Preface

Epilepsy is the most common neurological disorder globally, affecting approximately 50 million people of all ages. It is one of the oldest diseases described in literature from remote ancient civilizations 2000–3000 years ago. Despite its long history and wide spread, epilepsy is still surrounded by myth and prejudice, which can only be overcome with great difficulty. The term *epilepsy* is derived from the Greek verb *epilambanein*, which by itself means to be seized and to be overwhelmed by surprise or attack. Therefore, epilepsy is a condition of getting over, seized, or attacked. The twelve very interesting chapters of this book cover various aspects of epileptology from the history and milestones of epilepsy as a disease entity to the most recent advances in understanding and diagnosing epilepsy.

The first chapter is an introductory chapter written by the editors. In this chapter, we trace the earliest records and the major milestones in the history of epilepsy since the early civilization in Mesopotamia (the ancient name of Iraq), almost 2000–3000 B.C. These early establishments include the Sumerian, Babylonian, Assyrian, and Akkadian civilizations. The first description of epilepsy was written in the Akkadian language in about 2000 B.C., in which the author described a condition similar to epileptic seizures in a patient. The contribution of the ancient Egyptian, old Chines, and Greek civilizations to the history of epilepsy is also described in this chapter. The father of medicine, Hippocrates, in his book "Sacred Disease" written in 400 B.C, raised the first dispute about the divine origin of epilepsy. He said ''This disease is in my opinion no more divine than any other; it has the same nature as other diseases and the cause that gives rise to individual diseases. This chapter also follows the evolution of epilepsy as a disease entity and the discovery of anticonvulsant therapy throughout the middle ages and provides a short review about the misconceptions, incorrect beliefs, and myths surrounding epilepsy.

The second chapter by Vanessa Lin Lin Lee and Mohd. Farooq Shaikh, briefly discusses how neuroinflammation is involved in epileptogenesis as well as the status of inflammation in post-epileptic conditions; whether it is the cause or consequence of epilepsy, together with experimental evidence. The exact cause of epilepsy is still unknown, but there is mounting evidence showing that the development of epileptogenesis can be linked to a wide array of factors such as genetic predisposition, developmental disorders, and neurological insults. Neurological insults, which contribute to up to 60% of epilepsy cases, include traumatic brain injuries, cerebrovascular accidents, central nervous system infections, and strokes. Inflammation is one of the key features of epileptogenesis. However, the role of inflammation in epilepsy is still being actively studied, with various arguments on whether inflammation is the cause or consequence of epilepsy. The blood-brain barrier (BBB), which functions as a protector of the central nervous system, has an important role in regulating the transfer of blood constituents in the brain extracellular space. Increased BBB permeability or BBB leakage is said to be one of the earliest characteristics of the pathophysiology of epileptogenesis. BBB dysfunction may contribute to epileptogenesis via a cascade of events triggered by leakage of inflammatory mediators into the central nervous system (CNS), which causes neuroinflammation.

**II**

**Chapter 7 107**

Epilepsy - Therapeutic Aspect **131**

**Chapter 8 133**

**Chapter 9 147**

Recent Advances in Epilepsy **169**

**Chapter 10 171**

**Chapter 11 193** Components of Soft Computing for Epileptic Seizure Prediction and Detection

Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

The Role of Nondrug Treatment Methods in the Management of Epilepsy *by Natalia Shnayder, Ekaterina Narodova, Valeriya Narodova, Andrey Narodov* 

Ketogenic Diet Therapies in Children and Adults with Epilepsy

*by Shuzhang Zhang, Yudan Zhu, Jiwei Cheng and Jie Tao*

*by Alexey Kholin*

*and Evgeniy Erakhtin*

*by B. Suguna Nanthini*

*by Matthew Charles Lee Phillips*

**Section 5**

**Section 6**

The third chapter is by Jawad Laadraoui and Abderrahman Chait in which they evaluate the convulsive effects of intracerebroventricular administration of cigarette smoke condensate in rats and compare the intensity of seizures with kainic acid induced-seizures as a model of epilepsy. They also evaluate the role of the cholinergic system using mAChRs antagonist in cigarette smoke condensate induced seizures. Tobacco smoke is a complex multi-component system, in which there are more than 4800 compounds, many of which are carcinogens. As a result, chronic obstructive pulmonary disease, chronic bronchitis, cardiovascular disease, emphysema, stroke, and many forms of cancer are directly related to smoking. The results of this study indicate that the central injection of cigarette condensate provides an epileptic behavior similar to that induced by kainic acid. However, pretreatment with atropine reduced seizures and all their parameters.

In the fourth chapter, Dr. Boulenouar Mesraoua et al describe non-convulsive status epilepticus (NCSE) in patients with altered mental status admitted to Hamad General Hospital, Doha, Qatar. The authors aim to update the current status of NCSE with particular emphasis on NCSE in the Middle Eastern and North African region, to find the prevalence of NCSE in patients with altered mental status, describing the clinical presentation, EEG findings, etiology, neuroimaging, treatment and outcome of NCSE in Qatar, and to discuss the time it takes to record NCSE in the intensive care unit using continuous EEG monitoring in patients with altered mental states. This study shows disappointing results regarding NCSE, which appears to be an emerging condition requiring rapid diagnosis and rapid treatment.

The fifth chapter, by Halil Kocamaz, is dedicated to gastrointestinal disorders associated with epilepsy. The gastrointestinal system communicates with the brain via the vagus nerve fibers and gut-brain axis. There is a well-known relationship between autoimmune diseases and epileptogenesis and this may explain why gut microbiota can interfere in the course of epilepsy. Many seizures that are described, depending on the severity and/or duration, as benign may have gastrointestinal origin. Epilepsy and related neurological symptoms may alert the clinician for additional life-threatening conditions and complications during the course of gastrointestinal-based chronic diseases such as inflammatory bowel disease and celiac disease. As the gut is the only exposed part of the inner body to environment gut-microbiota, novel therapeutic options that targets the gut may be promising in many diseases including epilepsy.

The sixth chapter, by Otman Fernandez-Concepcion and Melvin Lopez-Jimenez, reviews epileptic encephalopathies in infants and children. The concept of epileptic encephalopathies is based on the clinical descriptions of some epileptic syndromes during the last century. It represents a group of devastating epileptic disorders that appear early in life and are characterized by drug-resistant, generalized or focal seizures, persistent severe EEG abnormalities, and cognitive dysfunction or decline. In this review, the authors discuss the clinical and electroencephalographic characteristics, evaluation, and management of age-related epileptic encephalopathies, recognized by the International League Against Epilepsy. These include early infantile epileptic encephalopathy (Ohtahara syndrome), early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), myoclonic–atonic epilepsy (Doose syndrome), Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spike-and-wave during sleep, and Landau-Kleffner syndrome. Their etiologies, clinical features, treatment, and prognoses are presented and updated.

**V**

distribution.

In the seventh chapter, Professor Alexey Kholin gives a description of malignant migrating partial seizures in infancy, also known as Coppola-Dulac syndrome. This syndrome is a rare and usually unrecognized epileptic syndrome of infancy. The first publication presented by G. Coppola and colleagues in 1995 and O. Dulac in 2005 summarized 24 patients' follow-up in the Saint Vincent de Paul Hospital in Paris. Clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy. Seizure onset is before the age of 6 months. From the age of 1 to 10 months, seizures become very frequent and polymorphic, usually clustered in nature, with mental and motor retardation clear. Clinical manifestation of seizures may include head and eye deviation, lateralized clonic eyelids twitching, fixed gaze, tonic or clonic spasm of one limb or hemi spasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. Video-EEG monitoring plays the most important role in the diagnosis. Ictal EEG patterns involve different areas of the cerebral cortex of both hemispheres, the initial zone of ictal patterns shifts from one region to another. It is a drug-resistant

The eighth chapter is by Irma Khachidze and is about the dynamics of EEG characteristics in epileptic children during treatment with valproic acid. In this chapter, the author discusses the results of her original article aiming to investigate the alteration of different characteristics of interictal EEG in epileptic children during AED therapy. The analysis of the dynamics of background EEG reveals possible early predictors of the treatment's benefits or adverse effects. Determination of the efficacy of AED based on EEG criteria is very important for optimization of anti-epileptic therapy in individual patients. The result of this study concludes that reduction of high-amplitude low-frequency waves and suppression of epileptiform patterns simultaneously with clinical improvement at three to six months after treatment can serve as an indicator of effective therapy. Brain mapping reveals the essential prognostic or predicting value of morphology of the theta-waves and their

The ninth chapter is by Natalia Shnayder et al and it is about the role of non-drug treatment methods in epilepsy treatment in adult patients in Russia and abroad. An important problem of epileptology is ensuring the safety and acceptability of the treatment as well as prevention of adverse drug reactions of antiepileptic drugs. The emergence of ASEs can often decrease patients' life quality, thereby offsetting the positive effect of the treatment. Moreover, such adverse side effects as depression and anxiety may aggravate epileptic seizures. The authors conduct a literature review to reveal the basic non-drug epilepsy treatment options. However, not all of these options have a sufficient evidence base, and some of them are not safe. Particularly, methods with a low level of evidence include acupuncture and aromatherapy. One of the methods, which can influence the pathogenesis of epilepsy, is the physical activity for patients with epilepsy since epileptiform activity on the EEG was reported to disappear during exercise. The positive results of the applica-

tion of art therapy (music therapy) is also described in modern literature.

Dr. Matthew C.L. Phillips, in the tenth chapter, discusses the influence of the ketogenic diet in the treatment of epilepsy in children and adults. Despite a wide array of anti-epileptic drugs and the option of surgery, one-third of children and adults with epilepsy continue to suffer from drug-resistant seizures. Many of these patients may benefit from a ketogenic diet, a non-pharmacologic therapy proven to improve seizure control through a variety of mechanisms that collectively stabilize

type of epilepsy with serious prognosis.

In the seventh chapter, Professor Alexey Kholin gives a description of malignant migrating partial seizures in infancy, also known as Coppola-Dulac syndrome. This syndrome is a rare and usually unrecognized epileptic syndrome of infancy. The first publication presented by G. Coppola and colleagues in 1995 and O. Dulac in 2005 summarized 24 patients' follow-up in the Saint Vincent de Paul Hospital in Paris. Clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy. Seizure onset is before the age of 6 months. From the age of 1 to 10 months, seizures become very frequent and polymorphic, usually clustered in nature, with mental and motor retardation clear. Clinical manifestation of seizures may include head and eye deviation, lateralized clonic eyelids twitching, fixed gaze, tonic or clonic spasm of one limb or hemi spasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. Video-EEG monitoring plays the most important role in the diagnosis. Ictal EEG patterns involve different areas of the cerebral cortex of both hemispheres, the initial zone of ictal patterns shifts from one region to another. It is a drug-resistant type of epilepsy with serious prognosis.

The eighth chapter is by Irma Khachidze and is about the dynamics of EEG characteristics in epileptic children during treatment with valproic acid. In this chapter, the author discusses the results of her original article aiming to investigate the alteration of different characteristics of interictal EEG in epileptic children during AED therapy. The analysis of the dynamics of background EEG reveals possible early predictors of the treatment's benefits or adverse effects. Determination of the efficacy of AED based on EEG criteria is very important for optimization of anti-epileptic therapy in individual patients. The result of this study concludes that reduction of high-amplitude low-frequency waves and suppression of epileptiform patterns simultaneously with clinical improvement at three to six months after treatment can serve as an indicator of effective therapy. Brain mapping reveals the essential prognostic or predicting value of morphology of the theta-waves and their distribution.

The ninth chapter is by Natalia Shnayder et al and it is about the role of non-drug treatment methods in epilepsy treatment in adult patients in Russia and abroad. An important problem of epileptology is ensuring the safety and acceptability of the treatment as well as prevention of adverse drug reactions of antiepileptic drugs. The emergence of ASEs can often decrease patients' life quality, thereby offsetting the positive effect of the treatment. Moreover, such adverse side effects as depression and anxiety may aggravate epileptic seizures. The authors conduct a literature review to reveal the basic non-drug epilepsy treatment options. However, not all of these options have a sufficient evidence base, and some of them are not safe. Particularly, methods with a low level of evidence include acupuncture and aromatherapy. One of the methods, which can influence the pathogenesis of epilepsy, is the physical activity for patients with epilepsy since epileptiform activity on the EEG was reported to disappear during exercise. The positive results of the application of art therapy (music therapy) is also described in modern literature.

Dr. Matthew C.L. Phillips, in the tenth chapter, discusses the influence of the ketogenic diet in the treatment of epilepsy in children and adults. Despite a wide array of anti-epileptic drugs and the option of surgery, one-third of children and adults with epilepsy continue to suffer from drug-resistant seizures. Many of these patients may benefit from a ketogenic diet, a non-pharmacologic therapy proven to improve seizure control through a variety of mechanisms that collectively stabilize

**IV**

treatment.

many diseases including epilepsy.

The third chapter is by Jawad Laadraoui and Abderrahman Chait in which they evaluate the convulsive effects of intracerebroventricular administration of cigarette smoke condensate in rats and compare the intensity of seizures with kainic acid induced-seizures as a model of epilepsy. They also evaluate the role of the cholinergic system using mAChRs antagonist in cigarette smoke condensate induced seizures. Tobacco smoke is a complex multi-component system, in which there are more than 4800 compounds, many of which are carcinogens. As a result, chronic obstructive pulmonary disease, chronic bronchitis, cardiovascular disease, emphysema, stroke, and many forms of cancer are directly related to smoking. The results of this study indicate that the central injection of cigarette condensate provides an epileptic behavior similar to that induced by kainic acid. However, pretreatment

In the fourth chapter, Dr. Boulenouar Mesraoua et al describe non-convulsive status epilepticus (NCSE) in patients with altered mental status admitted to Hamad General Hospital, Doha, Qatar. The authors aim to update the current status of NCSE with particular emphasis on NCSE in the Middle Eastern and North African region, to find the prevalence of NCSE in patients with altered mental status, describing the clinical presentation, EEG findings, etiology, neuroimaging, treatment and outcome of NCSE in Qatar, and to discuss the time it takes to record NCSE in the intensive care unit using continuous EEG monitoring in patients with altered mental states. This study shows disappointing results regarding NCSE, which appears to be an emerging condition requiring rapid diagnosis and rapid

The fifth chapter, by Halil Kocamaz, is dedicated to gastrointestinal disorders associated with epilepsy. The gastrointestinal system communicates with the brain via the vagus nerve fibers and gut-brain axis. There is a well-known relationship between autoimmune diseases and epileptogenesis and this may explain why gut microbiota can interfere in the course of epilepsy. Many seizures that are described, depending on the severity and/or duration, as benign may have gastrointestinal origin. Epilepsy and related neurological symptoms may alert the clinician for additional life-threatening conditions and complications during the course of gastrointestinal-based chronic diseases such as inflammatory bowel disease and celiac disease. As the gut is the only exposed part of the inner body to environment gut-microbiota, novel therapeutic options that targets the gut may be promising in

The sixth chapter, by Otman Fernandez-Concepcion and Melvin Lopez-Jimenez, reviews epileptic encephalopathies in infants and children. The concept of epileptic encephalopathies is based on the clinical descriptions of some epileptic syndromes during the last century. It represents a group of devastating epileptic disorders that appear early in life and are characterized by drug-resistant, generalized or focal seizures, persistent severe EEG abnormalities, and cognitive dysfunction or decline. In this review, the authors discuss the clinical and electroencephalographic characteristics, evaluation, and management of age-related epileptic encephalopathies, recognized by the International League Against Epilepsy. These include early infantile epileptic encephalopathy (Ohtahara syndrome), early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), myoclonic–atonic epilepsy (Doose syndrome), Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spike-and-wave during sleep, and Landau-Kleffner syndrome. Their etiologies, clinical features, treatment, and prognoses are presented and updated.

with atropine reduced seizures and all their parameters.

synaptic function. There are many similarities concerning patient selection, patient preparation, and diet implementation in children compared to adults, but there are also important differences. The most conspicuous challenge to the more widespread use of ketogenic diets in children and adults with epilepsy is a lack of access to ketogenic services in many regions of the world. Moreover, the culinary and social restrictions associated with conventional ketogenic diets pose a significant barrier to the diet for adults.

Shuzhang Zhang et al, in the eleventh chapter, highlight recent discoveries on the mutations in voltage-gated ion channels (VGICs), genes, and dysfunction of VGICs in epilepsy, focusing on the pathophysiological and pharmacological properties. VGICs are extensively distributed in the central nervous system and are responsible for the generation as well as modulation of neuroexcitability and are considered to be vital players in the pathogenesis of human epilepsy, by regulating the shape and duration of action potentials. For instance, genetic alterations or abnormal expression of voltage-gated sodium channels, Kv channels, and voltage-gated calcium channels are proved to be associated with epileptogenesis. Understanding the role of epilepsy-associated VGICs might not only contribute to clarifying the mechanism of epileptogenesis and genetic modifiers but also provide potential targets for the precise treatment of epilepsy.

The last chapter, by Dr. B. Suguna Nanthini, discusses the interesting subject about the development of automated expert systems in order to perform difficult jobs. The author discusses the components of soft computing include machine learning, fuzzy logic, evolutionary computation, and probabilistic theory. These components have the cognitive ability to learn effectively. They deal with imprecision and have a good tolerance of uncertainty. Components of soft computing are needed for developing automated expert systems. These systems reduce human interventions in completing a task. The system has been trained and tested using soft computing techniques. These systems are required in all kinds of fields and are especially useful in medical diagnosis. From these analyses, this chapter concludes that there are a number of features of the system that will allow for better accuracy of classification. The classifier, with a suitable learning method, can perform well for the automated epileptic seizure detection system. Furthermore, the level of decomposition of the EEG signal at level 4 is sufficient for seizure detection.

Section 1

Introduction

1

**Prof. Isam Al-Zwaini, PhD and Prof. Ban Adbul-Hameed Majeed Albadri** Department of Pediatrics, AL-Kindy Medical College, University of Baghdad, Baghdad, Iraq

Section 1 Introduction

Chapter 1

1. Introduction

3

Introductory Chapter:

of the Sacred Disease

Ban Adbul-Hameed Majeed Albadri

2. The major milestones in the history of epilepsy

Isam Jaber AL-Zwaini and

Epilepsy—The Long Journey

Epilepsy is the most common neurological disorder globally, affecting approximately 50 million people of all ages [1]. It is one of oldest diseases described in literature from remote ancient civilizations 2000–3000 years ago. Despite its old description and its wider spread, epilepsy is still surrounded by myth and prejudice which can be overcome only with great difficulties. These myths and prejudice might have its historical origin. The aim of this introductory chapter is to follow the origin of epilepsy in ancient cultures, highlight the myth and stigmatism associated with epilepsy, and follow the major milestone in its development as a disease entity. The term epilepsy is derived from the Greek verb epilambanein, which by itself means to be seized and to be overwhelmed by surprise or attack. Therefore, epilepsy means a condition of getting over, seized, or attacked [2].

The history of epilepsy goes together with the history of humankind in the globe. The earliest recorded account of epilepsy can be traced to the earliest civilization developing in Mesopotamia (the old name of the country IRAQ) almost 2000–3000 BC. These earliest establishments include the Sumerian, Babylonian, Assyrian, and Akkadian civilizations. The first description of epilepsy was written in the Akkadian language about 2000 BC in which the author described a condition similar to epileptic seizures in a patient. He described a patient whose neck turns to the left side, with his hands and feet being tense, with his eyes widely opened, and with his mouth drooling froth without him knowing. The condition diagnosed as antasubbû translated as the hand of sin brought about by the god of the Moon [5]. In a tablet from the Babylonian series (1067–1046 BC) present in the Babylonian collection of the British Museum(47,753), we find a report containing a detailed description of the symptoms of the condition known today as epilepsy with the supernatural forces suggested as an etiology (Figure 1). This table is written in Neo-Babylonian script dated approximately at the middle of the first millennium BC [4].

In this tablet, epilepsy was called Sakikku miqtu ("falling disease"), and the author describes various signs for the diagnosis, treatment, and prognosis of epilepsy. The etiology of epilepsy was presumed to be the effect of demons, evil spirits, and ghosts, and features of generalized seizures, simple and complex partial seizures, gelastic seizures, nocturnal epilepsy, febrile seizures, status epilepticus,
