Seizures: Mechanisms

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.