Elsevier

Neuroscience

Volume 222, 11 October 2012, Pages 89-99
Neuroscience

Epilepsy: Ever-changing states of cortical excitability

https://doi.org/10.1016/j.neuroscience.2012.07.015Get rights and content

Abstract

It has been proposed that the underlying epileptic process is mediated by changes in both excitatory and inhibitory circuits leading to the formation of hyper-excitable seizure networks. In this review we aim to shed light on the many physiological factors that modulate excitability within these networks. These factors have been discussed extensively in many reviews each as a separate entity and cannot be extensively covered in a single manuscript. Thus for the purpose of this work in which we aim to bring those factors together to explain how they interact with epilepsy, we only provide brief descriptions. We present reported evidence supporting the existence of the epileptic brain in several states; interictal, peri-ictal and ictal, each with distinct excitability features. We then provide an overview of how many physiological factors influence the excitatory/inhibitory balance within the interictal state, where the networks are presumed to be functioning normally. We conclude that these changes result in constantly changing states of cortical excitability in patients with epilepsy.

Highlights

► The epileptic brain exists in several states each with distinct excitability features. ► Cortical excitability is influenced by many physiological factors even in normal people. ► These factors influence the interictal state, where the networks should function normally. ► This results in constantly changing states of cortical excitability in patients with epilepsy.

Introduction

Epilepsy is a disorder characterized by the occurrence of recurrent seizures. These seizures reflect abnormal hypersynchronous electrical activity of neuronal networks, which are thought to be caused by an imbalance between excitation and inhibition (McCormick and Contreras, 2001). The ratio of excitation to inhibition is the major determinant of excitability in the brain. Epileptogenesis refers to the alteration of a normal neuronal network into a hyper-excitable network leading recurrent, spontaneous seizures to occur (Clark and Wilson, 1999). The proposed underlying mechanisms for this process include neuronal loss, neurogenesis, glial loss, gliogenesis, axonal and dendritic plasticity and intracellular channelopathies or receptor dysfunction. A complete discussion of these mechanisms is beyond the scope of this review and is extensively described elsewhere. The aim of this review is to draw attention to the dynamic variability in cortical excitability within each individual with epilepsy. The epileptic brain exists in many states, not just the well-established apparently normal or interictal state in between seizures during which the brain appears to function normally, and abnormal or ictal state characterized by widespread synchronous activity occurring in a paroxysmal way, thereby impairing brain functioning (Lopes da Silva et al., 2003). Not only are these two states separated by the preictal state during which physiological phenomena such as prodromal symptoms can occur and the postictal state during which the brain is recovering from the seizure, there are also many variations in cortical excitability within the interictal state itself. These changes are influenced by many physiological factors each of which has been the subject of multiple extensive reviews describing their pathophysiological basis and their relationship with epilepsy. To attempt to provide an exhaustive or full review of each in a single manuscript would be an unrealistic and unachievable goal and is far from our intention. We present a brief overview of these factors to show how they can all co-exist in the same person and influence clinical presentation. We attempt to draw the bigger picture; to demonstrate the complex interaction that results in constantly changing states of cortical excitability in patients with epilepsy.

Section snippets

Sleep–wake cycle

The relationship between sleep and epilepsy is well recognized. Most studies confirm that sleep and circadian variations in arousal not only affect the timing of seizure occurrence, but also the frequency, morphology and spread of interictal discharges on electroencephalogram (EEG). Synchronized non rapid eye movement (NREM) sleep facilitates seizures, whereas desynchronized rapid eye movement (REM) sleep discourages seizure occurrence (Foldvary-Schaefer and Grigg-Damberger, 2009).

The majority

Transition from the interictal to the ictal state

Epilepsy is regarded as a chronic and persistent condition with a persistent pathology. Therefore, it is fair to ask why the symptoms are (seizures for example) not persistent. The answer to this important question lies in the understanding of the ever-changing state of cortical excitability. The intermittency of epileptic seizures poses major challenges in developing robust treatments. Therefore, understanding the mechanisms underlying the transformation between the relatively normal

Maturational changes

In many types of epilepsy, especially childhood epilepsy, seizure types and EEG patterns are age dependent (Fig. 4). Many epileptic syndromes are only seen in children with striking age-dependent patterns that can evolve or resolve over time (Dulac, 1994). It is also known that the electro-clinical manifestations of seizures in newborns are different to those during infancy and childhood, and some types of seizures e.g. infantile spasms occur exclusively during this early period of development.

Conclusion

In this review we have highlighted the complex and highly variable patterns of cortical excitability in patients with epilepsy. As summarized in Fig. 5, changes in excitability can be a result of many factors however; it is a unifying theme in almost all epilepsies. Bursting behaviour in neurons may arise from a seemingly continuum of multiple parameters (Marten et al., 2009), thus homoeostatic and compensatory mechanisms may play an important role. In order to understand this and the

Disclosure

None of the authors have any conflict of interest to disclose.

Acknowledgments

The authors wish to thank Dr. Danny Flanagan and Mr. Simon Vogrin, for their insightful suggestions during the preparation of this manuscript and help with the figures.

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