00:01
So if those are the types of seizures,
what's going on when we see a seizure?
What's the mechanism
underlying seizure development?
Well, there's really 3 things
that happen in the brain
to result in a seizure
and an epilepsy.
00:13
The first is you have to
have a short in the circuit.
00:17
And in neurology, we call that a
paroxysmal depolarization shift.
00:21
And this is the short
that gives rise to that
initial seizure nidus
and seizure focus.
00:26
That's followed by driving
of normal neighbors.
00:29
So normal neurons have to
be co-opted into seizing
and this is called
neuronal synchronization.
00:36
A seizure will not spread
unless the surrounding neurons
get involved and into the action
and begin to seize as well
and be involved in
that seizure activity.
00:47
And then the third feature
is failure of inhibition.
00:50
And we call this the
transition to the ictus.
00:52
What really allows
the seizure to spread
and start in that one focus
and then spread to others
or other areas of the brain
is the lack of inhibition.
01:01
When there is sufficient
inhibition around a seizure focus,
the seizure won't spread.
01:05
And we often don't see manifestation
of seizures or symptoms.
01:10
And the goal of treatment is really
to restore this failure of inhibition
to increase inhibitory
tone in the brain.
01:18
Let's walk through each
one of those and understand
what's going on in the brain
with this short circuit
and with this a driving of normal neighbors,
and then the loss of inhibition.
01:29
We said step 1 is a
short in the circuit.
01:32
And we know that seizures
come from neurons,
they come from cell bodies
and the gray matter,
that's where all seizures arise.
01:39
But critical in that process
is all the other structures
that are around the neurons.
01:43
The astrocytes in particular,
we see that astrocytes, the cells
or groups of cells become excited
in the initial process
of instigating a seizure.
01:54
Those astrocytes are important
in normal neurotransmission.
01:59
Astrocytes bind up the glutamate that's
released by neurons recycle that glutamate
and sometimes can release
glutamate of their own accord.
02:08
Glutamate is the
excitatory neurotransmitter
and as a result of this lack
of scavenging of glutamate
and increased secretion of glutamate,
we see increased excitation of a neuron.
02:20
This results in increased
calcium signaling
and neurons become hyperexcitable, and
that's the initial short in the circuit
that can occur
anywhere in the brain
that will drive a
seizure to occur.
02:32
The end result is something we call
a paroxysmal depolarization shift
as the short in the circuit.
02:38
And that shows up on the surface
EEG as a spike and a slow wave.
02:43
That spike is that area that
nidus of hyperexcitable neurons
that are synchronized
in their activity.
02:49
And that is a sign of
underlying seizure activity
or where the short
exists in the brain.
02:57
On underlying EEG, if we were to
look at EEG of a single neuron,
this is what it would look like.
03:03
And it's that single neuron
that's hyperexcitable
and being excited multiple times
to drive that spiking activity.
03:10
And that's a critical signature of
this paroxysmal depolarization shift.
03:17
The paroxysmal depolarization shift, the
PDS is not sufficient to create a seizure.
03:22
We really need step 2 and 3, and step
2 is the driving of normal neighbors.
03:27
When we think about what happens
to lead to an action potential,
or activation of a
neuron, there's 3 steps.
03:34
There's this rising phase, the peaking
phase, and then the recovery phase.
03:39
And what we're looking at is the
threshold for excitation of a neuron.
03:44
In that first phase, sodium channels open
and we know that sodium enters the cell,
then potassium channels open and
potassium begins to leave the cell.
03:53
The sodium channels
close at that peeking.
03:56
We see that potassium leaves and rushes
out across its concentration gradient.
04:01
And then the potassium
channels close
and there's this period of
refractory period of the neuron
where it cannot be
excited or activated.
04:12
And ultimately,
the excess potassium outside
diffuses away and
the neuron is reset.
04:18
What happens in the epileptic
phenomenon with a seizure
is repeated paroxysmal depolarizations
of a large enough group of neurons
will increase
extracellular potassium.
04:30
That many spikes that
we saw on the last slide
will drive increase potassium
concentration in the extracellular fluid.
04:39
Increased extracellular
potassium tends to drive
depolarization of
surrounding neurons.
04:44
So that increased excitation that has
resulted in the surrounding neurons.
04:50
As more potassium builds up
in the extracellular space,
less potassium diffuses
from around the neurons
during the hyperpolarization
state of the cell,
and so neurons become
partially depolarized.
05:03
They're always ready to fire.
05:06
Increased extracellular potassium may
also flow down its concentration gradient
and aid in the depolarization.
05:12
That's really the phenomenon
that's contributing
to partial depolarization
of the neurons.
05:18
And so this is the process that
contributes to driving of normal neighbors
and the onset of a seizure.
05:25
The third step,
which is critical to the development
of long term epilepsy is
failure of inhibition.
05:32
And this is what ultimately results from
repeated paroxysmal depolarization shifts
and loss or driving of
those normal neighbors.
05:41
We see loss of after
hyperpolarization.
05:44
There's loss of that hyperpolarization,
that refractory phase,
loss of surround inhibition,
all those normal neurons
that drive inhibitory tone around
this ictal nidus are lost and reduced.
05:57
There's excess
glutamate stimulation.
05:59
Glutamate is the excitatory
neurotransmitter.
06:01
Too much glutamate is released
by astrocytes and neurons
into surrounding neurons and
we lose that inhibitory tone
and increase in
intracellular calcium.
06:12
Recurrent excitatory feedback circuit
is what is created from this process.
06:16
As a result of
loss of inhibition,
we get an excitatory circuit that wants
to drive subsequent seizure formation.
06:23
And as a result of
repeated seizures,
we can see long term changes
in neurons and in the brain.
06:29
Increased calcium over time results in long
term structural and functional changes
in the neurons themselves
to drive and beget seizures.
06:38
We say that seizures beget
seizures and that's in many parts
as a result of these long
term changes that occur.
06:45
There are second messenger activation
changes to gene expression.
06:49
Calcium activation turns on cell
pathways, cell death pathways
that can destroy surrounding inhibitory
neurons and increased excitatory tone.
06:58
The hippocampus is an important
place to think about this.
07:01
The hippocampus is
an epileptic region.
07:04
Long term potentiation is the
process in the hippocampus
that allows us to put down and lay
down new memories to make new memories
and that's where circuits of neurons can
become repeatedly activated very easily.
07:17
The hippocampus therefore is at
higher risk of developing seizures
and more prone to
developing epilepsy.
07:24
In fact, long term
seizures in one hippocampus
can co-opt the other hippocampus
into becoming a second nidus
of seizure development.