Page 16 - ILAE_Lectures_2015

The conceptual framework of the chain reaction of excitation through networks of
glutamatergic neurons was mainly developed by an iterative combination of experiments on
normal brain tissue exposed to convulsant drugs and computer simulations. Given these
experiments were on normal tissue (modelling symptomatic seizures rather than epilepsy),
the networks responsible for the epileptic activity exist to serve the normal operations of the
brain, not to cause seizures. Under physiological conditions the risk of excessive
synchronisation is controlled by several mechanisms, most notably the presence of inhibitory
interneurons. These GABA-containing neurons represent under 20% of neocortical and
hippocampal neurons, and come in a variety of types. Those, such as the basket cells,
responsible for ‘feedback inhibition’ provide a conceptually straightforward mechanism: they
receive excitatory input from many pyramidal cells, are relatively easily excited, fire action
potentials at very fast rates, and inhibit many pyramidal cells. They are therefore ideally
suited to detect the build-up of excitation in the pyramidal cell population and to respond by
blocking the ability of those pyramidal cells to generate action potentials in response to
excitatory synaptic input on their dendrites.

Other factors contribute to epileptic discharges. Networks of inhibitory neurons can have
proepileptic effects under some circumstances: e.g. changes in intracellular chloride
homeostasis can make inhibitory synaptic potentials excitatory, or in other cases
synchronised inhibitory activity can boost glutamatergic excitation to trigger epileptic events.
Electrotonic junctions (e.g. between inhibitory neurons) can contribute to synchronisation
and reduce seizure threshold. Electrical field or ephaptic effects produce rapid
synchronisation of action potentials on a millisecond timescale. Accumulation of neuroactive
substances, notably potassium ions, in the extracellular space will increase and sustain
neuronal excitability, and may play a role in prolonging epileptic discharges. Finally, glia
may play active roles both through the control of extracellular ions and transmitters, and in
releasing transmitters in response to activation.

Chronic epileptic foci

Epilepsy is by definition a chronic condition. Chronic epileptic foci depend on abnormal
functional organisation of the neuronal networks in the region. Many epilepsies are acquired.
Perhaps the clearest example is post-traumatic epilepsy, where a severe head injury has a
2030% risk of leading to spontaneous epileptic seizures after many months to several years,
both clinically and in the corresponding rat model. During the latent period, the process of
‘epileptogenesis’ takes place, which transforms normal brain networks into epileptic foci.
While seizures directly triggered by the injury over the following week or so can be blocked
by current antiepileptic drugs, the process of epileptogenesis cannot. Recent experimental
work suggests that it is possible to disrupt epileptogenesis, for instance by focal application
of tetrodotoxin to silence the tissue, or administration of cannabinoid receptor antagonists.
An effective treatment to prevent epileptogenesis is a major goal in current epilepsy research.

Several of the common chronic models of focal epilepsy, in particular temporal lobe epilepsy,
also depend on epileptogenesis. Initial insults include several that trigger acute status
epilepticus (e.g. kainic acid, pilocarpine, sustained electrical stimulation) and others that do
not (e.g. kindling, intrahippocampal tetanus toxin). With the exception of kindling, which
generally does not result in spontaneous seizures, these models usually have a latent period
of 12 weeks before spontaneous recurrent seizures start.

Cellular mechanisms in chronically epileptic tissue. A key issue is the nature of the
abnormalities in the functional organisation of brain tissue which makes it prone to generate
epileptiform discharges, while in most cases sustaining relatively normal activity most of the