The last half-century has witnessed a sea change in our understanding of the epilepsies, as evidenced by the scientific and clinical knowledge documented in this book. The original edition of Basic Mechanisms of the Epilepsies, published in 1969, was edited by Herbert H. Jasper, Arthur A. Ward, Jr., and Alfred Pope. They assembled 30 chapters, each followed by critical discussions that were products of a historic four-day workshop in Colorado Springs in 1968. A majority of the chapters were devoted to normal functions of cerebral cortex, microelectrode recordings of neuronal membrane firing, and the physiology of central neurotransmitters and synaptic inhibition. Experimental methods to induce seizures in healthy brain comprised six chapters, and other chapters examined electroencephalography, sleep, the immature brain, and reflex seizure mechanisms. The concepts of synchrony, spread, and propagation were addressed in only two chapters, one authored by Herbert Jasper himself. A discussion of the role of genetics in seizures and epilepsy was found in only a single chapter.

The reasoning behind the scant attention to the heredity of epilepsy was reflected in Chapter 1, where the editors argued the prevailing view that all epilepsies are symptomatic and that a seizure is merely a nonspecific outcome of many and varied pathological processes. They further proclaimed, “There may be no true epilepsy as a disease sui generis.” Adopting this premise downplayed the potential role for genetics in epilepsy, hence the widespread acceptance of the term idiopathic epilepsy, despite a report by Lennox in 1951 of concordance among monozygotic twins. The reluctance to accept a major contribution of genetics in epilepsy probably also reflected the hesitancy of epilepsy advocacy organizations worldwide, who were actively battling the social stigma of the disorder. As the editors of the first edition of Basic Mechanisms opined, “the epileptic is still the leper of the modern era.”

Thirteen years later, in 1982, Antonio V. Delgado-Escueta, with Arthur A. Ward, Dixon M. Woodbury, and Roger J. Porter, organized the second Basic Mechanisms of the Epilepsies workshops at the Kroc Foundation Ranch in the Santa Ynez Mountains. Two consequential participants solidified an important role for genetics in epilepsies. The first was Ray White from the University of Utah, who with David Botstein at Stanford had pioneered the use of restriction fragment length polymorphisms to locate the chromosomal sites of human disease-producing genes, and proposed applying the new technology to epilepsy. The second was a postdoctoral fellow, Jeffrey L. Noebels at Harvard, who discovered that single locus mutations in mice could initiate specific heritable neurological syndromes featuring different patterns of epilepsy, including childhood absence epilepsy. This finding provided the first proof of principle that epilepsy genes could produce seizure disorders as a disease sui generis, and it opened the door to the analysis of epilepsy in genetically defined mice. The workshops led to a call for more basic research on the causes of human epilepsies and their treatment, including the study of surgically resected brain tissues from drug-resistant human temporal lobe and frontal lobe epilepsies. J. Kiffin Penry, then chief of the Epilepsy Branch of the National Institute of Neurological and Communicative Disorders and Stroke, was instrumental in organizing both the 1968 and the 1982 workshops, and supporting the implementation of these goals. The 1982 workshop led to the second edition of Basic Mechanisms of the Epilepsies.

Three scientific conferences were organized to bring about the third edition. The first was a workshop at the Homestead in Hot Springs, Virginia, in 1992, followed by a second at Yosemite National Park in California in 1993. The third was an open symposium held in San Diego in 1996, where Herbert H. Jasper was welcomed as an honorary consulting editor. The third edition was honorifically titled Jasper’s Basic Mechanisms of the Epilepsies and was edited by Antonio V. Delgado-Escueta, Wilkie A. Wilson, Richard W. Olsen, and Roger J. Porter.

The next decade witnessed the development of the fourth edition, which was published in 2012. Planning workshops were held in 2009 at the Lodge at Yosemite Falls in Yosemite National Park. The topical coverage was greatly expanded to include brain circuit pathophysiology, ion channel and synaptic receptor disorders, epilepsy comorbidities, and a consideration of new treatment modalities. The editors of the fourth edition were Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Richard W. Olsen, and Antonio V. Delgado-Escueta.

Since the last edition there have been enormous technical strides in molecular genetic technology, de novo mutation analysis, cellular physiology, and optogenetics; and the genetic, viral, and cellular therapy of nervous system disorders. New molecular pathway approaches to epileptogenesis, progressive neurodegenerative seizure disorders, epilepsy comorbidities, and drug discovery are being explored. These advances have enabled new understanding of the fundamental mechanisms of the epilepsies, and have driven the conception of novel treatments and potential cures. This progress was reviewed at the workshops once again held at Yosemite National Park in March 2019, which as senior editors we were honored to organize. We are grateful to all who attended and participated in the lively interchange. Upon conclusion of the workshops came the task of assembling this volume with its eight sections and 79 chapters. This undertaking was propelled by the enthusiastic acceptance of the contributing authors and their diligence in meeting the required deadlines. We deeply appreciate their commitment and expertise.

The original Basic Mechanisms of the Epilepsies volume, and each subsequent edition, has been considered the “bible” of basic epilepsy research. We hope that this fifth edition will honor the tradition by serving as a useful reference and guide to the future of epilepsy research, and most importantly as an inspiration to the next generation of epilepsy researchers.