Epilepsy: A Comprehensive Textbook
2nd Edition

This is an exciting era for clinicians and investigators interested in the mechanisms of epileptogenesis. Advances in technology during the last three decades have made possible the detailed assessment of intracellular electrophysiologic changes, the determination of membrane responses to neurotransmitters, and even the identification and cloning of specific receptors and channels, some of which are mutated in inherited forms of epilepsy. Through these procedures, knowledge of the fundamental biology underlying cellular excitability and membrane stability has been acquired, sites of action and methods of modifying the function of various neurotransmitters have been determined, and our understanding of the manner in which neural networks enhance or impede seizure occurrence has greatly increased. These exciting developments in the laboratory sometimes result in a tendency to overlook important developments that have occurred within the same time period in the more clinically relevant areas of epidemiology, pathology, and genetics. As one peruses the chapters in this section, it becomes clear that these areas have been equally dynamic in terms of the development of new concepts and ideas. The substantial body of knowledge acquired in epidemiology, pathology, and genetics represents more than an addition to the assumptions that have been considered fact for the last three decades. Indeed, current concepts provided by recent studies in epidemiology and genetics contradict various ideas that were considered well established in the 1970s. The present state of our knowledge suggests various directions for future exploration, not only to students of these observational sciences, but also to those addressing basic neurophysiology.

Through application of the techniques of descriptive and experimental epidemiology, our understanding of seizures and the epilepsies as these conditions affect humans has been expanded substantially, and this expansion parallels the explosion of discoveries in basic neurobiology. The discipline of epidemiology provides the rigor and broad scope of view that is lacking in clinical series and case reports, which are often viewed with relative skepticism by basic scientists. It is true that the study of real people is complex, but the study of mechanisms at the level of the single cell is equally difficult to integrate into broader concepts.

The development of sophisticated study designs and analytic methods for human investigations is not the only reason for recent advances in knowledge. An emerging classification for seizures and the epilepsies not only provides definitions of seizure type¹ and aggregation of symptoms,² but also deals with specifics of etiologic classification and case assignment,³ thereby enabling the application of uniform definitions across studies. Although complex and in general relatively expensive, the studies of incidence performed during the last three decades have provided knowledge of the true frequency with which seizures and epilepsy occur in the general population and have also informed our understanding of the interpretive complexities involved in the much more readily available studies of prevalence. Although important in determining service needs, studies of prevalence provide no insight regarding the important areas of etiology, prognosis, and prevention. These discrepancies are elucidated in Chapter 5. The consistency of recent epidemiologic studies of incidence in terms of age of individuals affected and distribution of etiology and seizure type is impressive, and the now-well-accepted concept of epilepsy as a condition that affects the elderly as well as the very young, at least in Western countries, is clear.

The patterns of epilepsy in developing countries are explored thoroughly in Chapter 11. These studies are often difficult because of the lack of organized medical systems in many areas, and interpretations are blurred because of the lack of information derived from clinical and laboratory evaluations generally available in Western countries. Fortunately, incidence data from these areas allow a more accurate assessment of frequency and individuals at risk. It is clear that data from more economically developed countries cannot be directly applied to developing areas, but from many standpoints, epidemiologic patterns are similar. Additional clues are usually present that may allow hypotheses to account for any differences to be generated. For example, there is evidence for urban–rural differences in incidence. In rural areas of underdeveloped countries, many people with epilepsy have never been treated with antiepileptic drugs. Thus, a natural experiment can be undertaken to evaluate the effect of drugs on prognosis. Chapter 4 explores the sociocultural perceptions of epilepsy in such communities and further clarifies the reasons for the social consequences discussed in Chapter 11.

The exploitation of incidence and inception cohorts from industrialized countries (including but not limited to the United States, the United Kingdom, France, Iceland, Sweden, the Netherlands, and Japan) to identify antecedents has been a natural consequence of the identification of incidence cohorts. The results of the systematic evaluation of classic as well as novel risk factors are addressed in Chapter 6. The study of large birth cohorts^8,9 and cohorts with putative risk factors, such as stroke, head injury, infection, and degenerative disease of the nervous system, enable determination of the absolute risk for epilepsy and seizures, provide information regarding the impact of these putative risk factors that is more readily understandable and relevant to clinicians, and may lead to interventions. The role of factors such as adverse prenatal and perinatal events and febrile convulsions is being clarified, and questions regarding the influence of conditions not invariably associated with structural pathology of the brain, such as hypertension, cardiovascular disease, migraine, and such psychiatric disorders as depression and attention-deficit disorder, not only provide new insights into factors that have traditionally been considered
either consequences of epilepsy or only marginally related to epilepsy, but also supply the basis for possible new treatment strategies.^4,5,7

Another consequence of the identification of incidence cohorts is the ability to determine more precisely the natural history of epilepsy through systematic follow-up of patients. Chapter 7 provides data regarding the prognostic measure closest to the hearts of clinicians, namely seizure control. This review of natural history and prognosis also provides information about other outcomes, including social integration, intellectual function, and comorbid conditions. Contrary to opinions held even into the last decade, epilepsy must now be considered a condition that, in the majority of cases, is relatively benign. Most patients with newly diagnosed epilepsy achieve complete freedom from seizures, and the majority of those who become seizure free can be expected to discontinue antiepileptic drugs without experiencing further seizures. The challenge to clinical investigators now is to clarify those factors associated with good and bad prognoses.

Most studies of cohorts with epilepsy have suggested that individuals with epilepsy are at increased risk for death. The reasons for this apparent increase in mortality, particularly among those with epilepsy of unknown cause, are obscure. In Chapter 10, the proportionate increases in overall mortality and cause-specific mortality are reviewed and compared with data from the general population. The minimally increased mortality in individuals with idiopathic or cryptogenic epilepsy is encouraging, but exploration of the factors that differ between these individuals and the general population is important. Certain conditions affect unique subgroups of people with epilepsy. Sudden death in people with intractable epilepsy is an example of a problem that is not well understood and needs to be addressed further. This specific topic is dealt with in a later section (Chapter 189).

Inducers and precipitants of seizures are discussed in Chapter 9. The distinctions among precipitants (e.g., sleep deprivation), triggers (stimulus-sensitive epilepsies), and modulators (stress, hormonal variation) are reviewed. The need for identification of these factors in developing an individualized approach to people with epilepsy seems clear. Patients with acute symptomatic seizures, reviewed in Chapter 8, represent a unique subset of individuals for whom, unlike people with epilepsy, there is little question regarding cause and effect. These individuals in general would not be expected to have seizures in the absence of a concurrent medical condition or particular set of circumstances. In general, the mortality of people with acute symptomatic seizures is high, and survivors have an increased risk for subsequent epilepsy. The identification of acute symptomatic seizures is important for presenting an accurate and comprehensive picture of seizures and epilepsy in industrially advanced countries and meaningfully assessing prognosis. It also makes possible a comparison with data from developing countries, where survivors of this class of seizures can seldom be distinguished accurately from those with epilepsy.

Chapter 12 discusses the failure to identify structural or neurochemical features that might be causes of epilepsy and the difficulty of identifying specific pathology outside the hippocampus that may be associated with clinical seizures. This chapter also reviews the important issue of distinguishing pathologic changes that are the consequences of epileptic seizures from those that may be reasonably considered to be causative of them. Finally, the chapter discusses those brain lesions that are commonly associated with epilepsy, including neoplasms, inflammatory disorders, and brain injuries.

Changes in brain structure that may be attributable to epilepsy are also discussed. Chapter 13 reviews the unique pathology, electrophysiology, and molecular biology of hippocampal sclerosis. Hippocampal sclerosis is a consequence of an initial precipitating injury, which is not age specific and participates in the genesis of temporal lobe epilepsy. Recurrent seizures or status epilepticus modifies the pathology, but whether these are directly causal is controversial.

Our understanding of the neuropathology of epilepsy and epileptogenesis has been greatly modified in recent years. Chapter 14 discusses the role of cortical developmental malformations, which can now be readily identified in clinical practice by magnetic resonance imaging (MRI) brain scans and evaluated pathologically from surgical specimens. Such lesions are responsible for most of the identified structural pathology associated with epilepsy in children, and careful evaluation may provide clues to the timing and mechanisms of epileptogenesis. The single-gene disorders associated with developmental malformations also provide clues to underlying biologic behavior.

The identification of a chromosomal locus for some epilepsy syndromes and the elucidation in a growing number of cases of the responsible genes have been important developments and the focus of considerable recent attention. The necessary groundwork for many of these genetic advances is provided by population genetic studies, and Chapter 15 discusses the importance of family studies. This chapter considers the complexities involved in interpreting such studies and stresses such factors as genetic heterogeneity, pleiotropy, and the role of gene–environment interactions. The development of sophisticated mathematical models of inheritance patterns has been made possible by computer techniques.

Additional complexities entailed in family studies of epilepsy are addressed in the review of electroencephalographic (EEG) traits in Chapter 16. Many EEG patterns are clearly inherited, often as a single-gene trait. The relationship of these patterns to clinical epilepsy, however, is elusive. The failure to distinguish between familial aggregations of EEG patterns and familial aggregations of seizures or epilepsy continues to cause confusion and would appear to be an important area for further study.

Chapter 19 discusses the use of family data for patient counseling and the empirical risks for seizure and epilepsy within families. The important concept of presymptomatic detection of those at risk—now possible for only a few of the convulsive disorders—and its implications are also discussed. Although it is unlikely that such detection will play an important role in regard to the most frequently occurring types of epilepsy in the near future, investigators need to address the ethical considerations and approaches to such evaluation.

In a number of single-gene diseases, seizures are included in the constellation of symptomatology. Some of these are reviewed in Chapter 17. The review of the biochemical and structural bases of these syndromes can provide additional understanding of epileptogenic mechanisms. The question of why epilepsy develops in some individuals with a given genotype and not in others is the subject of active investigation.

Chapter 18 discusses genes specific for epilepsy. Those that have been identified most often involve channelopathies as the underlying primary mechanism.¹⁰ In many situations, however, the genetic mechanisms remain obscure in both mice and humans.⁶ An integrated effort by epidemiologists, molecular and population geneticists, and clinical and basic
neuroscientists is clearly needed to acquire a full understanding of specific genetic actions.

The rapidly growing pool of information regarding basic mechanisms of epileptogenesis emanating from modern laboratories has been paralleled by an increase in clinically relevant information. Both the laboratory and clinical approaches are important, and the results provided by each should be integrated to determine future research directions.