Despite the variety of clinically defined seizures, important insights into the generation of seizure activity can largely be understood by comparing the electrographic patterns of focal and primary generalized seizures. The defining feature of focal (and secondarily generalized) seizures is that the abnormal electrical activity originates from a seizure focus. The seizure focus is nothing more than a small group of neurons, perhaps 1,000 or so, which have enhanced excitability and the ability to occasionally spread that activity to neighboring regions and thereby cause a seizure.
The enhanced excitability (epileptiform activity) may result from many different factors such as altered cellular properties or altered synaptic connections caused by a local scar, blood clot, or tumor. A discrete focus in the primary motor cortex may cause twitching of a finger or jerking of a limb (sometimes called simple partial seizure), whereas a seizure focus in the limbic system is frequently associated with unusual behaviors or an alteration of consciousness (sometimes called complex partial seizure).
The development of a focal seizure can be arbitrarily divided into four phases: (1) the interictal period between seizures followed by (2) synchronization of activity within the seizure focus (Figure 50–4), (3) seizure spread, and finally (4) secondary generalization. Phases 2 to 4 represent the ictal phase of the seizure. Different factors contribute to each phase.
Much of our knowledge about the electrical events during seizures comes from studies of animal models of focal seizures. A seizure is induced in an animal by focal electrical stimulation or by acute injection of a convulsant agent. This approach and the development of in vitro brain slice preparations (Box 50–2) have provided a good understanding of electrical events within the focus during a seizure as well as during the interictal period
Box 50–2 Mammalian Brain Slice Preparation
The ability to record electrical activity in tissue slices revolutionized the study of the electrophysiological properties of mammalian neurons. Brain slices, which range from 70 to 400 μm thick, are prepared by quickly removing the brain and immersing it into chilled saline and then sectioning the tissue with a special type of microtome. This technique preserves the basic circuitry of neurons in the slice. The slice is placed in a recording chamber (Figure 50–5) through which oxygenated saline solution is circulated.
There are two principal advantages to recording from neurons in tissue slices. First, more stable electrophysiological recordings can be made because there are no mechanical pulsations resulting from respiration or the pumping of blood. This allows recording from very fine neuronal processes, such as dendrites.
Second, the tissue can be seen under a microscope. When the microscope is equipped with special optics, such as Nomarski differential interference contrast optics, one can actually see unstained living neurons. Direct observation of neurons allows them to be identified from their morphology or by genetic tagging of specific molecules or cell types with green fluorescent protein (Figure 50–6). Direct observation also facilitates patch clamping of individual neurons.
Recording from brain slices has been used to investigate various aspects of the function of mammalian neurons. Through the use of tissue slice techniques, cell- and molecular-biological approaches can be applied to virtually any part of the mammalian brain. Information obtained from recordings made in brain slices has provided important insights into such problems as synaptic plasticity, the mechanisms of epilepsy, and the actions of drugs on the brain.
Set-up for recording from neurons in a brain slice.
The slice is mounted in a chamber attached to the X-Y stage of a microscope. A water-immersion objective allows the slice to be viewed at high power through the saline solution. In this way, separate stimulation and recording electrodes can be placed in the tissue. (Adapted, with permission, from Konnerth 1990.)
Photographs of a rat hippocampal slice.
(Reproduced, with permission, from A. Konnerth.)
A. This light microscope image from the cut surface of the slice reveals the pyramidal cell layer in the CA1 region of the hippocampus. The contrast is enhanced using differential interference contrast (Nomarski) optics.
B. A single pyramidal cell has been filled with the fluorescent dye Lucifer yellow through a pipette directed at the cell body. The large apical dendrite projects toward the bottom of the photograph and the basilar dendrites toward the top.
Neurons in a Seizure Focus Have Characteristic Activity
How does electrical activity in a single neuron or group of neurons lead to a seizure? Each neuron within a seizure focus has a stereotypic and synchronized electrical response called the paroxysmal depolarizing shift, an intracellular depolarization that is sudden, large (20–40 mV), and long-lasting (50–200 ms), and triggers a train of action potentials at its peak (Figure 50–7B). The paroxysmal depolarizing shift is followed by an afterhyperpolarization.
Interictal spikes as measured in the EEG result from the synchronized discharges of a group of hippocampal neurons.
(Adapted, with permission, from Wong, Miles, and Traub 1984.)
A. Rhythmic firing is evident in an intracellular recording from a pyramidal cell in a hippocampal slice. An extracellular recording from the same slice shows the synchronized discharge of many neurons. This type of synchronized activity underlies interictal spikes in the EEG.
B. The hippocampal slice was perfused with bicuculline, which blocks the inhibition mediated by GABAA receptors in pyramidal cells and increases the occurrence of seizure-like activity. An intracellular recording from the slice shows several action potentials in one cell (top trace). On the next trial (lower trace) a hyperpolarizing current was injected to prevent the cell from firing, revealing the large paroxysmal depolarization shift that produces the sudden and long-lasting firing of neurons in a seizure focus.
The paroxysmal depolarizing shift and afterhyperpolarization are shaped by the intrinsic membrane properties of the neuron (eg, voltage-gated Na+, K+, and Ca2+ channels) and by synaptic inputs from excitatory and inhibitory neurons (primarily glutaminergic and GABAergic, respectively). The depolarizing phase results primarily from activation of AMPA- and NMDA-type glutamate receptor-channels (Figure 50–8A), as well as voltage-gated Na+ and Ca2+ channels. The NMDA-type receptor-channels are particularly suited to enhancing excitability because depolarization relieves Mg2+ blockage of the channel. Once unblocked, excitatory current through the channel increases, thus enhancing the depolarization and allowing extra Ca2+ to enter the neuron (see Chapter 10).
The conductances that underlie the paroxysmal depolarizing shift (PDS) of a neuron in a seizure focus.
A. The paroxysmal depolarizing shift is largely dependent on AMPA- and NMDA-type glutamate receptor-channels. The effectiveness of the NMDA-type is enhanced by the opening of voltage-gated Ca2+ channels (gCa). Following the depolarization the cell is hyperpolarized by activation of GABA receptors (both ionotropic GABAA and metabotropic GABAB) as well as by voltage-gated and calcium-activated K+ channels (g K). (AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate; GABA, γ-aminobutyric acid; NMDA, N-methyl-D -aspartate.) (Adapted, with permission, from Lothman 1993a.)
B. A simplified version of the inputs to a cortical pyramidal neuron. The orange terminals are excitatory, whereas the gray terminals are inhibitory. Recurrent axon branches activate inhibitory neurons, causing feedback inhibition of the pyramidal neuron. Extrinsic excitatory inputs can also activate feed-forward inhibition.
The normal response of a cortical pyramidal neuron to excitatory input consists of an excitatory postsynaptic potential (EPSP) followed by an inhibitory postsynaptic potential (IPSP) (because of the basic circuitry shown in Figure 50–8B). Thus the paroxysmal depolarizing shift can be viewed as a massive enhancement of the normal depolarizing and hyperpolarizing synaptic components. The afterhyperpolarization is generated by several types of K+ channels as well as a GABA receptor-mediated Cl– conductance (ionotropic GABAA receptors) and K+ conductance (metabotropic GABAB receptors) (Figure 50–8A). The Ca2+ entry through voltage-dependent Ca2+ channels and NMDA-type receptor-channels triggers the opening of calcium-activated channels, particularly K+ channels. The afterhyperpolarization limits the duration of the paroxysmal depolarizing shift; its gradual disappearance is an important factor in the onset of a focal seizure, as discussed later.
Thus it is not surprising that many convulsants act by enhancing excitation or blocking inhibition. Conversely, anticonvulsants act by blocking excitation or enhancing inhibition. For example, the benzodiazepines diazepam (Valium) and lorazepam (Ativan) enhance GABAA -mediated inhibition and are used in the emergency treatment of prolonged repetitive seizures. The commonly used anticonvulsants phenytoin (Dilantin) and carbamazepine (Tegretol) cause reduction in the opening of the voltage-gated Na+ channels that underlie the action potential. The ability of these drugs to block the Na+ channels is enhanced by repetitive activity associated with seizures.
The Breakdown of Surround Inhibition Leads to Synchronization
As long as the abnormal electrical activity is restricted to a small group of neurons, there are no clinical manifestations. The synchronization of neurons in the focus is dependent not only on the intrinsic properties of each individual cell but also on the connections between neurons. During the interictal period the abnormal activity is confined to the seizure focus by inhibitory effects of the excited region on surrounding tissue. This inhibitory surround is particularly dependent on feed-forward and feedback inhibition by GABA-ergic inhibitory interneurons (Figure 50–9A).
The spatial and temporal organization of a seizure focus depends on the interplay between excitation and inhibition of neurons in the focus.
A. In this hypothetical seizure focus in the neocortex, the pyramidal cell a shows the typical electrical properties of neurons in a focus (see part B). Activity in cell a activates another pyramidal cell (b), and when many such cells fire synchronously a spike is recorded on the EEG. However, cell a also activates GABAergic inhibitory interneurons (gray). These interneurons can reduce the activity of cells a and b through feedback inhibition, thus limiting the seizure focus temporally, as well as prevent the firing of cells outside the focus, represented here by cell c. This latter phenomenon creates an inhibitory surround that contains the seizure focus spatially. When extrinsic or intrinsic factors alter this balance of excitation and inhibition, the inhibitory surround begins to break down and the seizure activity spreads. (Reproduced, with permission, from Lothman and Collins 1990.)
B. The synaptic connections and activity patterns for cells a, b, and c. Cells a and b within the seizure focus undergo a paroxysmal depolarizing shift (see Figure 50–7B). However, cell c in the region surrounding the seizure focus is hyperpolarized because of input from GABAergic inhibitory interneurons.
During the development of a focal seizure the inhibitory surround is overcome and the afterhyperpolarization in the neurons of the original focus gradually disappears. As a result, the seizure begins to spread beyond the original focus and a nearly continuous high-frequency train of action potentials is generated (Figure 50–10).
A focal seizure begins with the loss of the afterhyperpolarization and surround inhibition.
(Adapted, with permission, from Lothman 1993a.)
A. At the onset of a seizure (arrow) neurons in the seizure focus depolarize as in the first phase of a paroxysmal depolarizing shift. However, unlike the interictal period, the depolarization persists for seconds or minutes. The GABA-mediated inhibition fails, whereas excitatory activity in the AMPA- and NMDA-type glutamate receptors is functionally enhanced. This activity corresponds to the tonic phase of a secondarily generalized tonic-clonic seizure. As the GABA-mediated inhibition gradually returns, the neurons in the seizure focus enter the clonic phase, a period of oscillation.
B. As the surround inhibition mediated by GABAergic interneurons breaks down, neurons in the seizure focus become synchronously excited and send trains of action potentials to distant neurons, thus spreading the abnormal activity from the focus. Compare the pattern of activity in cells a to c here with that during the interictal period in Figure 50–9B.
An important factor in the spread of focal seizures appears to be that the intense firing of the pyramidal neurons results in a relative decrease in synaptic transmission from the inhibitory GABAergic interneurons. This decrease may result from a change in the release of GABA (presynaptic mechanisms), a change in the chloride gradient responsible for the GABAA receptor-mediated ion flux, or a change in GABA receptor activity (postsynaptic mechanism). Other factors that may contribute to the loss of the inhibitory surround include changes in dendritic morphology, changes in the density of receptors or channels, or changes in the amount of extracellular K+ ion accumulation. Prolonged firing also transmits action potentials to distant sites in the brain, which in turn may trigger trains of action potentials in neurons that project back to neurons in the seizure focus (backpropagation). Reciprocal connections between the neocortex and thalamus may be particularly important in this regard.
Despite our understanding of such mechanisms, we still do not know what causes a seizure to occur at any particular moment. The inability to predict when a seizure will occur is perhaps the most debilitating aspect of epilepsy. Some patients become adept at adjusting their lifestyle to avoid circumstances that can increase the likelihood of a seizure, such as sleep deprivation or stress. But in many individuals seizures do not follow a predictable pattern. In a few patients sensory stimuli such as flashing lights can trigger seizures, suggesting that repetitive excitation of some circuits causes a change in excitability that is dependent on the frequency of neuronal firing.
Both NMDA-type glutamate receptor activity and GABAergic inhibition undergo changes in sensitivity that depend on the frequency of firing of the presynaptic neuron, providing a possible cellular mechanism for altered network excitability. On a longer time scale, circadian rhythms and hormonal patterns may also influence the likelihood of seizures, as demonstrated by patients who have seizures only while sleeping (nocturnal epilepsy) or during their menstrual period (catamenial epilepsy). New devices for continuous monitoring at or near a seizure focus may allow clinicians to predict the timing of seizure generation. Such approaches offer the possibility of acute therapeutic intervention such as direct cortical stimulation to prevent seizures. The modest success of implanted vagal nerve stimulators in epilepsy that does not respond to other treatments provides one example of such an approach.
The Spread of Focal Seizures Involves Normal Cortical Circuitry
If activity in the seizure focus is sufficiently intense, the electrical activity begins to spread to other brain regions. Spread of seizure activity from a focus generally follows the same axonal pathways as does normal cortical activity. For example, the neurons in the primary motor and sensory cortex are organized functionally into vertical columns that run from the pial surface to the underlying white matter (see Chapter 15). The major input to sensory cortex comes from the thalamus and terminates in layer IV, whereas the output cells are in layer V. Reciprocal thalamocortical pathways connect the thalamus and cortex. Intracortical connections occur via short U fibers between adjacent sulci and via the corpus callosum, the major connection between the cerebral hemispheres. These thalamocortical, subcortical, and interhemispheric pathways can all become involved in seizure spread.
Focal seizure activity can spread from the seizure focus to other areas of the same hemisphere or across the corpus callosum to the contralateral hemisphere (Figure 50–11A). Once both hemispheres become involved, the seizure has become secondarily generalized. At this point the patient generally experiences loss of consciousness. The spread of a focal seizure usually occurs within a few seconds but can also take many minutes.
Seizures propagate via several pathways.
(Reproduced, with permission, from Lothman 1993b.)
A. Focal seizures can spread locally from a focus via intrahemispheric fibers (1) and more remotely to homotopic contralateral cortex (2) and subcortical centers (3). The secondary generalization of focal seizure activity spreads to subcortical centers via projections to the thalamus (4). Widespread thalamocortical interconnections then contribute to rapid activation of both hemispheres.
B. Primary generalized seizures, such as a typical absence seizure, spread primarily through interconnections between the thalamus and cortex.
As the focal seizure begins to spread, the patient may experience some warning symptoms (an aura). If the seizure spreads slowly across the cortex, it may lead to a progression of clinical symptoms—a Jacksonian march in the case of a focal seizure involving the motor cortex. Focal seizures that quickly undergo secondary generalization provide little or no warning. Rapid secondary generalization is more likely if the seizure begins in the neocortex than if it begins in the limbic system (in particular, the hippocampus and amygdala).
An interesting unanswered question is what terminates a seizure. The only definitive conclusion at this point is that termination is not caused by metabolic exhaustion. During the initial 30 seconds or so of a typical secondarily generalized tonic-clonic seizure, neurons in the involved areas undergo prolonged depolarization and continuously fire action potentials (caused by loss of the afterhyperpolarization that normally follows a paroxysmal depolarizing shift). As the seizure evolves, the neurons begin to repolarize and the afterhyperpolarization reappears. The cycles of depolarization and repolarization correspond to the clonic phase of the seizure (Figure 50–10A).
The seizure is often followed by a period of decreased electrical activity, the postictal period, that may be accompanied by confusion, drowsiness, or even focal neurological deficits such as a hemiparesis (Todd paralysis). A neurological exam in the postictal period can lead to insights about the locus of the seizure focus.