Congenital Brain Anomalies: A Mechanistic Approach, Dr. Mai-Lan Ho (2-4-26)
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Today we are honored to welcome Dr.
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Mylon Ho for a lecture entitled, congenital Brain Anomalies,
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A Mechanistic Approach.
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Dr. Ho is an accomplished neuroradiology physician,
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scientist, and leader specializing in the full scope
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of advanced imaging.
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She has clinical expertise in advanced neuroimaging
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techniques and genotype, phenotype, correlation,
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and complex diseases.
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Dr. Ho also leads multiple national
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and international initiatives for data science
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and precision health, and serves on numerous society
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committees and editorial boards dedicated
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to advanced imaging and ai.
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At the end of this lecture, please join Dr.
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Ho in a q and a session
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where she will address questions you
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may have on today's topic.
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Please remember to use the q
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and a feature to submit your questions so we can get to
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as many as we can before our time is up.
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With that, we're ready to begin today's lecture. Dr.
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Ho, please take it from here.
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All right, so it's, uh, in this, uh,
1:25
hour I will be speaking about congenital brain anomalies,
1:28
a mechanistic approach.
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I think this is very important
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because, um, there are such a, a large spectrum
1:34
of potential, uh, disorders that we see at birth,
1:37
and there are so many different classifications,
1:39
and sometimes it becomes more confusing
1:41
to get into all of those details.
1:43
So I really wanted to provide a kind of biomechanical, uh,
1:47
holistic, um, integrated approach for all
1:49
of you, uh, in the next hour.
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So, today's objectives,
1:53
we will be highlighting the tic complexities
1:56
of brain development from multiple different, uh,
1:59
proposed classifications in the literature.
2:02
And then I will propose a holistic framework
2:04
that simplifies our understanding
2:06
and approach to malformation.
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So really, um, you know, more, more lumping than splitting,
2:12
but also more importantly,
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really understanding the first principles of why these occur
2:16
and why, uh, why you connect essentially the genetics
2:19
to the, um, anatomy and to the physiology.
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And we will essentially use a number of different cases
2:25
to rationalize the imaging manifestations based on these
2:28
fundamental mechanistic principles.
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All right, so now we're going to look at a variety
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of different historical
2:36
and literature classifications for, uh, congenital brain.
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So let's begin with, uh, embryology.
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And the caveat here is that many
2:44
of these classifications
2:45
are actually based on animal models.
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So zebrafish, chick mouse, right?
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They're not all direct, uh, human correlates,
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but we do know a good amount from, uh, human, uh,
2:55
fetal studies as well.
2:57
And so in terms of embryology, there are
3:00
essentially five major, uh, sequential,
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but partially overlapping, um, uh, stages in,
3:08
in, uh, brain development.
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And so we start with the dorsal induction, which is the,
3:12
the earliest, uh, in fetal life.
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And this is essentially the, um, induction
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of the neural plate and the folding up
3:18
to form the neural tube, which gives rise to the, uh,
3:21
CNS brain and spinal cord.
3:23
Next, we have ventral induction,
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and this is where you get the vesiculation, the, the primary
3:27
and secondary brain vesicles that give rise to the,
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you know, these primordial cells will essentially give rise
3:32
to the various parts of the brain and cord.
3:35
Um, and you also get the, uh, intra hemispheric,
3:38
um, cleavage at this point.
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And then the various neural
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and glial, uh, lines will, uh, differentiate
3:45
and then migrate out, uh, towards the surface of the brain.
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Uh, at the same time, you're getting some overlap
3:51
with the development of midline commissures.
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We'll look at this in more detail,
3:55
but these are essentially very selective processes
3:57
where certain groups of, uh, neuronal populations are guided
4:01
to cross the midline.
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And then toward the end of all of that, uh,
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once everything's migrated
4:07
and formed, you get increasing, uh, organization
4:10
of the cortex in the layering.
4:12
And so you can see this, uh, general pattern, um,
4:15
of development where you have sequential folding.
4:18
Um, there are a number of flexors in the brain which start
4:20
to straighten out, uh, over time and form the mature brain.
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And so you can see that this, uh, mammalian,
4:27
that cerebral cortex is, uh, extensively folded,
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but also that increasing, uh,
4:32
volume in the cranial vault four for that to straighten out.
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Um, interestingly, from an embryologic, uh, standpoint, we,
4:39
we keep that, um, we keep that cervical flexor,
4:42
the 90 degree orientation between the, the head
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and the spine, which, for example, other mammals, like,
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you know, dogs and cats and things do not have.
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So some of the, uh, evolutionary comparative, um,
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evolutionary biology does differ slightly in terms of the,
4:57
um, orientation, how we, uh,
4:59
how we term these, uh, structures.
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All right, so moving to the molecular, uh, patterning,
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there are a number
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of different things that we could talk about here.
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But at a high level, uh, you have these different, um,
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molecular, uh, spectra, basically,
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basically these are developmental, um, you know,
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the developmental concentrations that will pattern, uh,
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the brain in the anterior posterior, um, the left right,
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and the superior inferior axis.
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And you'll recognize many of these from a lot
5:30
of the craniofacial, uh, congenital genetic disorders, uh,
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as well as different, uh, tumor predisposition syndromes.
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But essentially, uh, long story short, these different, um,
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molecular concentrations will help pattern the brain
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and the x, y, z directions.
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Now, you'll also have heard the term
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that the face predicts the brain,
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or, you know, the, the brain determines the face.
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And so what happens is that the mesenchymal, uh,
5:55
condensations actually form over basically the primordial
5:59
facial structures form over the developing brain.
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And so they are actually subject to the same, um,
6:05
molecular gradients and patterning, uh,
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influences as the brain.
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And that's why when you get, uh, different features, uh,
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the hemispheres are too far apart
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or too close together, as we'll see later in this talk,
6:16
you actually get reflective kind
6:18
of facial malformations as well.
6:20
And so that can be the key to a number of genetic syndromes.
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And, uh, in terms of the, uh, glial sling,
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there's a transient kind of neuronal
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and glial population
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that actually guides certain axons to cross midline.
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So our corpus callosum, um, anterior posterior commissures
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and so forth, there are only certain select neural, uh,
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populations that are, uh, are guided to do so.
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And after that point,
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this sling essentially will undergo apoptosis and involute.
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So it basically is just a transient scaffold for, uh,
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for migration and, and evolution.
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So now let's look at the genetic, uh, underpinnings
6:58
of congenital brain, uh, anomalies.
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So, um, first we have to understand how genetics works.
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So not all genes are inherited from your parents.
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Uh, some of them are, and those are called the
7:08
germline, um, mutations.
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So basically, uh, you can inherit from your mother
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or your father, and then this, uh, affects your entire body
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and is passed down to your offspring.
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However, there are the so-called somatic
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or post zygotic mutation.
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So this is the zygote, this is the fertilized egg stage.
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If you have a mutation that's acquired
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after that stage, so you could have, you know, two cell,
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four cell, eight, 16, you know, 64, et cetera.
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So if you acquire a mutation due
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to some environmental exposure, um,
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that will essentially affect a fraction of your cell.
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So it could be half of them, like hemi hypertrophy,
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it could be a smaller number.
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So in this case, you know, the head only is affected.
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So basically you get this kind of mosaic pattern, kind
7:53
of like the tortoise shell cat, or only some of the cells.
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Basically, all of the dotter cells
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of this particular progenitor cell are affected.
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So an early somatic mutation can affect
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quite a large part of the body.
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A late somatic mutation can be a much smaller part.
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Um, and we actually accumulate these mutations throughout
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life with, uh, normal aging, you know, exposure
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to radiation, sunlight, um,
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environmental pollutants, things like that.
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And so you have a background, uh, germline genome, you know,
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in terms of those predispositions.
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And then you can acquire additional hits on top of that, uh,
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during, uh, development and during your lifespan.
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So in terms of congenital brain anomalies,
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which are present at birth, uh, there are actually a number
8:37
of known genes, and many still unknown and to be discovered,
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but you'll notice there's quite a bit of overlap.
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So it's really a very confusing picture if you look at it
8:46
this way, because, uh, really there's a lot
8:48
of common mechanisms.
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So the clinical features can be very nonspecific seizures,
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developmental delay, dysmorphism
8:55
of the, the brain in the face.
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Um, and then if you look at the kind of common
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pathways in terms of development,
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there are essentially these microtubules that will create
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a scaffold, a radio glial track of microtubules
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to guide the migration of, um, of these neurons,
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essentially from the vent, uh, ventricular margins
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to the surface, to the level of the basement membrane.
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And we'll talk more about that radio glial,
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uh, track in a bit.
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But essentially, there are all of these different molecules
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that are involved in that process,
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and really a mutation in any
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of them can create a disruption.
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Um, and both the severity, you know, the type of molecule,
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the timing of the insult, all of these things
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can create quite a bit of overlap in the resulting phenotype
9:41
or the imaging features.
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And so that's why you'll see that any given, um,
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mutation here, depending on the timing, the severity, uh,
9:48
is it complete
9:49
or partial loss of function, et cetera, et cetera.
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So there's a lot of overlap in the imaging phenotype.
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And so I'm not going to mention specific genes.
9:57
Um, in this lecture, I'm going to provide more
9:59
of a overall mechanistic approach
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because there's still so much we don't know.
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But, uh, be aware that all of those genes essentially, uh,
10:07
come back this common pathway in terms of development.
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So let's talk more about migration.
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I mentioned that radial glial track, uh, or line.
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So in terms of, um, neurodevelopment,
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there are actually a number of different, uh,
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developing neurons and glial cells,
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and it's quite complex, as you can see.
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The one I want you to focus on is actually these, uh,
10:30
radial, uh, these excitatory projection neurons.
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So these essentially will start at the level
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of the ventricular zone, the, uh, periphery of the,
10:39
the ventricle that a, that a penal, uh, level.
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And then they will migrate along that micro tubial, uh,
10:44
guided or radial glial track to the surface,
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really radially out from the ventricle.
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Uh, and then they stop at the level of the basement memory
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that signals them that they're done.
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And so, really, a lot of migrational anomalies have
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that kind of radial glial
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or trans mantle crossing the cortical mantle, uh, track.
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And that's very helpful to us.
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As you'll see in a bit, there are other, uh, types
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of neurons that have different pathways.
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So the inhibitory inter neurons will actually go more
11:10
tangential, and some of the malformations, uh, do have
11:13
that kind of, uh, architecture.
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And then there are multipolar, so, uh,
11:18
pathfinding neurons that do both.
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They can kind of go in between radial and tangential
11:21
and do what they want that are really trying to guide,
11:24
you know, these complex sets of fibers.
11:26
So it's really much more complex than,
11:28
than even this diagram.
11:30
But the major take home point is
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that these projection neurons have that radial glial line.
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And, and that is helpful to us when we're looking at
11:36
migrational abnormalities.
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Now myelination, so anyone who does, uh,
11:41
pediatric neuro needs to know about myelination.
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So at birth, uh, there's very little, uh, myelin on board.
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Uh, myelin is basically the fatty protein tenacious coating,
11:50
um, of axons, which enables that saltatory
11:52
or skip conduction.
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And so it creates a lot more efficiency, um,
11:56
in the CNS and even the PNS.
11:58
So myelination begins in the fifth month of fetal life,
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and it starts with the eloquent tract.
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So essentially the spinal cord, um, the cerebellum, a lot
12:07
of those tracts are, uh, ated by the time of birth.
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Um, and generally speaking,
12:11
things go from central to peripheral.
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So your corticospinal tracts,
12:15
which are T one bright T two dark, you can see here, um,
12:18
are gonna be myelinated at birth,
12:20
but then everything else starts to myelinate over time.
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And so the neonatal brain is very water.
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You see that as the inverse pattern of the adult.
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So it's not till, um, one year on t one weighted imaging,
12:34
uh, two years at TT weighted imaging on average
12:36
that you start to see the adult, uh, contrast in terms
12:39
of gray white matter.
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So in the middle, you have this transition
12:43
that happens on T one and T two, um,
12:45
and even more delayed on flare,
12:47
which is why we don't recommend doing a,
12:50
a fluid attenuated inversion recovery on
12:52
children less than two, three years of age,
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or sometimes even more delayed if they have, for example,
12:57
early onset seizures or, um, or other, uh, delays.
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So that's essentially the process of myelination.
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The reason it matters for congenital brain anomalies is
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that some of these gray white distinctions, uh,
13:10
that are often important for, uh,
13:12
for making the diagnosis are less apparent
13:15
when you have immature myelination
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or this kind of in-between developing myelin.
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And so you need to scrutinize these areas more,
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and also design imaging protocols that help
13:26
optimize your ability to identify these things.
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And if, interestingly,
13:30
a myelination progresses into adulthood.
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So it's been shown that the oligo dendro, uh,
13:35
site presented our cells are actually present, um, into, um,
13:39
are they're actually present throughout, throughout life
13:41
and, uh, remodel and,
13:42
and help with plasticity even in adults.
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So we are still progressively myelinating something into our
13:47
fourth decade with the association fibers.
13:50
Um, and after that point, it's more
13:51
of a maintenance than necessarily a progression,
13:54
but there is that potential.
13:57
All right, so let's talk about timing.
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So more than anything else, uh,
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the timing is really critical in terms
14:03
of the congenital brain,
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because I mentioned all of these developmental processes,
14:07
they are sequential, but there is some degree
14:09
of overlap as well.
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And so interruption at a a given stage will essentially
14:15
arrest, you know, or injure those migrating neurons
14:18
and glial cells, and you actually can mark,
14:20
based on the malformation, what timing, um, that, uh,
14:25
the fetus was at at that point.
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And even after birth, there is additional development
14:29
that happens, although much of that is more the myelination,
14:32
uh, the cortical organization, the cerebellar development.
14:35
So, um, whether it be genetic, um, you know,
14:40
genetic programming, uh, ischemia, infection, trauma, right?
14:44
Uh, it's really more the timing than the etiology that
14:47
that leads you to the mechanism and the imaging phenotype.
14:53
So we really looked at phenotypes, right?
14:55
Whether they be these various, uh,
14:57
imaging anatomic diagnoses
14:59
or these, uh, genetic syndromes, you can actually map these
15:02
to different stages in the, uh, fetal
15:05
and postnatal development.
15:07
But many of them are quite complex
15:08
and involve multiple stages.
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So there's a broad window of, of potential action.
15:13
It may depend on the mutation as well.
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And so it can get very confusing
15:18
when you look at it this way.
15:19
And so I don't want to split, you know, to this extent.
15:22
So it is very complex, this is true,
15:25
but we're here to actually learn how
15:26
to approach this in a simplified manner.
15:29
And so this is my holistic approach to,
15:32
to really understanding these, um, malformations.
15:34
So there's really three possibilities.
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Did the brain form correctly at all, you know,
15:40
or was it actually programmed incorrectly in the sense
15:42
that it never did form correctly from the beginning,
15:46
next possibility, was it forming correctly
15:48
to a certain point in development,
15:50
but then something happened?
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So an acquired insult, you know,
15:53
infection, trauma, whatever.
15:54
And so at that point, you know, freezing in time,
15:57
you're saying, okay, this is where the brain was,
15:59
and now we see an insult on that background
16:03
or migration.
16:04
So if you see things on that trans mantle,
16:07
that radial glial line,
16:08
and you see a pattern of abnormalities in
16:10
that track from the ventricle to the cortical surface,
16:13
then we can classify those as migrational abnormalities.
16:15
And so there's a subset of those that are very,
16:18
very characteristic imaging wise.
16:20
All right, so let's, uh, start with the formation.
16:23
Abnormalities of formation.
16:25
So in every child,
16:26
and honestly, adult, it's very important
16:28
to look at the midline sagittal, uh, T one image, right?
16:31
To see whether everything's actually there.
16:33
It turns out that the cobras callosum is only present in
16:36
placental mammals, so you don't have it in, let's say,
16:39
platypus or kangaroo.
16:40
They actually use their anterior commissure
16:42
as their main midline commissure.
16:44
So this one really enables a lot of the, uh,
16:46
int hemisphere communications,
16:48
a lot of the higher functions.
16:49
It starts out, um, at birth, very kind of thin, um, and thin
16:54
and elongated, and then it starts to mature
16:56
and thicken along with myelination.
16:58
And so this, um, the splenium is called the,
17:01
uh, forceps major.
17:03
It should actually have larger volume
17:05
and more traversing fibers than the forceps
17:07
minor meaning the genu.
17:09
And so if you're not seeing, you know, uh,
17:12
a very robust splenium, you have
17:14
to worry about colossal underdevelopment or fibrogenesis.
17:17
So while you're on this midline image, right,
17:19
you can also see the anterior and posterior commissures.
17:23
The, the bottom of the splenium actually blends in
17:25
with what's called the hippocampal commissure.
17:27
So, uh, you can't see it without doing a DTI,
17:29
you can't tell them apart.
17:31
But what can be helpful is to actually look at the coronal.
17:34
So the corpus callosum fibers, right?
17:35
The splenium will ate and,
17:38
and essentially connect the hemisphere.
17:40
So they're gonna wrap up,
17:41
whereas the hippocampal commissure is gonna wrap down
17:43
and connect to the hippocampal tail.
17:45
So basically in the middle is the,
17:47
is the, uh, transition point.
17:48
So sometimes with gliomas
17:50
and things, people will kind
17:51
of call plein when it's really hippocampal commissure.
17:53
And it's important because the way
17:55
that these things track right will,
17:56
will change depending on whether you're tracking up or down.
17:59
And then the A CPC line is what we define
18:02
for neuro navigation, is the true axial
18:04
for neurosurgical operations.
18:07
All right, so collosal dysgenesis, uh,
18:09
I mentioned the glial sling.
18:11
So you have these transient populations
18:12
that guide selective midline crossing.
18:16
And so there's a whole spectrum from complete agenesis to,
18:19
you know, partial fibrogenesis.
18:21
And so here you don't have a formed spleen
18:24
or hippocampal commissure, right?
18:26
And so there's this kind of classic posterior tapering.
18:28
There's also some blunting here where the rostrum should be.
18:32
And again, um, the, this is basically an incomplete, um,
18:36
corpus callosum, but mammalians have big four brains.
18:39
So you have more of this volume, you know, um, anteriorly.
18:42
But the fact that the splenium,
18:43
the forceps major is not present,
18:45
that should really have the largest volume in a fully
18:48
developed callosum.
18:50
You can also have short stuy ones or thin elongated ones.
18:53
Essentially the, uh, glial sling starts in the midline,
18:56
and then it kind of grows anteriorly and posteriorly.
18:58
So as the callosum develops completely, right,
19:01
it should actually realize that, uh, formation
19:04
of the four subs major and minor.
19:06
But until that eight, eight
19:07
or nine months of age, it may be difficult
19:08
to actually tell whether a lot of
19:10
that is, uh, fully developed.
19:12
But you can kind of guess by looking at h
19:14
matched, uh, controls.
19:16
Um, most of the time this is a continuous process.
19:18
So you do have just the, um, whatever malformation you have,
19:22
the callosum is still contiguous,
19:23
but there are, uh, kind of collosal congenital colossal dis,
19:27
uh, disconnection or the so-called, um, segmental, um,
19:30
agenesis of the callosum
19:32
where the intermediate zone is missing.
19:33
And essentially it's a defect of the glial sling.
19:35
It's quite rare, but you might actually have anterior
19:37
posterior segment and not, and missing the middle segment.
19:40
Again, that's that anomaly
19:41
of the guidance across the midline.
19:44
So let's start with
19:46
that biomechanical reasoning I was alluding to.
19:48
So, um, there are a lot of things
19:50
that you'll see in association with, uh, colossal, um,
19:53
agenesis fibrogenesis.
19:54
So it turns out that the hippocampus, um,
19:57
the hippocampal formation start out very kind of squared off
20:00
and globular, and the super tentorial folding actually
20:04
induces additional rotation over fetal life
20:07
and compression of the hippocampus
20:09
to form this nice seahorse morphology.
20:12
And so when this doesn't happen, right,
20:13
you don't have a umab here, then the cingulate gy don't, uh,
20:17
you don't have inversion to create cingulate soci,
20:20
the cingulate gyri stay averted.
20:22
You have this kind of steer horn appearance
20:23
of the frontal horns, and you get these persistently
20:26
globular, um, uncompressed hippo campi
20:29
with the dilated keyhole temporal horns.
20:31
So this is all expected for, uh,
20:33
colossal fibrogenesis spectrum, um, the colpocephaly
20:37
and the kind of steer horn frontal horn.
20:39
So I, I always wondered, you know, when I was in training,
20:42
why this is, and it's, it's actually very straightforward.
20:44
So, um, normally you have the callosum connecting
20:47
across the midline, right?
20:48
And you have the kind of these homopathic connections,
20:51
but in agenesis you have these probes, bundles,
20:54
you don't have any crossing over midline.
20:56
So the probes, bundles basically run, um,
20:58
on each side paramedian.
21:01
Um, and then you are supposed to have, essentially
21:04
what crosses over midline should be, uh,
21:06
the sagittal stratum.
21:07
So basically the, uh, the optic tracts should be back here.
21:11
And so that should kind of pack the, uh, atria
21:13
and occipital horns in nicely.
21:15
But because they aren't there, right in collosal agenesis,
21:18
essentially, uh, you have nothing to keep in the atria
21:22
and occipital horns, so they basically bulge in the back.
21:24
So then you ask, well, why is the front, you know,
21:26
why is the front still packed in?
21:27
Well, basically you've got the probes, bundles, medially,
21:30
and then you've got the basal ganglia laterally.
21:32
So everything in the front is still packed in
21:34
pretty well and parallel.
21:36
Um, and then in the back you get this bulging.
21:37
And so that kind of teardrop appearance, uh,
21:40
is very characteristic for cosal pathogenisis.
21:43
And a lot of, um, um, inexperienced centers,
21:45
people will say, oh, there's ventricular magaly.
21:47
We need to shunt this, and I would
21:49
highly recommend against that.
21:51
Um, this is, you know, treat the patient not the image.
21:54
And so this is how these patients are going to look.
21:56
If you shunt them, you may actually, uh,
21:58
create subdural hematomas that ossify
22:01
and armor the brain, basically keep it from growing,
22:03
so you don't wanna do things like that.
22:05
So essentially, this is just what's expected
22:07
for a colossal pathogenisis.
22:09
I mean, you can have other things as well.
22:11
You can have interhemispheric cyst.
22:12
So basically things don't happen well in the midline.
22:14
And so you can have arachnoid, you know, epidermoid,
22:16
neuro enteric type cysts.
22:18
The side of the cyst usually has more malformations
22:20
and has, you know, more, uh, severe deficits.
22:23
You can also have these, uh, anomalous connections
22:25
that the so-called sigmoid bundle.
22:27
Um, so rather than going from frontal to frontal
22:30
or occipital occipital,
22:31
you can actually get one frontal lobe connected into the
22:34
contralateral occipital or parietal lobe.
22:36
And so that's actually quite important in
22:38
terms of surgical planning.
22:40
For example, if there's a, I had a case
22:42
where there was an epilepsy focus,
22:43
and then later, many years later, the patient presented with
22:46
what seemed like seizure activity coming from the other
22:49
side in the occipital lobe.
22:50
And it was really just the encephalomalacia from
22:52
that original surgery kind
22:53
of transmitting across the sigmoid bundle.
22:55
So important to be aware that, that these exist.
23:00
Okay, so let's move on to forebrain malformation.
23:02
So we have a septal optic dysplasia,
23:04
and this is kind of a wastebasket term, honestly,
23:07
so it's also known as optic nerve hypoplasia spectrum,
23:10
but it's a, a variety of genetic
23:12
and sporadic anomalies
23:13
that can affect basically anything in the forebrain.
23:16
So, um, this includes the optic nerves,
23:19
but even the olfactory, you know, so the kelman syndrome
23:21
of olfactory hypoplasia, uh, small optic nerves, um,
23:26
the callosum, not just the, um, septum, right?
23:30
The septum fallin, which we don't care about
23:32
isolated septum abnormalities.
23:33
It's really the fact that the callosum is also hypo genetic
23:36
with these lowline fores, um, pituitary gland abnormalities.
23:40
So ectopic, hypoplastic, pituitary,
23:43
um, anything in the midline.
23:45
And then they can have additional abnormalities
23:47
as well in terms of white matter hypoplasia cortical
23:50
malformations, which is called septal optic dysplasia plus.
23:53
So the classic dier triad, the optic nerve stuff,
23:57
the pituitary, and then the callosum
23:59
slash midline abnormalities.
24:00
You'll notice that only one of that triad is
24:03
actually an imaging diagnosis.
24:04
The other two, optic
24:06
and pituitary, you may, if it's, if it's marked,
24:09
you may see an abnormality on MRI,
24:11
but it's really ophthalmology exam
24:13
and endocrinologic testing that are more definitive.
24:17
And so this is not really, you know, as radiologists,
24:20
we should just describe what we see
24:22
and if we see something additional.
24:23
Now, it's not just a triad, it's, it's really four things.
24:26
And so the, the spectrum is so broad
24:29
that it's much more relevant, uh, to the clinician
24:32
to actually describe, um, these different features
24:35
because the spectrum is just, you know, really very varied
24:39
and very heterogeneous.
24:41
So also in the four brainin spectrum, right?
24:43
So holo cephalic is actually, basically,
24:46
SOD is like a form first of holo PRIs cephalic.
24:49
And so these are abnormalities, again, they can be genetic
24:52
or sporadic, but they involve the ventral floor pre, uh,
24:55
which gives rise to a lot of the four brainin structures.
24:58
And so, uh, you can have, you know, from most
25:00
to least severe a lobar, right?
25:02
So you don't have any lobe at all.
25:03
You just have fusion of the
25:05
frontal lobes across the midline.
25:06
It's kind of pancake brain
25:07
with the mono ventricle, semi lobar.
25:09
So now you have a lot of fusion,
25:11
but you have some basal ganglia,
25:13
and you have this kind of third ventricle communicating
25:15
with a dorsal cyst low bar.
25:18
So now you have, you know, fairly, uh, segmented brain,
25:21
but still some fusion across the frontal lobes.
25:24
And then sub lobar, or some people call the septal preop.
25:27
So this is, this can be missed often,
25:29
but it's just a little bit of fusion, right,
25:31
under the callosum in this kind of preop region.
25:34
So these can be quite subtle.
25:35
Again, it's really the presence of the, uh,
25:38
midline malformations, right?
25:39
So it's not just the septum is absent,
25:41
but it's really that you have a lot more in terms of
25:43
that, uh, frontal fusion.
25:45
And so when I mentioned that posterior tapering
25:47
and the cosal pathogenisis here,
25:49
you're not seeing the coum anterior, the posterior is fine.
25:52
And so that's a signal
25:54
because that's, this is not the normal pattern for,
25:56
you know, for collosal development, that it's not, it's not
25:59
so much that theum is deficient, is
26:01
that the frontal lobes are fused across.
26:02
You're just, you're not even having the callosum form in
26:05
those areas because the hemispheres themselves are fused.
26:08
So this is essentially a spectrum of, um, of,
26:11
uh, forebrain fusion.
26:13
And so here's a little schematic to show
26:15
that basically both the face
26:17
and the brain, this, the structures are too close together.
26:21
There's actually another variant of, uh,
26:23
holo person celi involving the dorsal or roof plate.
26:25
So that's actually a little farther back.
26:27
So the fusion that you see is actually
26:30
now the posterior frontal, um,
26:32
and, um, sorry, uh, poster frontal and anor pridal lobe.
26:35
So you see that the fusion is not,
26:37
not all the way in the front,
26:38
but a little bit farther back,
26:39
as you can see on the sagittal.
26:41
So people call this a centile celi or,
26:43
or int hemisphere colpocephaly.
26:46
And so the mutations are different.
26:47
They involve the dorsal riff plate,
26:49
but it's the same idea in terms of, um, abnormal kind
26:51
of midline crossing and signaling.
26:55
So again, it's that idea that both the face
26:57
and the brain structures are too close together.
26:59
So this is associated with piriform aperture stenosis.
27:02
So basically kind of the opening of your nose
27:05
and also the central mega incisor.
27:07
So like one single, you know, large central incisor
27:10
with kind of a triangular maxilla, um, instead
27:12
of having the two incisors.
27:14
So it depends on the, on the severity and so forth,
27:17
but it shows that the face and brain developed together,
27:19
and basically everything in the midline is partially fused
27:23
or, or getting too close together.
27:26
So then we have, um, the opposite situation.
27:29
So what if everything's too far apart?
27:30
That's called fronton nasal dysplasia
27:33
or split no cord syndrome.
27:35
So, um, this is where your palatal shelves don't fuse.
27:37
So you can get a cleft palate, you can actually have, um,
27:40
bifid tongue, um, the third ventricle,
27:44
normally the floor kind of comes down to a point,
27:46
but the mammary bodies
27:47
and tuber cerium actually will spread out
27:50
and form this kind of fusion body.
27:51
So this is not actually a hammer atoma, this is just
27:53
what you get in front of nasal dysplasia.
27:55
It's basically this dysplastic fusion body that kind of, um,
28:00
basically spreads along the bottom of the third ventricle.
28:04
Uh, you can also get duplicated odontoid processes,
28:06
duplex pituitary glands.
28:08
And so as you can see with the schematic,
28:10
basically everything with the face
28:11
and the brain is too far apart.
28:13
You can even get little, um,
28:15
inclusion cysts like epidermoids, uh, teratomas in the,
28:18
in the oral cavity as well, in this area
28:20
where the palatal shelves don't fuse.
28:23
It's called epic naus. Okay? So moving to hind brain, right?
28:27
So we all know about the qri malformations developmentally
28:30
the, um, posterior fossa, if, if it doesn't form, um,
28:34
doesn't, doesn't have enough, uh, space for the cerebellum,
28:38
then things can herniate downward.
28:39
So you basically have a dysplastic, kind
28:41
of elongated verus, uh, and tonsils.
28:43
You can have this, uh, cervical miral kink, uh,
28:47
with chiri two, it's,
28:49
it's not the primary posterior fossa abnormality,
28:51
but it's actually A CSF leak in utero, right?
28:54
So spontaneous intracranial hypotension in an adult just
28:58
gives you saggy tonsils, brain sag.
29:01
But in a developing fetus, you don't just get low tonsils,
29:04
but the skull is still developing.
29:06
It's very plastic. So you actually get that, you know,
29:08
lemonhead with the biconcave, um, appearance.
29:12
And then the folding of the brain is actually altered.
29:14
So you end up getting a lot
29:16
of super tentorial malformations.
29:18
Um, the collosal pathogenesis, the steno gyre, the,
29:21
and then you have the small posterior FoST
29:23
with upward downward, um, cerebellar herniation.
29:26
We know this is basically a biomechanical process
29:28
because if you do fetal surgery
29:30
and close this leak, uh, then the tonsils come up
29:33
and the brain falls, although not completely,
29:35
normally much closer to it.
29:37
So, so there is a biomechanical effect
29:39
of those low CSF pressures, uh, tactile beaking,
29:42
mass intermediate, again, all of these kind
29:44
of spectrum of QRA two.
29:46
And then qra three, same idea.
29:48
But the CSF leak is now in the neck.
29:49
It's a cervical occipital encephalocele.
29:51
So again, if you close this,
29:53
although it's higher risk, you would get, um, resolution,
29:56
uh, but without you end up having all of the similar kind
29:59
of, uh, intracranial, uh, malformations.
30:01
There are a few case reports in the literature
30:03
of qri two type malformation without a known CSF leak.
30:08
It turns out in those cases,
30:09
there was a leak that closed up.
30:11
So it was essentially, uh, a, um, a meningocele
30:14
or, um, um, or lumbo, yeah, myel mengual or,
30:19
or something encephalocele.
30:20
But essentially it was leaking developmentally
30:23
and then closed up by the time of birth,
30:25
but it was still present and, and,
30:27
and caused those biomechanical symptoms.
30:30
Uh, so then we come to cerebellar,
30:33
you know, rotation and development.
30:35
So as the during, uh, development,
30:38
the cerebellum actually has to undergo a, a 90 degree, um,
30:42
rotation to convert from like a superior inferior axis
30:44
to the, um, uh, medial lateral to so that it can actually,
30:49
uh, cleft and create the vermes and hemispheres.
30:52
And so there is this process of, if you're in the sagal,
30:56
you know, if you're looking at this, uh,
30:57
in a standard sagal plane, this, this, uh,
30:59
clockwise downward rotation
31:01
and then continued development, um, of the cerebellum.
31:04
So in the most severe malformation in Danny Walker,
31:07
you have the occipital cephas.
31:08
So you actually have an open, uh, dural defect that needs
31:11
to be closed, and a very rudimentary, you know,
31:13
hypoplastic verus and hemispheres.
31:16
Uh, when you get to the variant,
31:17
you have some underdevelopment
31:19
and under rotation of the, um, of the cerebellum,
31:22
but it's less, and you don't have the encephalocele,
31:24
but this is still clinically relevant
31:26
because you don't have all
31:27
of your loation of your cerebellum.
31:29
So they do have some cognitive deficits, um,
31:32
make it a ci sternum magna.
31:33
I often don't even mention
31:34
because it causes more trouble when, when people try
31:37
to look these things up in the report.
31:38
So you can see that there are ci sternum, magna septa here.
31:40
These are the residual, uh, of the Blake pouch cyst,
31:43
which have involuted, but there is no arachnoid cyst, right?
31:46
This gets, um, miscalled a lot
31:47
that there's no walled off cyst,
31:49
there's no eccentric thing causing mass effect in pushing.
31:52
This is very much symmetric, you know,
31:54
in the posterior fossa.
31:56
And yes, there's a little bit of scalping back here,
31:58
but that's not mass effect,
31:59
that's actually just the patterning, um, of the mega ci
32:01
and magna along the lepto meninges.
32:03
It doesn't have anything. There is no true
32:05
walled off cyst here.
32:07
The cerebellum is just fine. There's complete loation.
32:10
So in some cases, I won't even mention this,
32:12
we're all buried in the impression.
32:15
And then the, the actual Blake pouch,
32:16
this is when you don't have perforation of the
32:19
teia down here along the roof of the fourth ventricle.
32:21
So these patients tend to present with hydrocephalus
32:23
because you don't have flow through,
32:25
you see this thin walled cyst that hasn't perforated
32:27
and created the framing of majdi.
32:29
So there's actually ballooning of all of the outflow tracks.
32:33
Um, they can present with kind of chiari like symptoms.
32:36
Typically, the cerebellum is fully developed,
32:38
but just, you know, pushed to the side.
32:40
But in some cases it's also hypoplastic.
32:42
And those can be a little bit, uh, challenging to diagnose,
32:45
but again, you're looking for a cyst wall
32:47
and the presentation of hydrocephalus.
32:50
Okay, then the last set of, um, malformed, uh, this is kind
32:53
of like the most challenging part of the lecture, I think,
32:55
um, the, the hind brain.
32:57
So I'm just gonna show, um,
32:58
four very classic examples of morphology.
33:00
So BER syndrome, the molar tooth malformations.
33:04
These are essentially where you don't have the midline
33:07
crossing or dation of the superior cerebellar peduncles.
33:10
And so basically you get this, this is basically the crown
33:13
of the molar tooth, right?
33:14
So it's not like a Mickey mouse,
33:15
but the midbrain looks like a molar tooth
33:17
because you have a deep intraocular cistern.
33:19
And then you have these thickened parallel cps,
33:22
because there isn't that decussation, you don't have
33:24
that kinda red decussation of the DTI,
33:26
and they can have, um, cerebellar
33:27
mal rotation and other things.
33:29
So these are linked to primary ciliary disorders that cause,
33:31
you know, axonal path finding and guidance.
33:35
The pontic metal cap is also very, you know, characteristic.
33:39
So nothing else looks like this.
33:40
You have, like, the normal belly of the pons is,
33:42
is hypoplastic or absent.
33:44
And actually those transverse pontine fibers are abnormally,
33:48
they don't find their normal path.
33:49
And so they actually are trans located to the dorsal pons.
33:53
And so you basically have this dorsal pontine bump.
33:56
So if you do, uh, fiber tracking,
33:57
there's actually some very abberant, uh,
33:59
fibers that form as a result.
34:02
Uh, this is the hg PPS.
34:04
So basically they have a horizontal gaze palsy
34:06
and scoliosis, and this is due to the robo three gene.
34:08
Essentially, they don't have good ations across the midline
34:12
in multiple parts of the brain stem.
34:14
So you get this kind of butterfly appearance
34:16
where there's indentation both eventually and dorsally,
34:20
and then rmbo cephalic synapsis very severe.
34:22
This is basically abnormal cerebellar patterning.
34:25
So you don't have a, verus you have fusion
34:27
of this cerebellar folia across midline.
34:29
You have this kind of triangulated diamond appearance
34:32
of the fourth ventricle.
34:34
The, um, deep gray nucleo can be close together
34:36
or even fused, kind of like a cyclops appearance,
34:39
and they often have, um, sial abnormalities as well.
34:43
Uh, so some of these have known genetic linkages.
34:45
Some of these do not yet, but are presumed
34:47
because they all have issues to do
34:49
with axonal path findings.
34:50
So really you're looking at the morphology in
34:53
that posterior fossa to call these.
34:55
But, um, I think certainly genetic, uh, testing
34:58
and workup are merited and good family history.
35:02
All right, so that was, uh, migrational, you know,
35:04
like a primary disorders of formation.
35:07
Now, let's move on to destruction.
35:08
So this is, uh, this, this, uh, section is rather easier.
35:11
This is basically all about timing.
35:13
So you have an acquired insult
35:14
that really gives you the timing of the malformation.
35:17
So destructive insults are also known as ence clastic, um,
35:21
basically, um, something that, you know,
35:22
it's like iconoclast, right?
35:24
So basically something that, um,
35:25
that kind of, uh, injures the brain.
35:28
So the, the sev most severe earliest, um, manifestation
35:31
of an encephalopathic insult is the aran,
35:34
anencephaly, and cephalic spectrum.
35:36
Basically, if you're missing any part
35:38
of your skull in utero, the exposure
35:41
to the amniotic fluid is, um, chemo toxic.
35:44
And then you're also not getting mechanical insulation.
35:46
So the brain is bouncing around
35:48
and you know, not not being protected.
35:50
So unfortunately, if you have a, um,
35:53
if you have a calvarial defect,
35:56
your brain will start to degenerate.
35:57
And in the kind of mid phase,
35:59
it looks like anencephaly, right?
36:01
So basically you have cerebral hemispheres
36:03
that are hanging out and degenerating,
36:04
and it's, that's the Mickey mouse sign.
36:06
And the end stage, unfortunately,
36:07
there's no superal brain left, maybe just some angios stroma
36:11
and maybe some brainstem.
36:13
Uh, so this is called the frog face
36:15
because you just have bulging orbits, a no,
36:17
you know, intact brain.
36:18
And so these patients, if they are carried to term,
36:21
can have some basic brainstem reflexes like suck and gag,
36:24
but there's not really a capacity for, you know, um,
36:26
higher functions, unfortunately without a cerebral.
36:29
So basically a cranial absence of cranial vault,
36:32
anencephaly and celi and celi.
36:35
Um, sch celi is basically an early insult.
36:37
So I talked about the migration
36:39
of the neuroglial progenitors from the ventricular,
36:41
you know, um, uh, edge to the, to the cortical surface.
36:46
So if there's an insult,
36:47
like let's say an MCA territory infarct,
36:50
but those gray matter cells haven't migrated out yet,
36:53
and when they do so they are going to migrate to the edge of
36:56
where they think is the end of the brain.
36:57
They don't know that that's not the real edge of the brain
37:00
because everything was, you know, everything else is gone.
37:02
So basically you get a gray matter lined cleft.
37:05
It could be a, you know, open lip if it's a big insult,
37:07
uh, big ischemic insult.
37:09
It could be, you know, closed lip if it's very narrow.
37:11
But essentially you get a gray matter lined poly micro gyre,
37:15
um, uh, defect.
37:17
And that's, that's basically the sort of book definition
37:21
of schizo cephalic is gray matter
37:22
lined, you know, poly micro gyre.
37:23
But that's really the biomechanical reasons.
37:25
So these are kind of like late first,
37:28
early second trimester.
37:29
Um, and so even when it's closed lip
37:32
and you can't tell, is this heterotopia or is this
37:34
'cause ceal, you can tell because there's
37:36
an exo phenomenon, right?
37:37
This is the so-called, uh, peel lap penal seams.
37:40
So you're getting volume loss here.
37:42
There was a ence clastic insult
37:43
that injured, and you lost brain.
37:45
And so you have this xva little dimple, right?
37:47
This kinda like little dimple
37:49
and cortical cleft where that injury happened.
37:51
So even though it's gray matter lined
37:53
and the edges that are touching, you can tell
37:55
that there was actually an insult that happened here.
37:58
And then the porn celi is, you know, in the books,
38:01
they call it white matter lined, right, clean cavity.
38:03
But the reason is because it's a later insult. Right?
38:06
Now, the gray matter cells have
38:08
made it to the cortical surface.
38:10
Uh, and so what you get is a white matter lined, um,
38:13
cystic cavity, which can
38:15
or doesn't have to communicate with the ventricles.
38:17
Uh, but this is now like, you know, late second,
38:20
early third kind of, uh, timing.
38:23
And you'll notice as a pair compared to an adult that the,
38:26
the cysts are very clean,
38:27
and that's the difference between poor
38:28
Celine and Encephalomalacia.
38:30
So at that stage, the astro glial cells, um,
38:34
the astrocytes which create gliosis
38:36
or astro scoliosis, lots of scarring
38:38
and fibrosis, they're not mature yet.
38:40
So when you get the insulin, you just get a
38:41
very clean cavity.
38:43
Hydrocephaly is basically the most severe
38:46
manifestation of poor ence.
38:47
It's basically trans mantle, the entire mantle.
38:49
So if you get ICA bilateral ICA occlusion, for example, most
38:53
of your ator brain will be gone.
38:55
You get a little bit of residual basal ganglia, um,
38:58
posterior faucet because of autoregulation.
39:00
But again, in an adult, there'd be a lot of scarring, right?
39:03
A lot of encephalomalacia here.
39:05
You just get really clean, you know,
39:06
CSF fluid filled cavity.
39:08
So poor cephalic hydrated ence later, basally later insult,
39:11
you know, minimal scarring.
39:14
So then perinatally, so like late third trimester or
39:17
after birth, you get the encephalomalacia, right?
39:19
So now you're getting scarring,
39:20
cortical lanar necrosis fibrosis, right?
39:23
So this is more like the mature adult type
39:25
pattern of scarring.
39:28
And then eLog gyre, this is kind of a unique perinatal type,
39:31
I would say, you know, potentially up to first couple years
39:34
of life, but often, uh, has to do
39:36
with a perinatal brain injury.
39:37
Uh, eLogger, I think, um, stands for, I think it's Greek
39:40
for mushroom, right?
39:41
So mushroom jar, not your white mushroom,
39:44
but your kind of long stem mushroom.
39:45
There's selective watershed, um, insult in that vet, in
39:49
that neonatal period where it involves kind of the deep, uh,
39:52
sci and spares, the surface gyr.
39:54
So you end up getting, in this case, hypoglycemia
39:57
because the posterior fossa is more, you know, prone
39:59
to these kind of metabolic, um, and pressure phenomena.
40:03
So you, you can get, um, eLogger with this kind
40:06
of posterior predominance,
40:07
but um, also with vascular insults, you'll get that kind
40:10
of mushroom shaped gyri.
40:11
So even in an adult, you can, you can see this sometimes
40:14
with, uh, seizure, seizure manifestations.
40:16
And you can actually, uh, note
40:18
that this is a remote likely perinatal, uh,
40:21
ischemic insult when you have that unique pattern of kind
40:23
of mushroom gyri.
40:26
And then congenital infections can also, um, if they happen
40:30
during fetal development, create migrational abnormalities.
40:33
So there was a big to-do about Zika, you know,
40:35
from South America a few years ago.
40:38
There was a huge epidemic with the pregnant ladies going
40:39
for vacation, and in particular the first trimester.
40:42
So if you get Zika infection during the third,
40:45
it's pretty minimal mild symptoms.
40:47
Second, you may have some symptoms,
40:49
but the, the, the babies don't look nearly as affected
40:53
as first because that's when the virus
40:55
is actually neurotropic.
40:56
It's crossing the brain barrier and affecting the migration.
41:00
So then you would get very profound microcephaly
41:02
to the point that the scalp rouge are basically bunching up
41:06
over the shrunken brain and lots of malformations
41:09
because you are impairing the development so early.
41:12
Um, CMV can have various manifestations.
41:15
So fairly common unfortunately, you know,
41:17
um, congenital infection.
41:18
And you can see that, uh, these destruction,
41:20
so like the kind of, uh, these kind
41:22
of porn cephalic regions, the in ence clastic cyst,
41:26
white matter injuries and migrational anomalies.
41:28
And again, the severe completely depends on the trimester,
41:32
you know, the timing of the insults.
41:34
So early on you'll get more severe profound insults,
41:37
worse migrational anomalies,
41:39
and then later on you may just get some non-specific white
41:41
matter stuff in the third trimester.
41:43
So completely timing dependent, same etiology.
41:47
All right, so the last part,
41:49
and probably the most interesting from my perspective,
41:51
uh, is the migration.
41:52
So this is that radio glial line that micro tubial tech, uh,
41:55
track that we talked about.
41:57
So the International League against Epilepsy has a published
42:00
these classifications for focal cortical dysplasias or FCD.
42:05
It's actually pathologic classification, right?
42:07
So there are some imaging manifestations,
42:09
but it's not direct correlation.
42:11
Uh, the one that has the best, uh,
42:13
prognostic outcome is actually the FCD two B
42:16
as you'll see in a second because it has this classic trans
42:18
mantle sign and you can essentially almost shell out,
42:21
you know, you can basically see exactly what the lesion is
42:23
and have a small margin.
42:24
And it's, they're very, uh, good post-surgical outcomes.
42:28
The FCD um, one,
42:31
they're either really subtle or really obvious.
42:34
And then the fcd threes are the so-called dual pathology.
42:37
But I like to think it more as a kind
42:39
of coexistent pathology
42:40
because you have some underlying thing that gives rise
42:44
to dysplasia because developmentally you have a lesion
42:47
and that causes the neurons to not develop correctly.
42:51
And there's also the mild, uh, malformation
42:53
of cortical development where we don't see clear cortical
42:56
abnormality, but there are white matter changes.
42:58
And so that's actually a new, uh, classification as
43:00
of 22, 21.
43:02
So the radio ggl actually will, um, uh,
43:06
oversee the so-called inside out migration.
43:08
So the idea, as I mentioned, is
43:10
that you have the neuro gender cells going from the
43:12
ventricular zone all the way to the periphery.
43:15
And so I do this kind of search pattern
43:17
where I look at the skull to look for any encephalocele.
43:20
'cause sometimes that will,
43:21
that will be associated then the CSF space in the veins
43:24
because that can be enlarged or dysplastic.
43:27
And then, um, the cortex can look abnormally thick or thin.
43:31
It's not truly, you know, it's not normal cortex.
43:33
So basically you're getting blending in with white matter,
43:35
but you basically will track anything from a gray matter,
43:38
heterotopic nodule, uh, disc myelination along the track
43:41
of the radio gl.
43:43
And then it should really center if it's a real dysplasia
43:45
center at the bottom of the sulcus.
43:47
So really that, you know, really centered on the sulcus.
43:49
I'll often see, you know, um,
43:52
reports from like other centers
43:54
where people talk about dysplasia versus low grade glioma.
43:57
And they're very different, right?
43:58
Because dysplasias, they're basically pulling in the bottom
44:01
of the sulcus and they're centered on, whereas a glioma
44:04
start, you know, usually starts in the cortex.
44:07
It is puffy, it's typically eccentric,
44:09
you know, it's not at the bottom.
44:11
It's going to, you know, pooch into the CSF track,
44:15
a long white matter be eccentric.
44:16
It's not gonna follow this radio glial line.
44:18
So they're very different. So I don't think I've ever used
44:20
that differential, um, in a report.
44:24
Um, okay, so here are just quick examples.
44:26
The mild MCD where you have some white matter stuff
44:28
and maybe some anomalous location,
44:29
but not clear cortical malformation.
44:32
Here's an fcd one with, um, asymmetric, you know, uh,
44:35
folding in a little bit of blurring of the gray white along
44:38
that, uh, frontal insular region.
44:41
And fcd two, as you can see, that anomalous deep sulcus
44:44
and large subarachnoid space and cortical vein.
44:47
And that blurring, um, of the gray white,
44:50
here's that nice one.
44:51
I I mentioned the FCD two B.
44:53
If you see these, you're really lucky
44:54
'cause you almost never get a slam dunk.
44:56
But that bottom of the sulcus, um, that blurring
44:59
of the gray white, and then that track
45:00
of the radio glial line straight from the migrational,
45:03
you know, the, um, the edge of the ventricle all the way
45:06
to the bottom of the sulcus.
45:08
And then these are the, you know, dual or coexistent ones.
45:11
So you can have a dysplasia with mesial temporal sclerosis,
45:14
where essentially the, you know, temporal dysplasia gives
45:17
you essentially hippocampal sclerosis and epilepsy.
45:20
Um, these are, uh, low grade tumors like D nets
45:23
or pilocytics that, um, developmentally cause, uh,
45:27
dysplasias around them.
45:29
You could have a vascular malformation, so let's say A DVA,
45:32
but then there's anomalous ation around that DVA.
45:34
So this is an associated fcd three C
45:37
with a vascular malformation, and then early trauma
45:40
or ischemia, right?
45:41
So this was basically like an HIE hypoxic ischemic insult.
45:44
And then you see that in the areas
45:46
of ischemia there is also abnormal persil vian gyration.
45:53
So the FCD two B is actually in the so-called mTOR pathway,
45:56
the mammalian target of rapamycin.
45:58
And that's basically a cell cycle regulation,
46:00
and it leads to overgrowth.
46:01
That's somatic overgrowth, like I mentioned,
46:04
typically not germline.
46:06
Um, but you'll get somatic hits.
46:08
So that can be hemi hypertrophy, that can be other things.
46:10
So the fcd two B is basically a very,
46:12
very late segmental somatic mutation.
46:15
But if you have earlier somatic mutations, you actually get
46:19
manifestations, um, in the brain, um, as follows.
46:21
So you can have, so people talk about heme cephalic,
46:24
but you can have low bar mega cephalic.
46:27
You can have quadr hemispheric, that's the heme cephalic,
46:30
HME, and you can actually have somatic as well.
46:33
You can have, you know, diffuse.
46:34
And so what you see here is big disorganized gray
46:37
and white matter poly micro gyre, ventricular magaly.
46:41
So essentially this is all the same kind of, uh,
46:44
mechanism in terms of, uh, somatic and
46:47
or germline mutations that lead
46:48
to cerebral overgrowth and complexity.
46:52
Uh, heterotopia is
46:53
where you're arresting the gray matter at
46:56
the level of the ventricle, right?
46:57
So it never gets out to the surface.
46:59
And with these cases, you can have focal sporadic ones,
47:02
but I always look above
47:03
because these can be associated
47:05
with epilepsy if there is something that affects the cortex.
47:08
So here, for example, you see there is a trans mantle sign
47:11
tracking to the cortical surface.
47:12
So this, you know, cortex could be epileptogenic, um,
47:15
some people will do ablations
47:17
and things as well to be more minimally invasive,
47:19
but again, you're looking for
47:20
overlying cortical abnormalities.
47:22
Uh, periventricular.
47:23
These are more like, um, you know,
47:25
genetic things like filament A or arf G two, right?
47:28
So basically things that diffusely affect, um,
47:31
and arrest the gray matter, causing it
47:34
to cluster on the ventricles and not make it to the surface.
47:37
And then you can have, um, more, uh, focal, you know,
47:40
like a kind of subcortical.
47:41
So how is this different from the sch celi,
47:44
the gray matter line, you see
47:45
that there's actually kind of a pseudo mass.
47:47
It's not enhancing, it's not a tumor,
47:49
it's just disorganized gray matter,
47:51
but it clearly pooches into the ventricle
47:54
and causes mass effect and is expansile
47:56
and kind of wrapping in the cortical veins.
47:58
It doesn't have that dimple cleft, the ex vacu that we saw
48:01
with the phao clastic insult of the sch cephalic, okay,
48:05
elicit cephas is under migration.
48:07
So, uh, this is, you know,
48:09
type one lissencephaly are classic.
48:11
Um, this is basically where the radio ggl don't work, so
48:15
that inside out, um, migration, I told you.
48:19
But the radio ggl allow basically newer, uh, neurons
48:23
to migrate past older neurons
48:25
and form the six liter of the cortex.
48:26
So basically the newest neurons end up superficial.
48:30
And if the radio ggl are detached, then that doesn't happen.
48:32
So basically the oldest neurons hang out at the surface,
48:36
and then the newer neurons never make it there.
48:38
So you end up with this thin cortex, a cell sparse zone,
48:41
and then this kind of a subcortical band.
48:44
So in age Gyre, this is basically like the most rudimentary,
48:47
you just have like very shallow Sylvia
48:49
and interhemispheric fissures,
48:50
and it never develops more than that.
48:52
This is the figure eight brain, no gyri, chy, gyre.
48:55
You have few and broader gyri,
48:57
so clearly not fully su located, but there's some gyration.
49:01
And you see there's a little bit thicker, more sued cortex
49:04
and a slightly thinner subcortical band.
49:08
Um, and then band head utopia is the least severe, right?
49:11
So basically now you have a thicker, more sued cortex
49:14
and a thinner subcortical band to the point
49:16
that the subcortical band can sometimes be extremely subtle
49:19
and even gets missed.
49:21
But this is basically a, you know, bifrontal case
49:23
that presented with multifocal epilepsy.
49:26
So this is a, a spectrum, you know, in terms of
49:28
what you call it, right?
49:29
If it's like, you know, pretty well-defined cortex,
49:31
thin cortical band, we call it band heterotopia.
49:33
Uh, if it's very underdeveloped, it's, you know,
49:35
h package ria, but it's all the same.
49:38
There are a lot of genetic, um, mutations.
49:40
Some are anterior predominant, some posterior, some diffuse,
49:44
some are even associated with, uh, you know, colossal and
49:47
or cerebellar, uh, pathogenesis, the variant lissencephaly.
49:50
So those are even more severe.
49:52
There are, uh, some, uh, populations, you know, like Amish,
49:55
I think, that has the very low density lipoprotein,
49:58
and they get severe ataxia.
49:59
For example, this used
50:02
to be called type two li cephalic, but that's inaccurate.
50:05
Now that we have better imaging,
50:06
we know it's a completely different,
50:07
it's really the other side of the spectrum.
50:09
This is over migration.
50:10
So the so-called cobblestone cortex comes from
50:13
defective basement membrane.
50:14
Remember I told you the basement membrane keeps the cortex
50:17
from, you know, it basically knows when
50:19
to stop migrating when it gets to the surface.
50:22
If you have a defect, the cortex doesn't know when to stop,
50:24
so it just keeps going and piles up.
50:27
And so depending on whether those defects, you know,
50:29
depending on the mutation, if they're big defects,
50:32
you get kind of like a thick, you know, cobblestoney.
50:35
And if they're tiny defects, you get a more fine, uh, look.
50:39
So this is, you know, here's an example that was fairly,
50:41
you know, fairly mild with some white matter stuff.
50:44
Um, and then cerebellar cys.
50:46
So it turns out that the, uh,
50:47
development in the cerebellum is different.
50:49
The external granule cells actually adhere
50:51
to the lepto meninges.
50:52
And if you lose that, if you have defects in the basement
50:54
membrane, you get inclusion Cys, CSF cys.
50:57
So the differential cerebellar, uh,
51:00
migration results in kind
51:01
of these little leptin meningeal inclusion cysts,
51:04
infant editorially, and then this kind
51:06
of a diffuse cobblestone
51:07
and white matter, um, hypoplasia sually.
51:11
And, uh, so here you can see very fine defects in the
51:14
basement membrane all the way around.
51:15
But this is very different from the under
51:17
migration of, of lissencephaly.
51:18
This is an over migration abnormality.
51:21
And here's one where the defects were very
51:23
big and thick, right?
51:24
So you have more of a piano key appearance where,
51:27
where everything's kind of like, um, uh, packaged together.
51:30
This is the most severe, the walker warberg.
51:32
Um, they have muscle, eye and brain problems
51:34
because the basement
51:36
and membrane is responsible for the guidance
51:38
and development of all three of those organs.
51:40
And they can have, you know, very severe, uh,
51:42
brain stem abnormalities too, because it never unfolds.
51:45
Those flexors never unfold the way they're supposed to.
51:47
Developmentally, uh, poly micro gyre, uh, this one is
51:52
where the gray matter has gotten to the surface,
51:54
but then it doesn't organize correctly, right?
51:56
So this is a late migration and early organization problems.
51:59
So we're talking like, you know, a third trimester
52:02
or you know, at, at best to late second.
52:05
So, um, again, uh, there are many genetic
52:08
but also, um, acquired somatic, uh,
52:11
etiologies of poly micro gyre.
52:12
You can have focal, again, many little small gyre, uh,
52:16
segmental in a certain area.
52:18
So this would be basically earlier development, very common
52:21
to see Perry Sylvia, right?
52:23
So this is like A-M-C-A-I-C-A ischemia, uh, developmentally
52:27
around the third trimester.
52:29
Um, and then global, right?
52:31
So there are some global overgrowth
52:32
malformations that do this as well.
52:34
And the bottom rows are actually a seven Tesla.
52:37
So with poly micro gy,
52:39
if you have limited spatial resolution,
52:41
you can get volume aging.
52:42
So those many small RIA might look different.
52:44
They might look fine,
52:46
or they might look, uh, you know,
52:48
more palisade sawtoothed, right?
52:49
So depending on the volume aging,
52:51
but it turns out at seven they all look the same.
52:53
They all have very tiny, you know, consistent, uh, size.
52:57
Uh, but it's just that with lower resolution, you may need
53:00
to impute based on bigger CSF space, prominent veins, lots
53:05
of, you know, cortical thickening and volume averaging.
53:09
And then some things defy diagnoses, right?
53:12
So I mean there, like we know that they're migrational,
53:14
but you know, there's not an I-I-L-A-E classification
53:17
for them because they are so rare.
53:19
Uh, so sub lobar, dysplasias, not the folo,
53:22
but there's a little ismi of tissue.
53:24
And this is basically just another
53:25
segmental, right, or subsegmental.
53:27
But basically this, you know, this gyrus rectus is kind
53:30
of hanging off and, and has its kind of isolated dysplasia,
53:33
whereas the rest of the frontal lobe is fine.
53:35
And then here's a compound one
53:37
where basically this whole ripe posterior quadrant,
53:39
there's poly myco, jia, there's some heterotopia,
53:42
there's white matter dysplasia, there's a DVA
53:45
with some cortical malformations.
53:46
So it's like, it's like several
53:48
of the malformations I described earlier.
53:49
So rather than trying to classify it,
53:52
I would just describe all of these malformations
53:54
and bring them together.
53:56
Mechanistically saying this is a, you know,
53:57
posterior quadrant overgrowth syndrome.
54:01
And then lastly, if you see pan migrational abnormalities,
54:04
but they're asymmetric, think about tubular neuropathies,
54:07
because most other things like congenital infections
54:10
or other genetic malformation, uh, mutations
54:13
and stuff, they'll affect lots of different areas,
54:15
but kind of symmetrically and consistently.
54:18
Whereas, uh, microtubules,
54:20
they have this dynamic instability.
54:22
They have a a minus and a plus end,
54:24
and they're constantly evolving
54:25
to the energetics of the cell.
54:27
So the only thing that can essentially create this very,
54:30
you know, kind of wonky, asymmetric pattern,
54:32
where do you have, uh, you know, differences on each side?
54:35
So they could be, um, less than ly poly, uh, package ra,
54:38
they could be poly micro GY spectrum.
54:40
You could have, uh, colossal, uh,
54:43
cere abnormalities, et cetera.
54:45
But the asymmetry of the basal ganglia, the hypoplasia
54:48
of the internal capsule, this kind of hooked appearance,
54:50
and particularly the asymmetry, right, the brain stem
54:53
and the basal ganglia, that happens
54:55
because the energetics at each part of the cell as it's,
54:58
as they're developing, are slightly different.
55:00
And that dynamic instability
55:02
of the microtubule results in slightly different
55:04
phenotypic manifestations.
55:05
So, um, there's a number of cases where I've invoked this
55:09
and, and been correct, because nothing else
55:11
really quite looks like this.
55:12
The alpha tubulin is the more stable one,
55:15
and this is supposed to be buried in the tubulin complex.
55:17
So those mutations tend
55:19
to be more severe than the beta tubulin,
55:21
which is more dynamic at the plus end, and,
55:23
and does have some level of turnover,
55:25
but they both still have that kind of wonky pain,
55:28
migrational asymmetric appearance.
55:31
And so that's it. Uh, brain development
55:33
and is, as you can see, is very complex.
55:36
Lots of interactions between the molecular, the genetic,
55:39
and the environmental factors.
55:40
So to make it, you know, um, simpler, easier to understand
55:45
and, you know, help radiologists really get their hands
55:48
around, um, these abnormalities.
55:50
I think the mechanistic approach really understanding the,
55:53
uh, the fundamental first principles
55:55
behind why these things look the way they do helps us relate
55:58
the pathogenesis to the imaging features, given
56:01
that we're always learning more about genetics
56:03
and that we have an incomplete picture,
56:04
but we have to make do with what we know at this time.
56:08
The theoretical classifications in the literature do require
56:11
ongoing refinement with advances in knowledge, the genotype,
56:14
phenotype, uh, correlation,
56:15
and these, uh, animal models with, um, with different,
56:19
you know, studies and knockouts and functional genomics.
56:22
So again, all of that is in process,
56:24
but basically I'm giving you kind of an up-to-date approach
56:27
to what we know now
56:28
and how, basically giving you the tools to put it together
56:31
for yourself in future when you are faced with some
56:33
of these complex and sometimes rule-breaking conditions.
56:36
Thank you so much for your attention.
56:38
Thank you so much for sharing that lecture
56:40
with us today, Dr.
56:41
Ho. Great job.
56:43
Uh, at this time, we will open the floor
56:46
for any questions from our audience.
56:48
You can submit your questions to that q
56:50
and a feature, if you'd like to go ahead
56:53
and take a look at that for us. Dr. Ho,
56:56
The q and a. If there
56:57
aren't any questions now, just
56:58
usually giving them a minute
57:00
or two to put them in there will do the job.
57:06
How do you grade HIE?
57:07
So I had another lecture maybe a few months ago on,
57:11
on modality that's available, um, to on neonatal brain.
57:15
So that's a completely different thing where
57:17
that's an acquired insult, um, after, after birth.
57:21
Uh, so basically there are a lot
57:24
of different systems out there.
57:26
They're all imperfect.
57:28
Some of them are, um, have been used for multicenter, tries
57:31
to try to provide some standardization,
57:33
but essentially, um, in
57:34
that other lecture I talk about areas that you,
57:36
that you want to look at and scrutinize.
57:39
I think the most important thing with, um,
57:41
with HIE knowing gestational age, uh, so
57:44
that you understand the patterns that, that the, uh,
57:47
babies are prone to, but,
57:49
but also really carefully reading the clinical history
57:52
because many different types of insults give you kind
57:55
of a final common pathway.
57:57
And there are also HIE mimics, you know, genetic, metabolic
58:00
and other, um, other extrinsic things.
58:02
So, um, you really wanna be very careful
58:04
because the neonatal, uh, physiology is such that a number
58:08
of, uh, different insults, uh, could lead
58:11
to similar imaging features.
58:13
And so before you even get to is this, uh, you know,
58:16
how you grade it, is this even HIE, right?
58:18
And then what pattern do we see?
58:19
There are many different kinds of patterns.
58:21
There are many different kinds of mechanisms.
58:23
There are many different co-factors that can,
58:25
um, exacerbate it.
58:27
Um, kindly recap on why FC D
58:30
and lurid gliomas are not differentials.
58:32
Yes, because, uh, the
58:35
fcd basically follow the migrational line
58:37
and they're usually volume neutral,
58:40
or sometimes even with epilepsy you get volume loss.
58:43
Uh, whereas low-grade gliomas are puffy.
58:47
You, you also have at at least a little bit of volume gain.
58:50
Um, they are essentially eccentric
58:53
to the bottom of the sulcus.
58:54
Unlike fcd, which track pull down the sulcus
58:58
and create kind of like a prominent CSF space,
59:00
the gliomas will, will kind of like pooch into the CSF,
59:03
they'll track along the white matter and infiltrate.
59:06
And so you also get a little bit of volume gain
59:08
and they look very, very different.
59:10
Like I would say there's maybe, you know, less than
59:14
0.5% of cases where I could even see
59:17
that being a reasonable differential.
59:18
So I, I personally have not ever, Ever mentioned
59:22
that in probably in my, in my last 10 years of working.
59:25
So they are very different.
59:27
Uh, you just have to, you have to be,
59:29
because if you follow them up,
59:31
loyal grade luma don't really, uh,
59:33
change over a short period of time either.
59:35
So it's really not a helpful thing to say,
59:37
oh, let's keep following this up.
59:38
So there's gonna be other features that really help you
59:41
to differentiate them.
59:42
So I think it's, it's one of these things where people do it
59:45
because they're uncomfortable with the differential,
59:47
but I really think that, uh, there are a number of, of
59:51
considerations that you can use to try to,
59:53
to inform the difference between them.
59:55
Neuro cutaneous disorder.
59:56
So I think, I believe I gave that talk for modality as well,
60:00
the osis, um, uh, correct me if I haven't,
60:03
but I, I have that talk available if we haven't done it yet.
60:07
What about the n neuro cutaneous disorders?
60:08
Well, those are all, uh, genetic and or somatic,
60:11
but those are essentially, uh, disorders of derma
60:14
that involve like, you know, skin, eye and brain, right?
60:17
So some of the, uh, concepts that I mentioned,
60:21
this talk do apply, right, in terms of, uh, the overgrowth,
60:23
the mTOR pathway, right?
60:25
That's, that's important for tuberous sclerosis.
60:27
Um, but, uh, that's sort of a different, uh,
60:31
talk altogether, right in, in the sense
60:33
that those are all linked to some sort of genetic pathway,
60:36
whether it be germline of somatic, um,
60:38
but certainly being able to describe some
60:41
of these malformations is helpful.
60:43
Is EULA gyri a differential for Sturge Weber?
60:46
The MRI seems similar. Uh, no.
60:49
So Sturge Weber is basically a, um,
60:52
so eula Gyre is just a, it could be from any kind of insult,
60:56
usually ischemic, right?
60:58
Um, in the perinatal period,
60:59
but it has that very unique pattern where the, um,
61:03
the deep sulci are injured in the surface gyre
61:06
or spare, sorry, about the tornado testing.
61:08
So, um, that's, and,
61:11
but there's no overlying vascular abnormality, right?
61:14
Starch Weber is basically, uh,
61:17
congenital developmental vascular,
61:19
slow flow vascular malformation, right?
61:22
So it's basically venous dysplasia
61:24
where you don't have good drainage in that part
61:26
of the brain, and so you get progressive venous
61:29
ischemia throughout your life.
61:30
So it starts out in the early phase with kind of, you know,
61:33
enhancement and hyperemia of that affected part
61:36
of the brain, that segmental area and, and often the face.
61:40
And then over time you get worse and worse flow.
61:42
So then you get encephalomalacia
61:44
and tram tract calcifications, you don't ever get ere
61:47
because basically the whole cortex is ischemic.
61:50
So basically the whole thing calcify.
61:51
So you don't have that selective pattern of the, um,
61:55
of the deep, uh, soci and sparing of the surface gyre.
61:58
So the, the MRIs actually look very different.
62:00
They don't have, the mushroom is a very, is a very specific,
62:03
you know, ELO gyre, which is very suggestive
62:05
of like a neonatal perinatal insult.
62:08
Sometimes Danny Wake Walker malformations look like mac
62:10
ci sternum magna, okay?
62:12
So that's the, the difference is gonna be
62:13
the cerebellum, right?
62:14
So Danny Walker malformations
62:16
by definition will have omega meso, sternum magna,
62:19
but they will also have cerebellar verian and
62:23
or hemispheric hypoplasia.
62:25
So that's how I make the cut point
62:27
because I don't care about meso sternum magna
62:29
by itself, right?
62:31
I only care about it if it meets criteria for dandy walker,
62:35
uh, variant, right?
62:37
So not the malformation which has the occipital
62:39
encephalocele, not the full malformation,
62:41
but the variant which has underdevelopment of the cerebellum
62:44
because that actually matters for cognitive
62:47
and long-term outcomes.
62:48
So yes, the MCM is a, is is is part of that spectrum,
62:52
but the, the cerebellar stuff is more important.
62:56
At what age do you begin
62:58
to question whether an asymmetric terminal zone
63:00
of myelination is pathologic?
63:02
Uh, asymmetric. Okay.
63:03
So terminal zones of myelination actually can, uh, in the,
63:07
particularly in the peri atrial regions,
63:08
and sometimes the subcortical regions can be
63:10
there for quite a while.
63:12
Um, you know, I've, I've even seen some, I mean,
63:15
if they're more confluent in stuff, um, then you know, you,
63:19
you start to worry a little bit more about them.
63:21
I think a lot of it depends
63:22
because there is a lot of normal variation.
63:24
A lot of it depends on the clinical picture.
63:26
So if the terminal zones look a little prominent,
63:29
but they're developmentally normal,
63:31
like I'm not gonna make a big thing of it, right?
63:33
I think especially in peds, you wanna kind of round down
63:35
because the parents are anxious and, and all of this,
63:37
and you don't wanna make more of something than you have to.
63:40
But at the same time, that same finding in someone
63:43
with not just delayed milestones,
63:45
but regressive milestones could be a very early harbinger
63:48
of a neurodegenerative disorder like Batten disease, right?
63:51
So I think the Bayesian combination of your limited,
63:56
you know, imaging data
63:58
with the clinical course is incredibly important.
64:01
If you're having asymmetric, that's different, right?
64:04
So asymmetric really means that you must have had some kind
64:08
of an in insult or, or something, right?
64:10
So I'm trying to think
64:12
of when you would have asymmetric if it were like
64:14
an HIE or something.
64:15
So if you have an actual injury on board, like a perinatal,
64:19
you actually, it's not just T one ISO as in on myelin,
64:23
it's T one dark.
64:24
So you actually end up getting some of the glio changes
64:27
because you actually destroy whatever myelins on board.
64:30
So, um, I think the T one signal,
64:33
like it's T two flare bright,
64:35
but is a T one ISO or T one dark.
64:37
So if you're actually seeing T one dark, then you're,
64:39
you're dealing with a background injury,
64:40
the so-called static insult,
64:42
and then on that background insult, maybe the myelination is
64:46
progressing or it's impaired
64:48
because you had a background insult.
64:50
The other reason, let's say you don't have a, a,
64:53
a focal injury, but you have asymmetric myelination,
64:56
I would think of something like maybe seizures, right?
64:58
Because why else would you have asymmetry?
65:00
Um, I guess I can think of one other thing which,
65:03
which would be, since we're talking about malformation.
65:05
So if you have, let's say overgrowth
65:07
or some weird, you know, ipsilateral malformations,
65:10
the myelin on one side could be dysplastic, right?
65:13
So, so it's never really normal.
65:15
So that's one other possibility for, uh, for myelination
65:18
and Sturge Weber, interestingly,
65:20
early on the myelination is accelerated
65:22
because you have hyperemia
65:24
and so there's actually more blood pooling in that region.
65:26
So there are, uh, kind of malformations
65:29
that can cause asymmetric myelination,
65:31
but also early onset seizures, whether they are due
65:33
to a malformation or something else,
65:35
they are neurotoxic to the brain, right?
65:37
Seizures are neurotoxic. So, uh, I've seen cases of, uh,
65:41
delayed myelination that are worse on the side
65:43
of the seizure, right?
65:44
And so that could be, you know, another etiology.
65:47
So I guess my point would be it's gonna be secondary, right?
65:50
So if you're seeing true asymmetry in terminal zones,
65:52
then you're looking for underlying preexisting injury
65:56
or ongoing injury,
65:57
ipsilateral malformation, something like that.
66:00
So yeah, I would, I would say that in general,
66:02
germal zones should be reasonably symmetric
66:04
and so true, like profound asymmetry,
66:07
I think honestly at any age, right?
66:09
Any, any, um, even not just germal zones,
66:11
myelination asymmetry in general should be interrogated like
66:14
in a watery neo no brain.
66:16
Sometimes those dysplasias manifest with subtle, um, uh,
66:20
myelination asymmetries or tuberous sclerosis, right?
66:22
You can actually see it quite well in the neonate
66:24
before they start to myelinate.
66:26
So I think that asymmetry
66:27
or focal areas of dys myelination are always relevant.
66:31
Okay. Which imaging features
66:32
and malformations of cortical development are most
66:34
predictive of drug resistant epilepsy
66:36
and surgical candidacy?
66:39
So the epilepsy field is extremely heterogeneous, right?
66:42
There's, uh, individual, um, physiology
66:45
and then the MCD, so obviously a more extensive MCD,
66:50
um, you know, like more volume the cortex, uh, is going
66:53
to be, uh, relevant,
66:55
but like, let's say a heterotopia, right?
66:57
Some or even perine poly caria, some people, um, present,
67:02
you know, very early in life, others much later.
67:03
So it's a combination of genetics and environment.
67:06
I think it's, it's very hard to predict in any individual
67:09
a surgical candidacy.
67:10
See, so that's really a multidisciplinary thing, right?
67:13
So it's really saying,
67:14
and some people are well controlled
67:16
with drugs, others are not, right?
67:17
So in terms of actually trying to resect
67:19
or ablate something, you want
67:21
to actually have good concordance between the malformation
67:23
with EEG, semiology, you know, phase one and two monitoring.
67:28
If you don't have that concordance,
67:30
the surgical outcomes will not be good.
67:32
So like the FCD two B that I showed, right?
67:34
That one would generally be highly concordant.
67:36
You can take it out, be seizure free.
67:38
Um, sometimes you see malformations,
67:40
but the seizures localized somewhere else,
67:42
or there are many malformations like tube sclerosis
67:45
and it's non localizing.
67:46
So in those cases, people will not, you know, uh, do surgery
67:50
or they would do a palliative surgery, right?
67:52
Because you haven't proven
67:54
that the malformation is actually causing all
67:56
of the majority of seizures.
67:58
So why risk ticking out, you know,
67:59
potentially important brain?
68:01
So you can do things like a, you know,
68:03
vagal nerve stimulator, um, recurrent nerve stimulator,
68:06
um, DBS, right?
68:08
Deep brain stimulation. So you can do neuromodulation
68:10
to decrease the burden of seizures
68:12
or try to, um, you know,
68:13
change the brain wiring when a seizure comes up rather than
68:16
trying to resect something that you don't know
68:17
for sure is causative.
68:19
So I don't think there are, you
68:20
know, definite imaging features.
68:21
They need to be correlated with the clinical picture
68:23
and with, uh, physiologic recording.
68:26
Uh, certainly for something like tube sclerosis, um,
68:28
they've shown that calcification basically like the advanced
68:31
stage of the disease with dystrophic calcification
68:33
can be more irritating.
68:35
And so some of those have higher, uh, disease burden.
68:38
Um, there's been some, you know, radio like AI type studies
68:41
to look at certain features on advanced imaging
68:44
or basic imaging that might predict,
68:46
but again, these are kind of single center limited studies,
68:49
so I wouldn't say that that would generalize to, um,
68:52
anyone else's population readily.
68:55
Okay. Last, uh, question etiology of tubulopathy.
68:58
So basically, I, I described this kind of in on that slide,
69:02
but, um, and throughout the lecture,
69:03
but microtubules are basically the scaffolds, right?
69:06
They're the scaffolds for the brain for migration.
69:10
And so if you mess that up,
69:12
you mess up migration everywhere.
69:14
But, uh, microtubules are unique
69:17
because they have that dynamic instability with the plus
69:19
and minus N, which is A GTP hydrolysis dependent.
69:23
It's energetic dependent.
69:24
So not only do you screw up migration everywhere,
69:27
but you do it in an energy dependent fashion.
69:29
And so because the energetics in the cell varies throughout,
69:33
you know, uh, the spatial, uh, this, you know,
69:36
the basically the geography of the brain,
69:39
then you get subtly different asymmetric
69:41
malformations throughout.
69:42
Uh, so things are disrupted,
69:43
but in a very st stochastic manner.
69:47
Oh, Dr. Ho, it looks like you knocked
69:48
those out real quick.
69:49
Good job.
69:51
Excellent. All right, well thank you everyone.
69:52
Uh, happy to take any more by email if, uh, if needed.
69:55
And yeah, Chi, I don't know if I did the fake osis
69:58
for this group, but I'm happy to do
69:59
it in the future if needed.
70:01
Yes. Uh, thank you so much for the lecture
70:03
and answering all those great questions.
70:04
And thank you to everyone here
70:07
that participated in the Noon conference today.
70:10
You can access a recording of today's conference
70:12
and all our previous noon conferences
70:13
by creating a free account.
70:15
And we'll also be sending out a link to the replay
70:19
by email later today.
70:21
Be sure to join us next week on Wednesday,
70:24
February 11th at 12:00 PM where Dr.
70:28
Emily and Binder will deliver a lecture entitled
70:31
Birads V 2025 update.
70:34
You can register for that@modality.com
70:36
and follow us on social media
70:37
for updates on all our future noon conferences.
70:40
Thanks again, and have a great day.
Mai-Lan Ho, MD
Professor and Vice Chair of Radiology
University of Missouri
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