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13
EPILEPSY
A
Alpha
Beta
Theta
Delta
B
Fig. 13.3 EEG recording and major wave types. (A) Normal EEG recording during the awake state. The traces represent wave recordings from
various electrode combinations. (B) Major wave types. C, Central; F, frontal; Fp, frontoparietal; O, occipital; P, parietal; T, temporal. (A, From Shin
et al. (2014) Review of epilepsy—aetiology, diagnostic evaluation and treatment. Int. Journal of Neurorehabilitation. 1:130. B, From Guyton AC,
Hall JE. (2006) Textbook of medical physiology, 11th ed. Philadelphia: Elsevier Saunders.)
multiple electrode combinations, reflecting various wave
patterns. The major types of EEG waves are shown in
Fig. 13.3B. EEG waves are also described in Chapter 16
(Box 16.8, Fig. 16.4), with reference to their link to sleep
and wakefulness. In general, an EEG wave that is of low
amplitude and high frequency, with no obvious pattern,
indicates an alert or awake state. Healthy adults typically
manifest relatively low- amplitude, mixed- frequency background rhythms, also termed desynchronized. These are
beta waves and have a frequency of 13–30 Hz. This type of
desynchronized activity occurs because the brain neurons
are all working independently so that many of the different frequencies of activity cancel out each other. However,
when a person is relaxed, especially with their eyes closed
as in sleep or quiet contemplation, the amplitude increases
1 sec
but the frequency is low. This rhythm of activity is the
alpha rhythm and occurs because neurons are now firing synchronously. These slow synchronous waves are
of relatively low amplitude and have a frequency of 8–12
Hz. They are largest in the parieto- occipital region, but if
a relaxed person is disturbed, opens their eyes or become
anxious, the alpha rhythms abruptly stop. Occasional
slower theta (4–7 Hz) or even delta (1–3 Hz) frequencies
transiently may be seen during normal wakefulness, but
usually these slower activities only become prominent
during drowsiness. Therefore, theta and delta waves are
not normally seen in awake adults. Irregular theta waves
(4–7 Hz) are common in children and are seen in adults
during rapid eye movement (REM) sleep. Low- frequency
(4 Hz or less), high- amplitude delta waves are only seen in
50 µV
279THE NERVOUS SYSTEM
13
sleep or during anaesthesia or coma. Other characteristic
EEG patterns can occur, such as the sudden high amplitude bursts called ‘sleep spindles’, which happen during
EPILEPSY
stage 4 sleep. Sleep is characterized by very specific EEG
profiles for each sleep stage (Fig. 16.4). When the brain
ceases activity (i.e. death), the EEG pattern becomes a flat
line.
Electroencephalogram patterns in epilepsy
The EEG is an essential element in the diagnosis of epilepsy. It provides important information about background activity and epileptiform discharges, and is
required for the diagnosis of specific syndromes. This
guides the selection of anti-epileptic medication and
prognosis. There are often dramatic and very characteristic changes in the EEG patterns of patients with epilepsy, as shown in the example EEG recording of a young
patient with Lennox- Gastaut syndrome, which is a
severe form of childhood- onset epilepsy characterized by
multiple seizure types (Fig. 13.4), but unless the recording is prolonged, the patient may not have a seizure during the EEG procedure.
characteristic epileptiform activity between seizures; this
is the interictal activity. In some cases, it is also possible
to induce abnormal activity by forced hyperventilation
(3 min) or flashing lights (stroboscopic photic stimulation). As noted in Fig 13.4, EEG changes may take the
form of ‘spikes and waves’, which reflect the underlying
Around 50%–70% of patients with epilepsy will show
depolarization of the cortical neurons. Certain patients
with epilepsy show no abnormal interictal activity, while
a significant number (0.5%–2%) of randomly selected
individuals without epilepsy show similar interictal EEG
patterns. These false positive results rise to 5%–10% in
first- degree relatives of patients with confirmed epilepsy.
During a seizure, the large- amplitude spikes and
waves may be generalized, occurring in all electrodes or
they may only occur in a subset of the recordings. The
region of focal epilepsy origin can be determined by the
pattern of the EEG abnormalities. This is necessary for
the surgical treatment of epilepsy.
In absence seizures (Fig 13.5), the EEG shows a rhythmic 3–4 Hz spike-and-wave potential from most scalp
electrodes, whereas in ‘grand mal’ seizures, the EEG
shows higher- frequency, irregular, large- amplitude waves
from most recording sites. In some cases the EEG may
show the focal discharges spreading across the brain to
give a generalized pattern. Fig. 13.6 shows the EEG typical
of a ‘grand mal’ seizure. There is an abrupt onset of generalized rapid spikes at the start of the tonic phase, and as
the spike firing frequency decreases, the individual spikes
become far enough apart that each spike can generate a
separate clonic jerk, representing the clonic phase.
A development in the management of epilepsy, based
on EEG recording is the potential prediction of seizures.
There is accumulating evidence that seizures often have a
specific circadian pattern, and that they develop minutes
to hours before their clinical expression. In the future, it
may be possible to define the exact characteristics of the
Fp2–F4
F4–C4
C4–P4
P4–O2
Fp1–F3
F3–C3
C3–P3
P3–O1
Fig. 13.4 EEG recording in Lennox- Gastaut syndrome. The traces show generalized sharp spike and slow- wave discharges on the EEG of a
9- year- old child with intellectual disability and uncontrolled typical absence, tonic, and atonic generalized seizures. This combination of clinical
and EEG features constitutes Lennox- Gastaut syndrome. (From Emerson RG, Hahn CD (2022) Bradley and Daroff’s neurology in clinical practice.
8th edn. Edited by J Jankovic, NJ Newman, JC Mazziotta, SL Pomeroy. Philadelphia: Elsevier Inc.)
1
2
3
4
5
6
50 µV
7
8
1 sec
9 y/o
280 SYSTEMS OF THE BODY
13
Fp1 - F7
F7 - T7
T7 - P7
P7 - O1
Fp1 - F3
F3 - C3
C3 - P3
P3 - O1
Fz - Cz
Cz - Pz
Fp2 - F4
F4 - C4
C4 - P4
P4 - O2
Fp2 - F8
F8 - T8
T8 - P8
P8 - O2
P7 - T7
T7 - FT9
FT9 - FT10
FT10 - T8
F8 - P8
FT9 - FT10
ECG 1
Fig. 13.5 EEG recording in absence seizure. The traces show an EEG in a 2- year- old boy presenting with absence seizures at only 23 months of
age. High voltage, generalized 3–4 Hz paroxysmal slow waves superimposed upon a normal background, accompany staring spells. The lowest
trace shows the electrocardiogram (ECG). (From DiBacco ML, Gibson KM, Pearl PL (2022) Bradley and Daroff’s neurology in clinical practice. 8th
edn. Edited by J Jankovic, NJ Newman, JC Mazziotta, SL Pomeroy. Philadelphia: Elsevier Inc.)
EPILEPSY
Fp1–F3
F3–C3
C3–P3
P3–O1
Fp2–F4
F4–C4
C4–P4
P4–O2
75 µV
1 sec
Fig. 13.6 EEG characteristics of tonic–clonic seizure. Example of
generalized spike- wave patterns in primary generalied (idiopathic)
epilepsy. This patient had mainly tonic–clonic seizures with occasional
absence attacks. (From Emerson RG, Hahn CD (2022) Bradley and
Daroff’s neurology in clinical practice. 8th edn. Edited by J Jankovic, NJ
Newman, JC Mazziotta, SL Pomeroy. Philadelphia: Elsevier Inc.)
EEG changes that precede a seizure, and devise a therapeutic strategy to prevent the onset of the clinical seizure.
There is some evidence that seizures can be predicted
from changes in the EEG at least 20 min before they
occur, with some more subtle changes occurring up to 90
min before seizure onset. An implantable device could
warn of the impending seizure and intervene with focal
stimulation (closed- loop stimulation) or focal application
of drugs, so that the seizure can be prevented.
Other diagnostic techniques
Structural changes in the brain that lead to epileptic foci
can be studied by MRI and computed tomography (CT).
An MRI can reveal previously undetected structural
abnormalities that may play a causal role. Therefore, it
is used for investigating aetiology and also for selecting
patients for surgical treatment. The technique can reveal
several types of cerebral abnormality such as hippocampal sclerosis, small lesions (invisible on CT scans) and
cortical dysgenesis.
Magnetic resonance spectroscopy (MRS) can detect
changes in the biochemistry of the brain. The analysis of
nervous tissue proton MRS spectra shows three major
peaks: N- acetylaspartate (NAA), creatine and phosphocreatine, and also a peak for choline- containing compounds. A reduction in the NAA peak is generally viewed
as reflecting neuronal loss or dysfunction. A reduction in
the NAA peak and a concomitant increase in the other
two major peaks may indicate neuronal loss accompanied
by gliosis. MRS spectra can also provide information on
tissue inositol, lactate, gamma-aminobutyric acid (GABA)
and glutamate concentrations. Also, MRS can help in the
detection of hippocampal sclerosis and abnormal cortical
foci. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be used
to investigate brain metabolism and also the presence of
neuroinflammation, using specific markers; they may
enable the detection of seizure foci. Especially when several of these investigations are used in combination, they
281THE NERVOUS SYSTEM
13
can be of help in refining the diagnosis and devising the
best therapeutic strategy.
EPILEPSY
Fig. 13.1 details that there are three main types of seizure
onset: focal onset, generalized onset and unknown onset.
The type of onset is determined based on clinical characteristics, EEG and imaging data. Examples of characteristic features of various types of seizures are given below.
Focal onset seizures
These seizures occur when the seizure activity starts in
a focal brain area. In a large proportion of cases, the seizures are limited and there is full awareness. In some
cases, awareness may be lost and the seizures may generalize, as described below.
Focal seizures
In the simplest type of focal seizures, there is no loss of
consciousness. The origin of focal seizures leads to symptoms that depend on the area involved. For example, convulsive limb movements on one side of the body indicate
an epileptic focus in the motor cortex of the contralateral
side. The patient may experience weakness in the affected
muscles after the seizure. Other focal symptoms may
include tingling, hallucinations (visual, olfactory or gustatory) and swallowing or chewing movements. The latter
are indicative of temporal lobe epilepsy, which is the commonest form of focal epilepsy. Because of the temporal lobe
involvement in memory, it is not surprising that the focal
symptoms can include a feeling of ‘déjà vu’, a feeling of a
rush of memories, or memory loss. The patient may appear
detached and slow, and may have repetitive movements
such as lip- smacking and chewing movements and make
unusual noises. Sometimes this behaviour is more complex
and may be aggressive. The other area commonly affected
in focal seizures is the frontal lobe. Focal epilepsies are
often associated with structural changes, which can include
developmental abnormalities in the young, and traumainduced damage or tumours in older patients.
consciousness. They are often more severe forms of temporal lobe epilepsies and may last for between 30 s and
1–2 min. Although the patient may be unable to communicate or respond to commands, consciousness may
not be completely impaired. During the seizure patients
may be able to continue simple motor behaviour. Usually
there is no loss of postural control. In general, patients
are amnesic of the seizure.
Focal seizures with secondary generalization
Focal epilepsy may sometimes spread over the cerebral
cortex, first on the side of the initial focus, and then to
Examples of types of seizure
Some focal seizures can be associated with impaired
the opposite hemisphere. This can be seen in the EEG
by a gradual increase in the ictal activity, starting with
the focal area and gradually including all the traces. A
particular example of this type of seizure is known as
Jacksonian epilepsy, in which the focal signs start either
in the face or at the extremities of a limb. Movements
then rapidly spread across the face or ascend the limb,
leading to a generalized seizure (see below). As the focal
seizure may spread very rapidly, the patient may not
remember the focal start of the seizure. The only indication that this is not a primary generalized seizure (apart
from an EEG, which may be hard to obtain) is the evidence of focal movements (as reported by an observer)
and unilateral postictal motor weakness (known as
‘Todd’s paralysis’), which may be seen if the initial focus
of the seizure is in the motor cortex.
Generalized onset seizures
Generalized seizures involve both hemispheres of the
brain and abnormalities can be seen simultaneously in all
the EEG traces. Seizures of this type are thought to originate from midline structures such as the thalamus, which
diffusely innervate the entire cortex, thus triggering a
generalized seizure.
Absence seizures
This type of seizure, also known as ‘petit mal’, usually
starts in childhood and may occur many times each day,
lasting for only 5–15 s. The condition is reminiscent of ‘daydreaming’, with the patient staring vacantly, sometimes
with eye- blinking and eye- rolling. The EEG shows a characteristic bilateral 3- Hz waveform, seen in all traces, with synchronized spike- and- wave patterns. This type of epilepsy
is often diagnosed following the poor school performance
of an inattentive child. It is thought that this type of seizure
results from abnormalities in T- type Ca2+ channels.
Tonic–clonic seizures
This is the type of seizure suffered by Gaby (Box 13.1).
These seizures, also called ‘grand mal’, are the most typical type seen in adults. Prior to an attack, some patients
may experience vague symptoms, called an ‘aura’. This
may be a smell or a taste, or just ‘feeling strange’. It may
last for a few seconds, which may be enough for the
patient to be able to lie down, thus preventing injury due
to falling during the seizure. However, many patients
have no warning. The typical seizure of this type has
three phases. The first is the tonic phase, which lasts for
about 10–40 s. The patient becomes very rigid, as all the
muscles in the body undergo tonic, sustained contraction. The patient falls rigidly and, as the respiratory and
laryngeal muscles are also contracted, may let out a cry
or grunt as air is forced out of the chest through the taut
vocal cords. During this time there is no respiration, so
the patient becomes cyanotic. This is followed by the
clonic phase, during which the muscles go into strong,
282 SYSTEMS OF THE BODY
13
random contractions. This limb- jerking may be accompanied by urinary and faecal incontinence, and there may
be tongue- biting and frothing at the mouth. Breathing is
jerky and inefficient, and there is tachycardia. This phase
usually lasts for 2–3 min, although it can last for longer.
The third phase is a coma (the patient is unconscious and
the muscles are flaccid) in which the patient’s breathing
becomes regular and their colour returns to normal. The
length of this period is related to the duration of the previous tonic–clonic phases. When patients wake they may
be confused and have a headache.
During a seizure of this type the levels of neuronal
activity are very high but, because of the reduction (or
lack) of respiration, blood oxygenation is poor. During
this time there is an accumulation of lactic acid in the
brain, and it is this hypoxia and acidosis which is probably the cause of the coma. Blood tests show a low pH
and low pO2. There are increases in creatine phosphokinase and serum prolactin levels.
Repeated seizures can lead to neuronal degeneration, which is thought to be due to the excessive release
of glutamate during the seizure. This can cause cell
death through the mechanism known as excitotoxicity,
which is also implicated in cell death due to stroke (see
Chapter 11).
Febrile seizures
Also known as febrile convulsions, this type of seizure, which may be generalized or focal, occurs commonly in young children under the age of 5 years
and is triggered by fever. Comparison of the EEGs of
children and adults shows that the electrical activity
of the adult brain is more stable than that of children,
and this instability of the immature brain seems to
be increased by fever. These seizures cause anxiety in
parents, who may be worried about the future development of epilepsy. However, these seizures usually
occur only once, and in the small proportion of cases
where epilepsy does develop later, there are other
associated risk factors (Table 13.1).
Table 13.3 Examples of anticonvulsant drugs
First generation drugs New drugs
Phenytoin Lamotrigine
Sodium valproate Vigabatrin
Carbamazepine Topiramate
Phenobarbitone Tiagabine
Acetazolamide Gabapentin
Clobazam Levetiracetam
Ethosuximide Perampanel
Clonazepam Stiripentol
Primidone Zonisamide
Status epilepticus
Usually, epileptic seizures are self- limiting, but sometimes
the seizures continue without the patient regaining consciousness. Status epilepticus is defined as a convulsive
seizure that continues for a prolonged period (> 5 min),
or convulsive seizures that occur one after the other (e.g.
more than 2 seizures within 5 min), with no recovery
between seizures. Status epilepticus is an emergency and
requires immediate medical attention. Convulsive status epilepticus is associated with a mortality of 10%–15%
and is one of the reasons why the mortality of patients
with epilepsy is three times that of age- matched controls.
Deaths during convulsive status epilepticus are due to
the hypoxia and intense acidosis that occur during a seizure. If there is no time for recovery between seizures, this
condition worsens and can lead to cerebral oedema, brain
damage and cardiorespiratory failure. A non-convulsive
form of status epilepticus can also occur and may follow
convulsive status epilepticus. It is characterized by continuous seizure activity, as detected by EEG.
Neurobiology of epilepsy
The cellular basis of epilepsy is still incompletely understood, but from a fundamental neurophysiology perspective
it is believed that epilepsy may be due to intrinsic neuronal
hyperexcitability (e.g. due to dysfunctional voltage- gated
ion channels), increased activity at excitatory synapses or
insufficient activity of inhibitory circuits. As mentioned elsewhere in this book, the major neurotransmitters mediating
fast neurotransmission in the brain are the amino acids glutamate and GABA. These neurotransmitters play a large part
in controlling the excitation–inhibition balance in the central
nervous system (CNS). In addition, many other ligand- gated
and voltage- gated ion channels contribute to the modulation
of the excitability of neuronal networks.
Glutamate transmission
Glutamate receptors are of two main types: ionotropic
and metabotropic (see Chapter 15). The fast, ionotropic receptors are divided into N- methyl- D- aspartate
(NMDA) and non-NMDA receptors. NMDA receptors
are permeable to both Na+ and Ca2+ and are blocked
at normal resting potential by Mg2+. This blockade is
removed by depolarization, so NMDA receptors can
only be activated in a neuron that is already partially
depolarized. NMDA receptors are involved in a process called long- term potentiation (LTP; see Chapter 14).
During LTP, the simultaneous activity of multiple inputs
to a neuron will activate NMDA receptors, which consequently strengthens the connection between the active
neurons, which is why the indiscriminate blockade of
NMDA receptors may have very unfavourable effects on
cognition (as LTP is critical for learning and memory).
The non-NMDA receptors are AMPA receptors
(named after the preferred agonist 4- amino- 3- hydroxy- 5
- methyl- 4- isoxazolepropionic acid [AMPA]) and kainate
EPILEPSY
283THE NERVOUS SYSTEM
13
N
III III IV
receptors (named after kainic acid, which is an agonist). These non-NMDA receptors can be activated at
normal resting potentials, and their activation leads to
EPILEPSY
depolarization. When activity levels are high, the neuron will be sufficiently depolarized for both NMDA and
non-NMDA receptors to be activated. This will allow
Ca2+ to enter the cell, where it acts as a second messenger.
Glutamate receptor agonists, such as kainic acid and ibotenic acid, can induce various types of seizure in animals.
Furthermore, structural changes in glutamate receptors
have been found in surgical specimens from epileptic
patients. The pyramidal cells of the cortex are glutamatergic and there is some evidence that glutamatergic dysfunction may be associated with certain types of epilepsy.
However, NMDA receptor antagonists have limited antiepileptic activity and induce unacceptable adverse effect;
therefore they cannot be used clinically. However, in
recent years, it has become apparent that AMPA receptors
can be successfully targeted for the treatment of epilepsy.
The involvement of AMPA receptors in epilepsies is also
supported by the existence of genes associated with epilepsy that encode for AMPA receptor subunits, and also
proteins involved in the anchorage of AMPA receptors to
membranes.
GABA transmission
There are two main types of GABA receptor: GABAA receptors, which are ionotropic receptors, and GABAB receptors,
which are metabotropic and G- protein- coupled receptors.
When activated, GABAA receptors, which are multimeric
proteins composed of several different subunits, open
an integral Cl- channel. This tends to clamp the neuronal
potential closer to the resting potential. GABAA receptors are postsynaptic, whereas GABAB receptors are found
both post- and presynaptically. There are many different
types of inhibitory non-pyramidal cell in the cortex. Many
of these cells do not have dendritic spines and are termed
non-spiny neurons. Some of these inhibitory cells have synapses on the pyramidal cells that are close to the cell body,
while excitatory inputs tend to arrive on the pyramidal cell
dendrites. This means that activity in inhibitory synapses
that use GABA will have a powerful influence on the firing
patterns of the excitatory pyramidal cells. Inhibitory postsynaptic potentials are the mechanism by which neurons
are prevented from firing. Some theories of the genesis of
epilepsy postulate that a reduction in GABAergic activity allows the uncontrolled discharge of large numbers of
neurons. Lower than normal numbers of GABAergic neurons have been found in tissue from patients with epilepsy
refractory to treatment. Furthermore, increasing GABAergic
activity is the mechanism of action for several of the drugs
used to treat epilepsy.
Ion channels and neuronal excitability
Neuronal membrane excitability is controlled by complex mechanisms, which depend on the coordinated
activity of multiple ion channels. A wide range of
loss- of- function mutations in Na+ channels are associated with epilepsy. It has been suggested that fast firing inhibitory neurons are particularly affected by these
mutations. The rising phase of the action potential is
caused by a current that flows through fast- inactivated
Na+ channels. This current is also associated with a
slow- inactivation component. The blockade of this
component can lead to a switch in the firing of neurons
from regular spiking to burst firing. Certain types of
genetically determined epilepsies, such as the familial
generalized epilepsies with febrile seizures, are associated with changes in the molecular structure of Na+
channels; such mutations decrease the rate of inactivation of Na+ channels (Fig. 13.7).
K+ channels also have a role in excitability; in particular, they are critically involved in the repolarization
of the membrane. The blockade of the K+ M-current
(which is inhibited by the activation of muscarinic acetylcholine receptors) leads to a shift towards greater
depolarization of the membrane. The K+ channel subunits KCN2 and KCN3 contribute to this current, and
mutations in the genes that encode these subunits
are associated with the phenotype of benign neonatal
familial convulsions.
Finally, Ca2+ currents are also an important element
in the control of neuronal excitability, and converging
evidence suggests that dysfunctional Ca2+ channels may
be associated with epileptogenesis. Absence epilepsies
have been associated with changes in a low- threshold
Ca2+ current in neurons of the reticular nucleus in the
thalamus.
N
C
N
β1 subunit
Missense mutation
subunit β2 subunit
α
1
Fig. 13.7 Mutations in Na+ channel subunits associated with idiopathic epilepsy.
Deletion
C
C
284 SYSTEMS OF THE BODY
13
Intracellular EEG recording showing
Mechanisms underlying seizures and
epileptogenesis
There is ample evidence that changes in excitatory and
inhibitory signalling, and also in the intrinsic excitability of neurons, play a significant role in epilepsy.
This is supported by the genetics of epilepsy (Box 13.2).
Nonetheless, it is also important to note that the majority
of mutations in epilepsy are not linked to ion channels.
The reason why seizures start and how they are maintained remains incompletely understood in most cases.
The timing of the development of secondary, acquired
epilepsy is also enigmatic; for example, more than 50%
of individuals who suffer a traumatic brain injury are at
risk of developing a seizure disorder, but this may take
months or years. This silent period suggests that there
is a very gradual transformation in the neural networks,
which leads to a new abnormal set point.
Experiments carried out in animal models of epilepsy,
using various protocols that induce seizures, have investigated the events underlying interictal and ictal electrical activity. Recently developed genetic mouse models
recapitulate many of the features of human epilepsy
resulting from a specific genetic defect in a particular
receptor or voltage- gated ion channel. One of the key
challenges is to understand the development of epileptogenesis, that is, the process by which normal brain
activity progresses towards the generation of abnormal electrical activity. This is a key process for the evolution of the acquired epilepsy that follows a traumatic
brain injury, a stroke or an episode of status epilepticus.
Furthermore, the present view on epileptogenesis is that
it does not cover just the period between the initial stimulus and the first secondary seizure, it may also characterize a new state of the brain, which is long lasting, and
possibly irreversible, with ongoing epileptogenesis as a
form of aberrant neuroplasticity across a lifetime.
There are several different ways of producing epileptiform activity in animals. Some of these involve drugs
that either inhibit GABA or increase glutamate activities.
GABAA antagonists such as bicuculline and picrotoxin, and
glutamate agonists such as kainic acid can all produce seizure activity. A well- established model in epilepsy research
is called ‘kindling’, in which repeated high- frequency stimulation of parts of the limbic system can produce long- term
changes in excitability, so that seizures can be produced by
quite low levels of stimulation for months after the initial
stimulation period. Some models analyse changes in brain
tissue slices, where the layered structure of the brain and
local electrical circuits can be maintained. Intracellular and
extracellular recordings from these preparations reveal
some common underlying patterns.
Neurons in a region with epileptogenic activity fire
bursts of action potentials. This is thought to be due to a
slow depolarizing shift, called a ‘paroxysmal depolarization
shift’. This induces action potentials from a group of neurons, and these are superimposed on the shift (Fig. 13.8).
This is followed by a period of hyperpolarization, during
EPILEPSY
Surface EEG recording showing
interictal spike
the underlying depolarization
Fig. 13.8 An interictal spike produced by slow depolarization
underlies the burst firing of neurons.
which the activation of both voltage- and Ca2+- sensitive K+
channels stops the spiking activity.
When the interval between interictal spikes shortens,
the period of hyperpolarization is reduced. As a result
of increased neuronal firing, there is an increase in extracellular K+ levels, which depolarizes neurons and puts
them closer to the firing threshold. However, the mechanism by which local inhibition is sufficiently reduced
to allow the synchronous discharge of large numbers of
neurons, is not known.
Another aspect of the pathophysiology of epilepsy is
linked to the structural changes that may underlie epilepsy. In one common type of epilepsy in adults—mesial
temporal sclerosis (MTS)—seizures originate in the hippocampus and sometimes progress to secondarily generalized seizures. Possibly due to neuronal damage in
infancy, there are losses of neurons in specific hippocampal areas (Fig. 13.9). In response to the cell loss, there is
sprouting of the axons of excitatory glutamatergic granule cells (also known as mossy fibres) (Fig. 13.10). These
form connections with other granule cells of the dentate
gyrus, which are not inhibited by the normal inhibitory
connections. This leads to a set of excitatory loops that
have a high propensity to produce seizures.
Another theory of epileptogenesis involves deficits
in specific inhibitory neurons, for example, the chandelier cells of the cortex. They are a subset of GABAergic
inhibitory interneurons that release GABA via axoaxonal contacts onto the initial segment of pyramidal cells
(Fig. 13.11). Histologically, they appear as cartridges
or ‘chandelier’ profiles. These cells express high levels
of the GABA transporter GAT1, which can be used as
a marker for their presence. In some forms of epilepsy
there is a loss of chandelier cells, as shown by a detectable loss of GAT1 in brain tissue. It is suggested that loss
of just a few of these cells would have a significant effect
on the excitability of the pyramidal cells. This is because
a single chandelier cell innervates a few hundred pyramidal cells. The theory also suggests that, because of the
normal individual variation in the number of GABAergic
neurons, loss of chandelier cells would be sufficient to
produce epilepsy in an individual with lower than average numbers of inhibitory neurons.
285THE NERVOUS SYSTEM
13
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B
EPILEPSY
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Fig. 13.9 Sclerosis of the hippocampus in epilepsy. Neuronal immunoperoxidase staining for the NeuN antigen shows in (A) normal cell
distribution and density and in (B), (C) and (D) significant loss of neurons in various fields of the Cornu Ammonis (CA). 0, no loss of pyramidal
neurons in the CA; 1A, loss in CA1, CA3, CA4; 1b, severe loss in all subfields; type 2, loss in CA1. (From Savitr Sastri, B.V., Arivazhagan, A., Sinha,
S., et al. 2014, ‘Clinico-pathological factors influencing surgical outcome in drug resistant epilepsy secondary to mesial temporal sclerosis’, Journal
of the Neurological Sciences, vol. 340, no. 1-2, pp. 183–190.)
CA1
ml
PP
Hilus
Granule cell Pyramidal cellMossy cell
Fig. 13.10 Fibre sprouting in the hippocampus in epilepsy. (A) Shows the hippocampus circuitry in a normal brain and (B) shows the sprouting
of mossy fibres into the dentate inner molecular layer in an epileptic brain, following the loss of hilar cells. ml, Molecular layer, P P, perforant path.
(From Cavarsan, C. F., Malheiros, J., Hamani, C., et al. 2018, ‘Is Mossy Fiber Sprouting a Potential Therapeutic Target for Epilepsy?’, Frontiers in
Neurology, vol 9, article 1023.)
Granule
cell layer
Mossy
fibre
PP
CA3
'
PP
CA1
Granule
cell layer
Mossy
fibre
PP
ml
Hilus
CA3
286 SYSTEMS OF THE BODY
A B
Fig. 13.11 Pre- and postsynaptic markers for GABAergic
neurotransmission. Chandelier cells labelled with GAT1 (A) synapse
onto pyramidal neurons (P) labelled with an antibody against the
GABAA receptor (B). (From Volk, Lewis. Physiology and Behaviour
2002; 77: 501–505.)
Neuroinflammation (involving microglia and astrocytes) and changes in energy metabolism (in particular mitochondrial deficits) have also been linked to the
pathophysiology of epilepsy. Mitochondria are essential
organelles involved in cellular energy- generating processes. Compromise of the mitochondrial ability to produce energy in the form of ATP can disrupt multiple
functions, and the deficit in energy production alters
the balance of neuronal excitation and inhibition, which
can lead to seizures. Microglial activation is one of the
earliest cellular events described in epileptogenesis
models. Activated microglia can release a host of chemokines and cytokines. Inflammatory cytokines, such
as interleukin- 1β (IL- 1β), tumour necrosis factor- α (TNF-
α) and interleukin- 6 (IL- 6), can contribute to both acute
neuronal excitability and chronic molecular changes that
could play a part in the development of epilepsy. There
may be increases in the activity of tissue proteases, which
remodel the brain extracellular matrix. Astrocytes can
downregulate glutamate transporters and potassium
channels, acquire a pro- inflammatory phenotype and
proliferate. Neuroinflammation is also linked to disruption of the blood- brain barrier which is a consequence of
the direct action of cytokines and chemokines released
by activated glia.
There is evidence that epileptogenesis is also associated with epigenetic changes such as alterations in DNA
methylation, histone acetylation and changes in the
expression of non-coding RNAs.
13
EPILEPSY
Pharmacological treatment of epilepsy
There is a wide range of anticonvulsant drugs available for the treatment of epilepsy (Table 13.3). The term
‘anticonvulsant’ or ‘anti-epileptic’ are used interchangeably, but it could be argued that the present drugs only
act symptomatically and do not change the process of
epileptogenesis, therefore the term ‘anticonvulsant’ is
more appropriate. Because patients already have epilepsy when they are diagnosed, the drugs used at present
are, strictly speaking, anticonvulsants, that is, they prevent or reduce the established seizure activity. In the past
decade many new drugs have been introduced, as well
as improved formulations of older anticonvulsant drugs.
In cases where epilepsy is likely to develop, for example,
following head trauma or perinatal hypoxia, drugs that
could prevent the future development of seizures—true
anti-epileptics—would be useful, but no such compounds have yet been developed for clinical use. Active
attempts are being made in animal models of epilepsy
to understand the mechanisms that underlie epileptogenesis, that may open up new therapeutic avenues.
However, evidence suggests so far that even when drugs
are introduced early, and they at least partly control the
seizures, they do not affect the progression of epilepsy.
It is important to note that primary generalized seizures are usually more easily controlled than focal epilepsies. Many patients can, after a period of remission,
stop their treatment but there may be a recurrence of
seizures, which may have consequences for employment
and activities such as driving (see below).
Mode of action of anticonvulsant drugs
Ion channel inhibitors
Several different anticonvulsant drugs, from first generation drugs to more recent drugs, inhibit voltage- sensitive
channels, thus reducing neuronal excitability.
Phenytoin—one of the oldest anticonvulsant drugs—
blocks voltage- sensitive Na+ channels preferentially
in their inactive state. This occurs just after the channel
opens, which means that the blockade is use- dependent.
This therefore tends to block activity in those pathways
showing high- frequency repetitive discharges. Phenytoin
blocks the spread of seizures, but has little effect against
the epileptic focus. The pharmacokinetics of this drug
is complex and can change over the therapeutic range.
At higher doses, it can show saturation (or zero- order)
kinetics, so called because of enzyme saturation. At that
point, small increases in the dose can lead to significant increases in plasma concentration, so monitoring
of the plasma concentration is required. Phenytoin is an
inducer of hepatic microsomal enzymes and therefore
can interfere with the metabolism of other drugs. It has a
number of side effects, including gum hypertrophy, acne
and hirsutism, and it is teratogenic. It is used in all forms
287THE NERVOUS SYSTEM
13
Table 13.4 Efficacy of anti-epileptic drugs against common seizure types
EPILEPSY
Drug Focal seizures
Phenytoin 1 1 1 2 2
Carbamazepine 1 1 1 2 2
Valproate 1 1 1 1 1
Lamotrigine 1 1 1 1 2
Gabapentin 1 1 ?1 ? 2
Topiramate 1 1 1 ? 1
Clobazam 1 1 1 1 1
Phenobarbitone 1 1 1 0 ?1
Tiagabine 1 1 ?1 2 2
0, ineffective; ?1, probably effective; 1, proven efficacy; ?, unknown; 2, precipitate or worsens seizures.
of epilepsy, with the exception of absence seizures, which
it can aggravate (Table 13.4).
similar to that of phenytoin. It can induce rash, hepatotoxicity and blood dyscrasia. It is also an enzyme inducer and
has teratogenic effects. It can be used for simple and complex partial seizures and tonic–clonic generalized seizures.
venting absence seizures, acts by blocking the T- type
Ca2+ channels found in thalamic neurons, which are
thought to generate this type of seizure activity.
one of its mechanisms of action is the inhibition of Na+
channels. The drug can also block L- type Ca2+ channels.
Furthermore, it may increase GABAergic transmission by
stimulating GABA synthesis and inhibiting its metabolism. It is effective in patients with all types of seizure,
easy to use and generally well tolerated, although it can
induce unwanted effects such as tremor and weight gain.
the function of ion channels. Lamotrigine induces usedependent blockade of Na+ channels and reduces Ca2+
currents. Gabapentin is also associated with a reduction in voltage- dependent Ca2+ currents. Topiramate
has a complex pharmacology, but part of its mechanism of action is also the blockade of Na+ channels.
Levetiracetam has no effect on voltage- dependent Na+ or
L- , P- , Q- or T- type Ca2+ channels, but selectively inhibits
N- type Ca2+ channels, with no effects on other channels.
Zonisamide blocks both Na+ and Ca2+ channels.
GABA receptor modulators
Benzodiazepines such as clonazepam and clobazam,
and barbiturates such as phenobarbitone, act by binding to the GABAA receptor. GABAA receptors are pentameric proteins, made up of five subunits surrounding
Focal—Secondary
generalized seizures
Carbamazepine has a mode of action on Na+ channels
Ethosuximide, which is effective specifically in pre-
Sodium valproate has a complex pharmacology, but
Some of the newer anti-epileptic drugs also affect
Seizure type
Tonic–clonic
seizures Absence seizures Myoclonic seizures
a Cl- channel. The majority of GABAA receptors in the
brain contain α- , β- and γ- subunits, each of which can
be transcribed from a family of genes (for more detail
see Chapter 16). On the GABAA receptor complex there
are binding sites for GABA and also modulatory binding sites for a number of other compounds. There are
sites for both benzodiazepines and barbiturates, and
these compounds act as positive allosteric modulators at
the GABAA receptor, that is, they amplify the response
to GABA. Benzodiazepines increase the frequency of
Cl- channel opening, whereas barbiturates increase the
duration of channel opening. At high concentrations,
barbiturates can have intrinsic effects, independent of
the presence of GABA. They commonly induce sedation
and their therapeutic window is much narrower than
that of benzodiazepines. Clobazam is used as adjunctive therapy, whereas clonazepam is used for generalized seizures and absence seizures (if ethosuximide fails)
and can also be used for status epilepticus. Both compounds suppress the spread of seizures, but have little
effect at the epileptic focus. In contrast, phenobarbitone
can suppress activity at the epileptic focus. Primidone is
metabolized in the body to phenobarbitone. Stiripentol
is a drug recently introduced for the treatment of Dravet
syndrome (see Box 13.2). It enhances GABA signalling through an effect similar to that of barbiturates, by
enhancing the duration of the channel opening. It can
also modulate GABA uptake and metabolism. Felbamate
is a drug that can act as a positive modulator of GABAA
receptors and as a blocker of NMDA receptors; its use is
restricted for severe forms of epilepsy, such as LennoxGastaut syndrome.
Agents that increase the levels of GABA
The metabolism of GABA is a cycle, involving glutamate
and glutamine, occurring between neurons and glial cells.
288 SYSTEMS OF THE BODY