DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

seizures arise from the reciprocal firing of the thalamus
and cerebral cortex (Huguenard and McCormick,
2007). Among the diverse forms of generalized
seizures, absence seizures have been studied most
intensively. The striking synchrony in appearance of
generalized seizure discharges in widespread areas of
neocortex led to the idea that a structure in the thalamus
and/or brainstem (the “centrencephalon”) synchronized
these seizure discharges. Focus on the thalamus
in particular emerged from the demonstration that lowfrequency
stimulation of midline thalamic structures
triggered EEG rhythms in the cortex similar to spikeand-wave
discharges characteristic of absence seizures.
Intra-cerebral electrode recordings from humans subsequently
demonstrated the presence of thalamic and
neocortical involvement in the spike-and-wave discharge
of absence seizures.
Many of the structural and functional properties
of the thalamus and neocortex that lead to the generalized
spike-and-wave discharges have been elucidated
(Huguenard and McCormick, 2007).
The EEG hallmark of an absence seizure is generalized spikeand-wave
discharges at a frequency of 3 per second (3 Hz). These
bilaterally synchronous spike-and-wave discharges, recorded locally
from electrodes in both the thalamus and the neocortex, represent
oscillations between the thalamus and neocortex. A comparison of
EEG and intracellular recordings reveals that the EEG spikes are
associated with the firing of action potentials and the following slow
wave with prolonged inhibition. These reverberatory, low-frequency
rhythms are made possible by a combination of factors, including
reciprocal excitatory synaptic connections between the neocortex
and thalamus as well as intrinsic properties of neurons in the thalamus
(Huguenard and McCormick, 2007). One intrinsic property of
thalamic neurons that is pivotally involved in the generation of the
3-Hz spike-and-wave discharges is a particular type of Ca 2+ current,
the low threshold (“T-type”) current. T-type Ca 2+ channels are activated
at a much more negative membrane potential (hence “low
threshold”) than most other voltage-gated Ca 2+ channels expressed
in the brain. T-type currents are much larger in many thalamic neurons
compared to neurons outside the thalamus. Indeed, bursts of
action potentials in thalamic neurons are mediated by activation of
the T-type currents. T-type currents amplify thalamic membrane
potential oscillations, with one oscillation being the 3-Hz spike-andwave
discharge of the absence seizure. Importantly, the principal
mechanism by which anti–absence-seizure drugs (ethosuximide, valproic
acid) are thought to act is by inhibition of the T-type Ca 2+ channels
(Figure 21–4) (Rogawski and Loscher, 2004). Thus, inhibiting
voltage-gated ion channels is a common mechanism of action
among anti-seizure drugs, with anti–partial-seizure drugs inhibiting
voltage-activated Na + channels and anti–absence-seizure drugs
inhibiting voltage-activated Ca 2+ channels.
Genetic Approaches to the Epilepsies
Genetic causes contribute to a wide diversity of human
epilepsies. Genetic causes are solely responsible for
Ca 2+ Ca 2+
Ca 2+ valproate
Ca 2+
ethosuximide
Figure 21–4. Anti-seizure drug-induced reduction of current
through T-type Ca 2+ channels. Some anti-seizure drugs (shown
in blue text) reduce the flow of Ca 2+ through T-type Ca 2+ channels
thus reducing the pacemaker current that underlies the thalamic
rhythm in spikes and waves seen in generalized absence
seizures.
rare forms inherited in an autosomal dominant or autosomal
recessive manner. Genetic causes also are mainly
responsible for more common forms such as juvenile
myoclonic epilepsy (JME) or childhood absence
epilepsy (CAE), the majority of which are likely due to
inheritance of two or more susceptibility genes. Genetic
determinants also may contribute some degree of risk to
epilepsies caused by injury of the cerebral cortex.
Enormous progress has been made in understanding the
genetics of mammalian epilepsy. Mutant genes have been identified
for a number of symptomatic epilepsies, in which the epilepsy is a
manifestation of the underlying neurodegenerative disease. Because
most patients with epilepsy are neurologically normal, elucidating
the mutant genes underlying familial epilepsy in otherwise normal
individuals is of particular interest; this has led to the identification
of 25 distinct genes implicated in distinct idiopathic epilepsy syndromes
that account for < 1% of all of the human epilepsies.
Interestingly, almost all of the mutant genes encode voltage- or
ligand-gated ion channels (Reid et al., 2008). Mutations have been
identified in Na + , K + , Ca 2+ , and Cl − channels, in channels gated by
GABA and acetylcholine, and most recently, in intracellular Ca 2+
release channels (RyR2) activated by Ca 2+ . The genotype-phenotype
correlations of these genetic syndromes are complex; the same mutation
in one channel can be associated with divergent clinical syndromes
ranging from simple febrile seizures to intractable seizures
with intellectual decline. Conversely, clinically indistinguishable
epilepsy syndromes have been associated with mutation of distinct
genes. The implication of genes encoding ion channels in familial
epilepsy is particularly interesting because episodic disorders involving
other organs also result from mutations of these genes. For example,
episodic disorders of the heart (cardiac arrhythmias), skeletal
muscle (periodic paralyses), cerebellum (episodic ataxia), vasculature
(familial hemiplegic migraine), and other organs all have been
linked to mutations in genes encoding components of voltage-gated
ion channels (Ptacek and Fu, 2001).
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CHAPTER 21
PHARMACOTHERAPY OF THE EPILEPSIES