Preface

A seizure is the manifestation of an abnormal, hypersynchronous discharge of a population of cortical neurons that may produce subjective symptoms or objective signs, in which case it is a clinical seizure.

Clinical seizures are usually classified according to the International Classification of Epileptic Seizures proposed by the International League Against Epilepsy (ILAE), which is the best one currently available. This classification introduces different levels of classification with respect to the semiological mode of onset (focal, generalized, or unknown), physical manifestations (motor, non-motor, or unknown), etiologies (structural, genetic, infectious, metabolic, immune, unknown), state of consciousness, and possible evolution to a bilateral tonic-clonic seizure.

The incidence of new-onset seizures in the general population is approximately 80 per 100,000 per year; approximately 60 percent of these patients will have epilepsy.

The diagnosis of a particular seizure type, and of a specific type of epileptic syndrome, directs the clinical diagnosis of these patients and their initial therapy.

Some types of epilepsy are more common in children, such as Self-limited Epilepsy with Centro Temporal Spikes (SECTS) also known as Rolandic epilepsy. SECTS is quite common in children: 15%–25% of all epileptic syndromes are diagnosed between the ages of 5 and 15 years, with a peak around 6 years. In children, it is common to find an association between epilepsy and neurodevelopmental disorders such as autism. Autistic disorders are common in children with genetic anomalies including Rett syndrome, fragile X syndrome, tuberous sclerosis, Potocki-Lupski syndrome, Smith-Lemli-Opitz syndrome, and cortical dysplasia. About 30 percent of autistic patients have epileptic anomalies in electroencephalography (EEG) registrations. The relation between autism and epilepsy can probably be explained by the existence of common neural networks characterized with alterations in subcortical systems or basal ganglia-substantia nigra connectivity. Other studies show evidence of dysfunction in cerebral neuroreceptors such as glutamate receptors, serotonin receptor 2A, and GABA-A receptors; for example, excessive glutamatergic activity is associated with epileptiform activity.

In adults, secondary forms of epilepsy are frequent after cerebrovascular insults such as cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage. In this case it is especially important to distinguish between early seizures and late seizures, since the former are more indicative of symptomatic seizures, while the latter could be a signal of post-stroke epilepsy and thus should be treated with specific antiepileptic drugs.

In the last two decades, enormous advances have occurred in the understanding of epilepsy. Techniques such as EEG, neuroimaging, neurosurgery, and neuropsychology are giving us a better understanding of the mechanisms of the pathogenesis of epilepsy.

EEG is the gold standard for diagnosis of epilepsy and a useful examination, especially when epileptic abnormalities emerge as paroxysmal activities or typical epileptic grapho-elements. EEG is an instrument for monitoring the course of the disease and the efficacy of treatment. EEG is useful for investigating epilepsy especially in combination with rating scales and clinical examination.

Recent EEG techniques have allowed automatic detection of epileptic seizures, classification of EEG signals, and distinguishing seizures and pre-seizures. Techniques consisting of quantitative analysis of EEG have been potentially used in spike detection, localization of epileptic focus, and determination of the type of epilepsy. EEG evaluation can determine antiepileptic drug efficacy in the management of epileptic children.

Additionally, major developments are taking place in the laboratories of scientists studying genetics, embryogenesis, neuropathology, neurochemistry, and pharmacology. These advances provide a much better understanding of why patients develop epilepsy, improving the way in which epileptic patients are cared for.

This book discusses the pharmacological treatment of epilepsy with older antiepileptic drugs (e.g., phenobarbital, carbamazepine, phenytoin, valproate) as well as newer drugs (e.g., topiramate, zonisamide, levetiracetam, lamotrigine, lacosamide, perampanel), neurosurgical treatments, and treatments based on the use of stem cells. Pharmacological approaches sometimes cause side effects such as dizziness, nausea, headache, and diplopia. Antiepileptic drugs (AEDs) can potentially interfere with other drugs in the treatment of special groups of patients such as children or women (increased risk of teratogenicity). One of the most common side effects of AEDs are cognitive disorders that adversely affect information processing, reaction times, and levels of concentration. Cognitive side effects are more common with older drugs and can be identified via neuropsychological examinations by experienced neuropsychologists. Strategies to reduce cognitive side effects include using monotherapies, slowly increasing medication dose, and considering the quality of life and performances of patients.

The surgical approach to epilepsy can be proposed in patients with drug-resistant epilepsy, a condition that affects about 30 percent of patients. When treating these patients, it is important to consider the potential cause of drug resistance as an inappropriate choice of AEDs or problems of poor compliance, often considered as "pseudoresistence." Surgical candidates must be evaluated by neurophysiology techniques (interictal EEG, video EEG), structural imaging (MRI protocols, diffusion tensor imaging, PET, SPECT, fMRI, MEG), neuropsychological assessment (eventually associated with WADA test of fMRI), psychiatric assessment, and invasive studies (invasive EEG monitoring, use of subdural electrodes, intracerebral electrodes, epidural electrodes, foramen ovale electrodes). A neurosurgical approach may involve curative surgery (e.g., callosotomy, hemispherectomy) or modulatory surgery (deep brain stimulation, vague nerve stimulation, gamma knife radiosurgery). Stem cell therapies are promising for epilepsy. Mesenchymal stem cell (MSC) therapy was discovered for the first time in 1966, but only in 2007 was it suggested for use in epilepsy, after evidence that cytokines and other factors secreted by MSCs could stimulate endogenous protection and recovery response. Approaches based on stem cell transplantation can use different sites of administration (endovenous, intraperitoneally, intra-hippocampal transplantation) and with different measures of investigation (electrophysiological, behavioral task, the study of GABA levels, histopathological investigations, immunohistochemically essay).

Neural stem cells or neural progenitor cells have the potential for use in temporal lobe epilepsy, which accounts for approximately 40 percent of all epilepsy cases. Models of stem cell transplantation using different sites of administration (intravenous, intraperitoneal) seem to show positive effects such as anticonvulsant effects, changes in the anatomy of the epileptic hippocampus, and micro-changes in neural circuitry.

> **Sandro Misciagna** Neurology Department, Belcolle Hospital, Viterbo, Italy
