FOCAL SEIZURE MECHANISMS

The normal functioning of neuronal circuits depends on an intricate interplay between excitatory and inhibitory mechanisms. Experimental manipulations interfering with inhibition are a powerful trigger for seizures, and conversely, many antiseizure medications (ASM), such as benzodiazepines and barbiturates, act by promoting inhibition. Similarly, manipulations that enhance neuronal or synaptic excitation are proconvulsant. The most common mechanism of action of ASM is to reduce neuronal excitability, for instance by promoting the inactivation of sodium channels (e.g. phenytoin, carbamazepine, lamotrigine, lacosamide), and perampanel directly reduces glutamatergic synaptic transmission.¹ Epilepsy is often described as a state of ‘excitation/inhibition imbalance,’ but this concept does not capture the full complexity of instability characterising the disorder. First, inhibition cannot be equated with the primary inhibitory neurotransmitter, GABA, or GABAergic interneurons. Other neuroactive molecules, such as adenosine² and some neuropeptides³ exert powerful inhibitory effects on principal excitatory neurons. GABAergic interneurons do not exclusively innervate principal neurons. A subset preferentially targets other interneurons, and there are instances in which GABAergic transmission can be excitatory; moreover, GABAergic inhibition synchronises the activity of networks of excitatory neurons.⁴ Inhibition can also be considered at the level of individual neurons. Potassium channels, for instance, generally act to maintain the resting membrane potential of neurons, countering the effects of excitation and inhibiting the generation of action potentials.⁵ 4‐aminopyridine (fampridine), a blocker of potassium channels, is a powerful chemoconvulsant when applied directly to the brain. ASM that activate potassium channels are in clinical trial⁶ These mainly target the same potassium channel subtype as retigabine, which was withdrawn because of side effects.

The concept of ‘excitation/inhibition imbalance’ alone does not explain why seizures are generally brief and intermittent phenomena in most people with epilepsy. Even in those with daily seizures, the brain spends over 99.9% of the time not generating seizures. The concept of ‘inhibitory restraint’ explains how local over‐excitation is contained by inhibitory mechanisms, which can intermittently fail (Figure 6.1), Epilepsy is better considered as an ‘instability’ rather than as an ‘imbalance’.⁷ Principal neurons may be overexcited because of various pathological processes such as disrupted neuronal migration in focal cortical dysplasia, aberrant axonal and synaptic connections, or loss of a subset of inhibitory interneurons. Rare causes such as autoantibodies or mutations affecting LGI1 may also predispose to over‐excitation.⁸ Regardless of the underlying abnormality, this may trigger a positive feedback loop, giving rise to excessive and persistent recruitment of principal neurons. At the cellular level, a sudden paroxysmal depolarising shift of principal neurons is observed, maintained by excitatory synaptic activity and the intrinsic excitability of neurons.⁹ Overactivity of principal neurons is usually contained by the rapid recruitment of GABAergic interneurons in the immediate vicinity, which is analogous to a fire blanket.¹⁰ It is speculated that such events correspond to interictal epileptiform discharges, typically lasting less than 200 ms, which are a frequent biomarker of epileptogenic tissue. Experimental data indicate that such spikes are associated with GABA release, likely originating from an annulus of interneurons that are brought to the firing threshold by the synchronous or near‐synchronous firing of a population of principal neurons. The effectiveness of this inhibitory recruitment has led to such discharges being considered ‘inhibitory,’ and interictal epileptiform discharges may serve as an indicator of effective inhibitory restraint.

Since there are such effective and robust inhibitory mechanisms, why do seizures occur, and how do they spread? Evidence indicates that seizure initiation and spread may have multifarious and distinct mechanisms. These mechanisms may vary between brain regions and different types of epilepsy.

In any brain, the excessive recruitment of principal cells will eventually lead to escape from inhibitory restraint (Figure 6.1).¹¹ An example is electroconvulsive therapy in which current is passed through the brain, resulting in excessive and synchronised neuronal recruitment, leading to a generalised convulsion. Two processes may be seizure‐promoting: the excessive activation of principal neurons and the failure of GABAergic inhibition. In some models, observations of seizure initiation suggest that intense GABAergic recruitment precedes excessive principal cell recruitment.

What processes underpin the failure or pro‐seizure effect of GABAergic inhibition? Several mechanisms have been proposed and may contribute variably to the generation of different seizures with different aetiologies.

1. GABA release from interneurons may not be sufficient to contain the discharge, for instance, if GABA‐containing vesicles are depleted from interneuron terminals or if presynaptic receptors inhibit GABA release, or if there is a change or down‐regulation of postsynaptic GABA receptors.⁷
   
2. During excessive neuronal activity, potassium accumulates around neurons, causing them to depolarise as their membrane potential tracks the equilibrium potential for this ion. This potassium accumulation occurs with neuronal firing and contributes to increased network excitability. GABAergic neuronal activity can contribute to this accumulation in a second way. GABA_A receptor opening results in chloride influx into neurons, which is then pumped out with potassium via the potassium‐chloride pump, KCC2. Such potassium accumulation has been suggested to be an initiating event for seizure generation.¹²
   
3. Neurons can also become overly depolarised, resulting in the inactivation of sodium channels necessary for action potential generation, thus preventing neuronal firing. This ‘depolarisation block’ may preferentially affect inhibitory interneurons, thus leading to failure of GABA release.¹³ If this process affects principal neurons, the same phenomenon has been suggested to contribute to seizure termination, and also to sudden unexpected death in epilepsy (SUDEP), in which a depolarisation block of brain stem neurons may lead to cardiorespiratory arrest.¹⁴
   
4. Inhibitory restraint can also fail because intense activation of GABA_A receptors on neurons innervated by interneurons eventually causes an excessive transmembrane shift in chloride ions. Because open GABA_A receptors normally inhibit neurons by allowing chloride ions to flow down their electrochemical gradient, thus hyperpolarising postsynaptic neurons, a collapse of the chloride gradient impairs this inhibitory action.¹⁵ Drugs that promote the activation of GABA_A receptors may also lose their effectiveness (one explanation for benzodiazepine resistance of prolonged seizures).¹⁶ Open GABA_A receptors, however, may still act to ‘short‐circuit’ excitatory transmembrane currents, so that sufficient activation of GABA_A receptors can still ‘shut down’ the neuron, which is why large (anaesthetic) doses of GABAergic drugs can still be effective even in the later stages of status epilepticus.

These mechanisms (failure of GABA release, a net pro‐excitatory action of GABA mediated by potassium fluxes, and failure of GABA to hyperpolarise postsynaptic neurons) are supported by experimental studies and are not mutually exclusive. Once a seizure has escaped local inhibitory restraint, it can propagate tangentially across the cortex.¹⁷ This explains, for instance, the Jacksonian march, which occurs as seizure activity gradually spreads across the motor cortex. Seizures also spread via subcortical routes to remote structures, explaining the recruitment of more distant regions. The mechanisms of seizure propagation overlap with those underlying seizure initiation.

Seizure termination likely occurs through multiple mechanisms.¹⁸ Depolarisation block may have an important role, as may depletion of glutamate‐containing synaptic vesicles. In addition to GABA, multiple inhibitory systems, involving, for example, the release of adenosine and neuropeptides, act to inhibit glutamate release. A further phenomenon is spreading depolarisation, a slowly advancing wavefront leading to significant shifts in extracellular ions and neurotransmitters, which is also implicated in the aura of migraine. It remains to be determined to what extent this contributes to the post‐ictal depression which is often observed in the scalp EEG.

THALAMOCORTICAL SEIZURES

Generalised epilepsy commonly manifests as either absence or tonic–clonic seizures, although the latter are non‐specific as they can also arise from secondary generalisation in focal epilepsy. There has been a considerable effort to understand the mechanisms of absence seizures, which have a typical semiology, pharmacology and electrographic signature. These can be modelled in rodents, mainly through genetic manipulations.

The reverberating loop generating absence seizures involves excitatory thalamocortical and corticothalamic neurons. Reticular thalamic GABAergic neurons also play a crucial role (Figure 6.2). Thalamocortical and corticothalamic axon collaterals innervate them, and they innervate thalamocortical neurons. The reticular GABAergic neurons and cortical neurons have prominent intrinsic bursting properties conferred by low‐threshold T‐type calcium channels,¹⁹ whilst thalamocortical neurons express a ‘pacemaker’ sodium/potassium current, I_h.²⁰ The T‐type calcium channels have the unusual property that they are partially inactivated at intermediate voltages or while the neurons fire single action potentials and are de‐inactivated by hyperpolarisation, such as occurs in sleep. I_h is analogous to the depolarising pacemaker sodium/potassium current in the heart; it is activated by hyperpolarisation and undergoes slow inactivation with depolarisation. I_h and T‐type calcium channels work together to generate rhythmic burst firing within the thalamo‐cortical circuit and contribute to the generation of physiological slow (delta) rhythms that occur during sleep.