatmyelin was fixed or inert
as the brain adapted.
What the study from Dr.Monje's lab demonstrated
was that this is not the case.
(10:48):
Actually, even after this process
of developmental myelination is complete,
recurrent patterns of neuronal activity
can, in fact, alter myelin structure
in a circuit-specific manner.
Moreover, those myelinchanges subsequently influence
the activity of that brain circuit.
It's a form of brainplasticity and adaptation
(11:11):
analogous to synaptic plasticity.
Where did my work come in?
I remember learning about this discovery,
which they called adaptive myelination.
At that time, I was thinkinga lot about pediatric epilepsy
as I took care of children with seizures
that had these recurrentpatterns of unhealthy behavior
in the form of seizures.
This prompted me to wonder
(11:32):
whether recurrent patternsof unhelpful brain activity
could also influence myelin structure.
If that were the case,
what impact might thatunhealthy myelin plasticity have
on the brain subsequently?
To study that question, Idid a postdoctoral fellowship
with Michelle and Dr. John Huguenard,
(11:52):
who is an epilepsy researcherand expert here at Stanford.
We looked in mouse and ratmodels of generalized epilepsy,
and what we found
is that seizures inducedmyelin structural change.
We found thicker myelin sheaths
and increased numbers of myelinated axons
in the seizure network of these animals.
(12:14):
We then did further experiments
where we genetically engineered mice
so that we could block myelin plasticity
during this period of seizures.
What we found is thatmice that have seizures
and normal myelin plasticityhave a progressive course
where the seizures become moreand more frequent over time,
and this is reminiscent of children
(12:35):
with severe forms of epilepsy,
especially generalized epilepsy
that have this progressive course.
By contrast, in the same type of mouse
when we blocked theactivity-dependent myelination
during the period of seizure progression,
we found that theseizures did not progress
to nearly the same degree.
They persisted at a very low level.
What this information indicated to us
(12:57):
is that seizures are infact inducing myelination
in an activity-dependent manner.
This seizure-inducedmyelination in turn reinforces
the same seizure pattern
and makes it easier forthe brain to have seizures.
We termed this phenomenon ofseizure-induced myelination
that reinforces seizuresmaladaptive myelination
(13:19):
to contrast it from theadaptive myelination
that was described byMichelle's group earlier
in which patterns of activity
that underlie learning induce myelination
that helps retune thenetwork to that same pattern
of sort of helpful activity.
- That's really exciting,
thinking about epilepsy notjust as a disorder of neurons
(13:40):
but as a condition influencedby this broader ecosystem
of neuron glial interactions.
It opens up so many newpossibilities for intervention,
especially if we can targetthese supporting cells
to disrupt the cycle of seizure.
- You hit the nail on the head.
These glial supporting cells,
(14:01):
like oligodendroglialcells and astrocytes,
are a part of this complexecosystem in the brain
and they play a underappreciated role
in sculpting brain network activity.
That is a new frontier
that we're just beginning to understand,
to understand the role ofneuron glial interactions
in health and diseases like epilepsy.
(14:22):
- That brings me to your 2022 study
on generalized epilepsy progression.
In that study, youdiscussed how myelin changes
may worsen seizures.
What does this mean fordeveloping treatments
that address both seizuresand their underlying causes?
- That is an open question thatmy independent research lab
(14:43):
started about threeyears ago is working on.
One lead that we stumbled on
in the course of our earlier work
is that we wanted topharmacologically block
myelin plasticity during the seizures
in complementary studiesto the genetic blockade
that I told you about a few minutes ago.
When the same mice
that have the progressivegeneralized seizures,
(15:04):
we treated them with a drug
that is a histone deacetylase inhibitor.
This drug prevents epigenetic changes
that are required foroligodendroglial cells to mature
so that they can form myelin sheath.
The type of HDAC inhibitor that we used
for our study in mice is not a drug
that we could likely use in children
because of its toxicity profile,
(15:25):
but there are otherFDA-approved HDAC inhibitors,
including one called phenylbutyrate
that's already being studiedfor children with epilepsy.
That's one interesting lead.
But we still have a lot more work to do
to understand the molecularand cellular mechanisms
that are going on inneurons and oligodendroglia
during this process ofmaladaptive myelination.
(15:46):
That's something thatmy lab is working on now
is identifying those specific pathways
that get activated in oligodendroglia
during maladaptive myelination.
And a key aspect of this work
is trying to identify mechanisms
that are relatively specific
to maladaptive myelination in seizures
compared to adaptivemyelination during learning.
(16:07):
Because we're talkingabout treating children,
we don't wanna give a drug
that would impair healthy plasticity
that's needed for learning.
- That's such a critical balance,
finding ways to disruptmaladaptive myelination
without interfering withthe healthy plasticity
that's essential forlearning and development.
It's really exciting that your work
is not just identifyingpotential drug targets
(16:30):
but also thinking abouthow to refine treatments
so that they can be botheffective and safe for children.
That also makes me wonderabout myelin plasticity
more broadly though,especially how it might change
across different age groups.
How does myelin plasticitydiffer in children
compared to adults?
And why is this difference important
(16:52):
for understanding pediatric epilepsy?
- Animal studies have shown us
that the brain has this capacity
for neuron activity-regulatedmyelin plasticity
well after the initialdevelopmental myelination
of the brain is complete.
However, that capacity doesdecline with older age.
The capacity for myelinplasticity peaks when we're young.
(17:14):
What that means for us whenwe think about children
with seizures and epilepsy
is that their brains are susceptible
to heightened plasticity that may result
from either healthy adaptivepatterns of neuronal activity
or maladaptive patterns ofneural activity like seizures.
- That is a compelling insight
since myelin plasticity isat its peak in childhood,
(17:37):
both healthy and maladaptivepatterns of brain activity
can have an outsized impact,
and it really underscoreswhat you mentioned earlier
that early intervention is so important
not just to stop seizures,but to potentially reshape
how these neuronalnetworks develop over time.
With that in mind, your work suggests
that myelin plasticity couldbe a novel therapeutic target.
(18:01):
What potential treatments ortherapies are on the horizon
based on your findings?
- I mentioned the HDAC inhibitor
that's being studiedin kids phenylbutyrate,
that's still in clinical trials.
My lab is actively investigatingtargeting specific pathways
that we know get activatedduring maladaptive myelination.
We don't as yet have a specific compound
(18:23):
that we're ready to sendto a clinical trial yet,
but I think that will come eventually.
One really exciting direction
for pediatric epilepsycare is neuromodulation.
This is a category of treatments
that includes vagus nerve stimulation
where peripheral repeatedlyprovides stimulation
to the vagus nerve that thentransmits that information
(18:44):
to the brainstem and thenthe rest of the brain.
Other forms of neurostimulation
include deep brainstimulators that are implanted
in the deep nuclei of the brain
and that are very interconnected
with other parts of the brain,
as well as more focal stimulators
such as responsive neural stimulators.
An open question is whetherthese types of treatments
(19:04):
that introduce new patternsof neuronal activity
into the brain can reversemaladaptive myelination
that has already occurred.
- Since these approachesare already being explored
in clinical trials, howclose are these therapies,
both neuromodulation andpharmacological interventions,
to actual deployment in practice?
- In the case of phenylbutyrate,
(19:25):
we're already in clinical trials.
In the case of theneuromodulation techniques
that I mentioned, VNSis already widely used
in children with refractory epilepsy.
DBS and RNS, the two other approaches,
are approved relativelyrecently for use in adults
and beginning to be used in children.
This is an exciting time to understand
(19:47):
how to optimize those approaches
to help kids with refractoryforms of epilepsy.
In terms of the other directions,
we're still in the reallybasic preclinical stages
of understanding mechanismsand how to target them.
That's a bit further out,but we're persistent.
- It's encouraging to hearthat some of these approaches
are already making a difference
in children with refractory epilepsy
(20:09):
and that the others like DBS and RNS
are starting to bridge the gapfrom adult to pediatric care.
As you mentioned, even though
some of the molecular targeted therapies
are still in the early stages,
it sounds like the progress in this field
is really promising.
That brings me to a questionabout the connection
between research and patient care.
How do you integrate thefindings from your research
(20:32):
into your everyday experiencesin the clinic with patients?
- I'm fortunate in thatmy work as a clinician
is really synergistic withwhat we do in the lab.
Working with kids thatare affected by epilepsy
and their families is the inspiration
for the hard work that we do in the lab.
It's my why.
It keeps me going in the labno matter what hurdles we face.
(20:53):
There is a lot of overlapin what we do in the lab
and what I do in the clinic.
My lab has two main focus areas.
We're interested, firstof all, in understanding
what leads to and what perpetuatessevere forms of epilepsy.
One example of that is themaladaptive myelination mechanism
that we discovered.
Then the other focus area
is that we study differentforms of genetic epilepsy
(21:15):
with a specific goal ofdeveloping precision treatments
that address the geneticcause of the epilepsy.
This work is intertwinedwith what we do in clinic.
I spend a good deal of my time
working in our genetic epilepsy clinic
where pediatric epileptologists like me
work alongside a genetic counselor
and a neurogenomics specialist
to identify genetic causes for epilepsy.
(21:37):
And genetic diagnosis canreally be a game changer.
It can open up new opportunities
for a child and theirfamily, like the opportunity
to try a precision therapyif one is available
or participate in a clinical trial.
It can help us to connect thefamily with support systems.
Sometimes there are foundations
for specific genetic disorders.
(21:59):
And it can also mark the end
of what we call the diagnostic odyssey
where we're doing lots of testing
to try to understand what'scausing the epilepsy.
It can also help us predict the future
and help the family plan
for what lies ahead for their child.
- I loved hearing about the synergy
between your research and clinical work.
Your unique perspective as botha scientist and a clinician
(22:22):
allows you to play such an important role
in advancing epilepsy research and care,
and it's truly inspiring to see
how your work not only helpsuncover mechanisms in the lab,
but also provides real solutions
for families navigating epilepsy.
Looking ahead, with allthe advances happening
in epilepsy research,
what are the most exciting breakthroughs
(22:43):
that you foresee in pediatric epilepsy
over the next 5 to 10 years?
- We're in a new genomic era of epilepsy.
We're increasingly ableto obtain genetic testing
and to identify a change in a single gene
as a cause of epilepsy.
The diagnosis of a specificgenetic cause for the epilepsy
(23:03):
opens up new lines of investigation
as to whether we can treat that epilepsy
with a precision therapy
that targets the underlyingroot genetic cause.
Some of the existing precision therapies
for these genetic forms of epilepsy
include already FDA-approved drugs
or gene-based approaches likeantisense oligonucleotides
(23:25):
or gene therapy.
These are precision therapies,
and some of them may turn out to be cures.
We are in a period of revolution.
Many of these precision treatments
are still in preclinical stages
or just beginning to betested in clinical trials.
We're just at the beginning of this,
but it's a really exciting time
to be practicing pediatric epilepsy.
- It truly sounds likewe are at the forefront
(23:47):
of a major shift in epilepsy care.
The idea that we're movingbeyond just managing seizures
to potentially curingcertain forms of epilepsy
through precision therapiesis groundbreaking.
And even though many of these treatments
are still in early stages,
the fact that we are in a genomic era
where targeting the root genetic cause
(24:09):
is becoming a real possibility
is incredibly exciting to hear.
I know we could keep thisconversation going for a long time
because there's so much more to explore,
but what really stands outto me from our discussion
is a complexity and diversity of epilepsy,
especially in children,
and how research in myelinplasticity is opening up
(24:30):
entirely new avenues for treatment.
I've also been so inspired
by how your work isn'tjust pushing the boundaries
of scientific discovery,
but also shaping the futureof how we care for patients.
The breakthroughs thatyou mentioned happening
in pediatric epilepsy giveus so much to anticipate,
and I really appreciateyou sharing your expertise
(24:50):
and your insights with us today.
Thank you for helping us understand
not just where the field isnow, but where it's headed
and what it means forpatients and families.
- Thank you, Ruth. It wasa pleasure to talk to you.
- This episode was broughtto you by Stanford CME.
To claim CME forlistening to this episode,
click on the Claim CME link below
(25:11):
or visit medcast.stanford.edu.
Check back for new episodes
by subscribing to "Stanford Medcast"
wherever you listen to podcasts.
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