Epilepsy: A Comprehensive Textbook
2nd Edition

Luigi Galvani (Fig. 3) created the foundation for the field of electrophysiology and, ultimately, electroencephalography through his monumental discovery of animal electricity in 1791.¹⁰¹ These fruits of his work would revolutionize the study of epilepsy in the 20th century. Galvani demonstrated that electrical charges produced by friction and stored in Leyden glass jars caused muscle contractions, whether the charge was applied to the muscle or the nerve (Fig. 4). For many years, Galvani’s seminal observations had little scientific impact, in spite of confirmation of the phenomenon by Alessandro Volta (Fig. 5) and others. In fact, it was Volta, inventor of the first storage battery, who was largely responsible for the 50-year delay in the general acceptance of animal electricity because of his misinterpretation of Galvani’s experimental findings. Volta
incorrectly and tenaciously ascribed all of Galvani’s evidence of intrinsic nerve transmission to direct muscle stimulation from a battery effect due to the inadvertent use of two dissimilar metals.²⁴¹ Galvani, who opposed Napoleon, lost his position at the University of Bologna and the Institute of Sciences, while Volta, a supporter of Napoleon, received many honors, and by outliving Galvani by three decades, used his prestige to continue to deny the validity of his countryman’s work. It was not until 1937, 200 years after Galvani’s birth, that Bologna’s Institute of Sciences celebrated his life and republished his treatise.

In his 1823 review of previous knowledge concerning epilepsy, Cooke⁶⁷ continued to insist that loss of consciousness and bilateral tonic–clonic seizures were required for diagnosis. From that time on, however, most authors, while still requiring transient loss of consciousness, have not emphasized bilateral convulsive behavior as a prerequisite for the diagnosis of epilepsy.^{39,87,124,205,216,234} Thus, at the end of the 19th century, Beevor¹⁴ could write that “epilepsy is the name given to sudden loss of consciousness with or without convulsions.”

This change in diagnostic requirements triggered an increased interest in the minor manifestations of epilepsy such as the brief losses of consciousness that Tissot²³² had described, termed by Calmeil⁴⁸ as “absences” and by Esquirol⁸⁷ as “petit mal.” Prichard²⁰⁵ had included these, along with superficially similar episodes characterized by a prodrome of which the patient was aware (i.e., simple partial seizures evolving into complex partial ones) in his subtype of “leiothymia,” a term that soon disappeared from use. He also described a tetanic type of epilepsy, probably the same or similar to present-day tonic seizures, and wrote of “partial epilepsy” largely in Cullen’s⁷⁰ sense of epileptic manifestations appearing only in a part of the body without alteration of consciousness. New epileptic

syndromes were described: First Bravais³⁵ and later Bright³⁹ and Todd²³⁴ reported focal motor seizures, before Jackson made them the subject of his special interest, and which Charcot later⁵⁵ associated with Jackson’s name. Todd, and before him Bright, noted the temporary “epileptic hemiplegia” after such focal seizures and which later became known as Todd paralysis. West²⁴⁵ described infantile spasms, sadly, in his own infant son, while Herpin¹³² provided a detailed account of juvenile myoclonic epilepsy but did not regard it as a separate entity within the “commotions” (i.e., myoclonic seizures). An increasing wealth of detail about the prodromes or auras became available in the literature, and Esquirol⁸⁷ recognized their occasional occurrence as isolated events without other manifestations of epilepsy. Herpin¹³² considered the aura to be not a warning but rather the actual start of the seizure: “la première manifestation de l’attaque.”

At the same time that a diverse and expanded repertoire of epileptic seizures was being recognized, there was a growing effort to define and limit those phenomena that could legitimately be included under the rubric of epilepsy. This latter development arose from an increasing attempt to classify diseases on an etiologic basis. At the onset of the 19th century, Maisonneuve¹⁷⁴ and later Prichard²⁰⁵ divided epilepsy into idiopathic and sympathetic types, with the latter further subdivided into gastric, intestinal, hysterical, and hypochondriacal subtypes, based on the part of the body where the first seizure manifestation was experienced. Esquirol⁸⁷ added a third type, a symptomatic form of epilepsy due to disease outside the central nervous system. Delasiauve⁷³ utilized the same three main categories, but his idiopathic epilepsy was restricted to cases of cerebral origin without brain pathology, while his symptomatic type was characterized by detectable cerebral pathology. Shortly thereafter, Reynolds,²¹³ in his 1861 monograph on Epilepsy: Its Symptoms, Treatment, and Relation to Other Chronic Convulsive Diseases, defined an entity of “epilepsy proper,” which meant cases without obvious brain pathology. Seizures due to detectable cerebral, or extracerebral, pathology were termed epileptiform and not epileptic. Unfortunately, defining epilepsy as a disease whose cause was the absence of a detectable cause was virtually guaranteed not to have enduring validity as knowledge advanced. Two decades later, Gowers¹²¹ extended this concept of epilepsy, almost surreptitiously, when he used the term epilepsy to refer to all seizures of cerebral origin without “active” pathology. Contemporaneously, new hypotheses of epileptic mechanisms emerged. In the first third of the century, seizures were commonly ascribed to brain hyperemia or venous congestion.^67,87,205 while Mansford¹⁷⁵ postulated that cerebral plethora caused charged electrical fluid to accumulate in the brain until it could no longer be contained, thus triggering a brain discharge and an epileptic seizure. Romberg²¹⁶ accepted both brain plethora and brain anemia as being capable of producing seizures. As an outcome of his study of the neural mechanisms underlying the reflex arc, Hall¹²³ postulated that excessive activity in the afferent limb of the reflex arc (eccentric epilepsy) or in the central element (centric epilepsy) produced the excessive motor response comprising the convulsion. He proposed that the initial convulsive tightening of the muscles of the neck and larynx obstructed the cerebral venous return, causing brain congestion that led to loss of consciousness. Hall’s interpretation did not account for epileptic auras and meant that bilateral convulsive movements began before consciousness was altered, contrary to the usual sequence of events in a seizure. Brown-Séquard⁴⁵ overcame these difficulties by postulating that excessive afferent activity, which was sometimes also responsible for the aura, in the central nervous system ascended to structures as high as the medulla oblongata. Upon reaching the medulla it produced a discharge at the medullary vasomotor center, which caused immediate cerebral arterial spasm leading to loss of consciousness. Reynolds²¹³ combined elements of both Hall’s and Brown-Séquard’s ideas, proposing that Brown-Séquard’s mechanisms initiated the seizure, while Hall’s mechanism of venous obstruction mechanism perpetuated the unconscious state with the resultant hypercapnia from cessation of breathing converting the initial tonic convulsion into clonic jerking.

Gradually these postulated mechanisms had become acceptable in explaining convulsive seizures and placed the central events in the medulla oblongata. Van Sweiten’ data²³⁹ also settled on the medulla as the critical brain region involved in epileptogenesis, while Sauvages²¹⁹ and Nothnagel¹⁸⁷ had claimed the production of convulsions in animals by stimulating the medulla. Kussmaul and Tenner¹⁶⁰ reported convulsions in experimental animals after rapidly exsanguinating them and through sections at different levels of the central nervous system showed that an intact brainstem in continuity with the spinal cord was essential for such anoxic convulsions to occur.

In his animal experiments, Todd (1809–1860)²³⁴ found that electrical stimulation of the spinal cord or the medulla produced tonic spasm of muscles and stimulation of the mesencephalon produced clonic convulsions, but stimulation of the cerebral hemispheres led only to slight facial twitching. On this basis he postulated that epileptic seizures arose in the cerebral hemispheres much like a discharge of static electricity from a condenser. If the discharge was restricted to the hemispheres, consciousness was lost but no motor symptoms occurred. If, however, the discharge reached the midbrain, clonic convulsive movements occurred in addition to loss of consciousness, but if it extended into the medulla and spinal cord, tonic components followed. Thus, Todd accounted for all of the elements of the convulsive epileptic seizure, except for the aura. He did not address epileptic unconsciousness without motor accompaniment. His ideas, however, did not attract a following among his contemporaries.

In contrast to all of these concepts that were based on brain overactivity, Radcliffe²⁰⁸ attempted to explain epileptic seizures as a manifestation of reduced neural activity. His ideas received a courteous reception, but were otherwise ignored and never developed further. Thus, by 1860, plausible explanations were available for the mechanisms underlying most aspects of epileptic phenomena, and a consensus had developed that the medulla oblongata was the critical brain region in the production of epileptic seizures. That state of knowledge formed the background against which John Hughlings Jackson’s work over the next 40 years was carried out.

In the 1860s, Jackson⁶⁸ (Fig. 6) set out to analyze and then interpret the mechanisms underlying epileptic seizures. His numerous writings were compiled by Taylor.²³⁰ Jackson, who initially attempted to study bilateral tonic–clonic seizures, soon realized that these were too widespread, developed too rapidly to be followed reliably by the observer, and the patient, being unconscious, could contribute little information. He therefore decided to first try to study focal motor seizures, as events were more localized and easier to follow, and the patient could often describe the experience. Such seizures were sometimes followed by temporary hemiplegia similar to that due to lesions in the internal capsule rather than the brainstem. Spenser’s psychology had prepared Jackson for the idea of localization of function within the cerebral hemisphere, although it had not yet been demonstrated. By the mid-1860s, Jackson had named focal motor seizures “corpus striatum epilepsy,” as he had perceived that they probably began in neuronal cell bodies in the neighboring striatal gray matter, which had become functionally overactive.

By 1870, after considering Broca’s^40,41,42 reports of aphasia from lesions in the posterior-inferior left frontal convolution, Jackson observed that temporary dysphasia occasionally coexisted with Todd paralysis after focal motor seizures involving the right face, and the association of focal motor seizures sometimes with syphilitic nodules in the meninges over the contralateral middle cerebral artery. Jackson¹⁴² concluded that focal motor seizures involving the face or hand probably originated in the lower part of the perirolandic cortex of the opposite cerebral hemisphere. This radical departure from the conventional interpretation of the site of epileptogenesis received independent support within a comparatively short period from Fritsch and Hitzig’s experimental studies of cortical stimulation and ablation in animals.⁹⁸ This work provided convincing evidence of localized representation of motor function within the cerebral cortex. During the next few years Jackson’s concept of epilepsy became increasingly wide ranging:

“Epilepsy is not one particular grouping of symptoms occurring occasionally; it is a name for any sort of nervous symptom or group of symptoms occurring occasionally from local discharge… A paroxysm of ‘subjective’ sensation of smell is an epilepsy as much as is a paroxysm of convulsion; each is a result of sudden local discharge of grey matter.”

Jackson’s idea that all convulsions and epileptic manifestations were symptoms was at first criticized on the grounds that he had not studied “epilepsy proper,” but merely one variety of epileptiform seizure. His reaction to this criticism consisted of convoluted and rather repetitive writing, in which he continued to draw a distinction between focal motor seizures and “epilepsy proper” to make his ideas more acceptable to his peers, in spite of his private belief that they were manifestations of epilepsy and even occasionally saying so.

In the 1870s experimental physiologists, such as Ferrier,^90,91,92 began to map out aspects of localization of function in the animal cerebral cortex. At the same time Jackson started to pay attention to the minor, often paroxysmal, expressions of human epilepsy. He used the knowledge of the site of pathology in conjunction with the experimental animal findings to locate sites for the representation of various functions within the human cerebral cortex. He accumulated data suggesting that the foot was represented in the upper part of the perirolandic cortex,¹⁴⁵ and that the site responsible for auditory hallucinations and the so-called dreamy state or “intellectual aura” was in the anterior part of the temporal lobe.^146,147 Jackson related visual hallucinations to the posterior half of the cerebral hemisphere without being able to more precisely localize the site of their origin. He deduced that consciousness depended on intact function of an extensive part of the prefrontal cortex of at least one hemisphere.¹⁴³ He attempted to explain the cortical origin of epileptic auras using these localizations and the belief that an epileptic discharge arose from a sudden release (at times he used the word “explosion”) of local brain energy. If the localized discharge achieved sufficient intensity and extent of spread, the aura would progress to unconsciousness and even convulsing. Extensive involvement of the prefrontal cortex by the discharge caused loss of consciousness, while involvement
of the cortical motor areas produced contralateral convulsing. Jackson had originally thought¹⁴⁴ that unilateral motor cortex discharges might finally activate the uncrossed pyramidal pathway, and thus convert contralateral convulsing into bilateral convulsing. Later, following Horsley’s experiments,¹⁴⁰ Jackson accepted the idea that the discharge must cross the corpus callosum and other brain commissures for bilateral convulsive movements to occur.

Thus, Jackson finally conceived, for the first time in the history of medicine, a single mechanism capable of explaining the full spectrum of epileptic phenomena: The aura, isolated or subsequent unconsciousness, contralateral and bilateral convulsive behavior. His concept is the basis of the modern understanding of epileptogenesis. Jackson’s complete view was in place by 1890, after some 30 years of sustained intellectual endeavor. His ideas did not include primary generalized epilepsy, but in his time, before electroencephalography (EEG) became available, there was no way of knowing that such an entity existed.

Jackson’s writing is often difficult to follow. He is often repetitive, using different wordings in different places for the same idea, leaving the reader uncertain if some subtle new insight was intended. It is sometimes further complicated by consequences of Jackson’s stated intention to abandon his comprehensive early vision of epilepsy and restrict the word to its then contemporary conventional meaning. Thus, there is some justification for the view that Jackson’s thought is more easily followed by reading his younger colleague William Gowers.

Gowers was probably the most important of Jackson’s colleagues. In his monograph Epilepsy and Other Chronic Convulsive Disorders,¹²¹ he discussed epileptogenesis. He used a reductionist approach weighing carefully clinicopathologic and experimental data to conclude the following:

“The conclusion, then, is that all the phenomena of the fits of idiopathic epilepsy may be explained by a discharge of gray matter; that the hypothesis of vascular spasm is as unneeded as it is unproved; that there are no facts to warrant seeking the seat of the disease elsewhere than in the gray matter in which the discharge commences; that this is in most cases within the cerebral hemispheres, probably often in the cerebral cortex, although in some instances lower down even in the medulla oblongata; that epilepsy is thus a disease of the gray matter, and has not any uniform seat.”

Unlike Jackson, who concentrated in one type, Gowers approached epilepsy as a whole. His interest actually included other disorders including hysterical attacks, which he tried to distinguish from real epileptic fits. In epilepsy the attacks tended to occur randomly and the limb movements did not resemble the pattern of voluntary movements, unlike the “quasi-purposive aspect and coordinated character” of the hysterical attacks. He preferred the terms “hysteroid” and “co-ordinated convulsions” to avoid Charcot’s confusing term “hystero-epilepsy.” In addressing the nature of Jackson’s discharging lesion, Gowers used the term “sudden explosive discharge,” essentially the same words that caused Wills to be ridiculed two centuries before. He postulated the storage of latent energy in each neuron and a resistance to prevent its appropriate release. He also conceived that the frequent breaking of this resistance could produce repeated seizures as well as increase the nutritive capacity of nerve cells, leading to a facilitation of seizures.

Gower’s espousal of Jackson’s ideas, his critical consideration of alternative theories, and his concise statement in direct English made Jackson’s ideas increasingly acceptable. Gowers almost inevitably tended to soften and harmonize Jackson’s more extreme views when writing of them. To perceive, however, Gowers’ book largely as a “translation” of Jackson’s thought is to ignore the significance of Gowers’ original insights into matters such as the effect of “resistance,” a notion similar to that of present-day inhibition, in explaining epileptic phenomena.

In addition to the more adequate interpretation of epileptic seizure mechanisms, in the first half of the 19th century an increasing disillusionment with the inadequacy of the available antiepileptic therapies had developed. Those who believed seizures arose from cerebral congestion continued to employ venesection and other measures to divert blood from the brain. Hall,¹²² quite independent of his studies on epilepsy, had already indicated the potential hazards of diminishing the blood volume too quickly. The ancient method of applying a ligature proximal to the site of the appearance of an aura in a limb, itself a comparatively uncommon event, continued to have some demonstrable efficacy. Hall,¹²⁴ believing that laryngeal spasm contributed to the loss of consciousness during seizures, advocated and employed tracheostomy, but this approach never achieved any widespread use. Recommendations for certain remedies continued (e.g., oil of turpentine²⁰⁵ and zinc oxide¹³¹). Esquirol⁸⁷ and Sieveking²²⁵ made scathing comments about the vast array of ineffective antiepileptic drugs that had accumulated over the years: “In fact, there is not a substance in the materia medica, there is scarcely a substance in the world, capable of passing through the gullet of man, that has not at one time or other enjoyed a reputation of being an anti-epileptic.”²²⁵

Into this scene of therapeutic destitute, one evening in 1857, came a totally unheralded event. At a meeting of the London Medico-Chirurgical Society following Sieveking’s presentation of 52 patients with epilepsy, Sir Charles Locock, the president of the Society, remarked that he had treated 15 women with hysterical (i.e., menstrual) epilepsy with potassium bromide, and had stopped the seizures in all but one. Since potassium bromide could cause temporary impotence in males, he thought it might have useful effects in menstruating women. His observation was never published, but it was recorded in the reports of the meeting published in the Lancet and the Medical Times and Gazette. Radcliffe’s²⁰⁸ experience with it, however, in “hysterical” epilepsy was even more encouraging, and he began to use it in all cases of epilepsy with generally good results. Gradually the use of potassium bromide became widespread, particularly after Wilks²⁴⁶ rediscovered it. He had sought an alternative to potassium iodide in treating syphilis and, in ignorance of Locock’s report, tried potassium bromide. He soon realized that its efficacy in controlling seizures due to cerebral syphilis was due to specific antiepileptic properties. Thus, the first reasonably effective antiepileptic agent came into use. By 1881 Gowers, after listing the numerous recommend antiepileptic therapies, wrote of potassium bromide:

“And the present generation has witnessed an advance in the treatment of these diseases equaled in perhaps no other branch of therapeutics. Thanks to the influence of one drug and its combinations, hundreds of epileptics have been cured, and thousands are leading useful lives who would otherwise have been incapacitated by the disease.”¹²¹

In 1886 Horsley, a pioneering English neurosurgeon, performed the first operations intended to relieve focal motor epilepsy by removing the probable focus of seizure in the human cerebral cortex after locating its expected site by electrical stimulation. He continued this approach for some years,^137,138,139 as it seemed to provide at least short-term benefit in seizure control.

In the mid-19th century, a renewed interest in the intrinsic electrical activity of muscle and nerve was sparked by Du Bois-Raymond’s book Untersuchungen über Thierische Elektricitat (Investigations on Animal Electricity).⁷⁷ In the second volume, an illustrated description of recording muscle potentials from the surface of the skin of a man established the basis for clinical electromyography.

Inspired by this book, Caton (Fig. 7) at the Royal Infirmary School of Medicine in Liverpool used similar nonpolarizable electrodes and a mirror galvanometer to extend the work on animal nerve and muscle.⁵¹ Based on Fritsch and Hitzig’s demonstration of motor responses following electrical stimulation of various cortical areas in the dog,⁹⁸ Caton hypothesized that reversely peripheral stimulation might evoke local electrical responses in the brain. In his historic paper,⁵² Caton was the first to demonstrate evoked cortical sensory responses in animals. Of much greater importance was that Caton is the first person to observe the continuous spontaneous electrical activity of the brain. He described “the existence of electrical currents…of the grey matter” and noted that “feeble currents of varying direction pass through the multiplier [amplifier] when the electrodes are placed on two points of the external surface, or one electrode on the grey matter, and one the surface of the skull.”⁵³

Caton’s achievements are better appreciated considering the experimental conditions under which he worked, without electric lights, vacuum tubes, or electronic amplifiers, more than 25 years before the invention of the string galvanometer by Einthoven. The Thomson mirror galvanometer that Caton used had a high-frequency response of only 6 Hz. A stationary “oxyhydrogen lamp” shone on the galvanometer mirror whose tiny movements reflected the light upon “a distant wall with a graduated scale some eight or nine feet in length.” The distance between the mirror and its image on the wall was his amplifier (multiplier). There was no photographic method to capture and hold the fleeting data once it had disappeared from the wall. A candle flame was used for photic stimulation. More than 50 years, however, would elapse before the first report of spontaneous electrical activity from the human brain was recorded.

Various organizations, both lay and professional, played an important role in improving the management of epileptics. Not only were the needs of the sufferers and their families recognized at last, but also professional attention was concentrated on their problems. The social burden that had been borne in silence by families either at home or in mental asylums was going to be hopefully relieved by the introduction of “colonies” or “colony farms” that offered a more caring and peaceful alternative. In Britain, the Charity Organisations Committee Report The Epileptic and Crippled Child and Adult in 1893, a historical landmark in social awareness, provided a clear picture of the needs of epileptics and the grave lack of available resources at that time to meet these needs. Early surveys of similar facilities in other countries were published in the early issues of Epilepsia.

The establishment of the International League Against Epilepsy (ILAE) in 1909 marked a major initiative worldwide to organize professional interest in epilepsy but also address scientific and social aspects. During the inaugural meeting in 1909, in Budapest, under the newly elected president, Prof A. Tamburini, ILAE adopted Epilepsia as the League’s official periodical and outlined the aims of the organization. It continued as a quarterly periodical until 1915, when World War I forced its closure. The first volumes are a rich historical source of the status of epileptology and the international activity of the professional epilepsy movement in the first decade of the 20th century. The political chaos after World War I, combined with the Great Depression of 1929, delayed any resumption of the ILAE activity until the mid-1930s. Coinciding with the second International Neurology Congress in London in 1935, a number of interested physicians met at Lingfield Colony, Surrey, to reactivate the League.

The ILAE once again undertook an international survey of the services and facilities available in various countries. In volume 1 of the second series of Epilepsia, considerable data had been assembled before World War II prevented members from corresponding with its editor. Since 1941 the journal has been published in the United States to preserve continuity throughout the war years without interruption. The ILAE was also preserved and resumed its active role after the war, constituting the central spindle of the professional world epilepsy movement ever since. In 1961, the International Bureau for Epilepsy was established.

Over the centuries, the clinical problems of epilepsy have always attracted wayward theories about its cause and treatment. The early years of the 20th century saw the flowering of two such theories, both of which caused considerable difficulties for sufferers and retarded development of the management and the perception of epilepsy both in medical circles and the community.

W. Aldren Turner (1864–1945) contributed to the conceptual epileptology in the first three decades of the early 20th century⁸¹ and also played an important role in establishing the ILAE as a researcher and contributor to Epilepsia. In keeping with the spirit of the times he espoused the cause of the social improvement of the sufferer. His first paper²³⁵ actually discussed the advantages of epilepsy management in colonies, instancing the Chalfont Colony for Epileptics. He correctly judged the severity of both medical and community problems occasioned by epilepsy, and the dire need for radical reform of management policies.

Subsequent papers examined prognosis, nature, treatment, and associated mental conditions. All this culminated in his book Epilepsy – A Study of the Idiopathic Disease²³⁶ that was later summarized in his Morison Lectures.²³⁷ They both provide an informed current status report of epileptology of the period. Turner’s approach was descriptive and statistical, with large patient numbers derived from three admittedly disparate groups: Private practice, hospital consultancy, and the Chalfont Colony. While fully aware of selection bias by including the patients from Chalfont, he demonstrated that mental decline depended on seizure severity, duration of epilepsy, and age of onset. Although he mentioned “facies epileptica,” he did not link it to the use of bromides.

His book²³⁶ summarized his work and clearly depicted the innate problems of the concept of “idiopathic epilepsy.” Historically it provides a detailed summary of the pathologic processes currently thought significant in the genesis of epilepsy. He noted Ammon horn sclerosis but did not recognize its significance. The book contains the work on systemic body metabolism including examination of blood, sweat, urine, cerebrospinal fluid, and endocrine function during the ictus and interictally in an unsuccessful attempt to identify triggers for seizures. In spite of this failure, the concept of the “systemic trigger” for seizures remained popular as expressed in Collier’s “metabolic dyscrasia”⁶⁴ and Brain’s emphasis on metabolic factors in epilepsy.³⁴

William Spratling (1862–1915) documented his vast experience as foundation director of the Craig Colony for Epileptics in New York in a textbook Epilepsy and Its Treatment.²²⁷ Particularly, Clark and Prout’s chapters on the neuropathology of epilepsy and status epilepticus, common conditions in epileptic colonies, was groundbreaking work.^23,59,60,223 Spratling’s conclusions are also flawed by selection bias. His basic concepts of the nature and causes of epilepsy offer an informative view of that period: They feature toxic-metabolic causes combined with an “inherited seizure proclivity” to explain the intermittent crises of refractory epilepsy. He hardly mentions jacksonian concepts, although it is clear from the text that he had personally discussed epilepsy with Jackson. Clark and Prout, on the other hand, emphasized the centrality of the cortex in seizure generation and in fact maintained that implication of its second layer (“a diseased state of the sensory elements”) due to “active nuclear poisons” underlaid seizure generation. Pathologic changes in Ammon horn were detailed, but their significance still remained uncertain. This well-documented text displayed the reigning conceptual confusion in epileptology at the turn of the century.

Hermann Oppenheimer (1858–1919), a prestigious German neurologist with numerous eponymous conditions named for him, offered a textbook that was the “gold standard” of neurology. The section on epilepsy¹⁸⁸ demonstrates again the universal confusion in the epileptology of that era. Although he was fully accepting the jacksonian concepts on the role of the cortex, he also entertained possible implications of other brain sites and also felt that “toxicopathic” processes were involved
in seizure generation as suggested by the monumental amount of laboratory data.

L. J. J. Muskens (1872–1937), representing the younger generation of epileptologists at the turn of the century, came to be personally identified with the newly established journal Epilepsia, of which he became secretary to the editorial board, and then the newly founded ILAE, where he assumed the role of secretary general. Even more importantly, he was central to the revival of the League in 1935 and republication of Epilepsia again in 1937. The 1928 English edition of his book Epilepsy—Comparative Pathogenesis, Symptoms, Treatment¹⁸⁶ (preceded by Dutch and German editions) offers a documentation of his experimental work on epilepsy and clinical and sociologic aspects of the disease.

In his experiments on myoclonic seizures in animals, he used a toxicologic approach. He thought that myoclonic activity was in fact reflex afterdischarge phenomena, and convulsive activity comprised an adaptive process designed to rid the body of toxic substances causing the seizures. He sited the seizure activity in brainstem structures, but accepted an additional cortical influence on these “medullary convulsive centres.” His conceptualization of the type of experimental epilepsy he studied bears similarities to that of Prichard²⁰⁵ emphasizing the role of reflexes in seizure generation. It is the final chapter of this book, where he discusses the global problem posed by epilepsy and describes his experience in the early days of the ILAE, that contains his main message to his colleagues working in this discipline. This message of advocacy for international cooperation for advancing both clinical enterprise and research in epileptology by a cooperative global effort has accorded him, though only recently, with his proper place in the history of epilepsy.⁸⁵

Samuel Alexander Kinnier Wilson (1878–1937) can be considered Hughlings Jackson’s direct heir. His early discovery, however, of hepatolenticular degeneration in 1912 delayed his entry into epileptology. His first communication on epilepsy was on “Temporo-sphenoidal forms of Idiopathic Epilepsy.”²⁴⁹ Jackson et al. had well documented that “coarse pathology” (tumors, infarcts) occupying the temporal lobe could present with seizures, although seizures could also arise without any evident pathology. The déjà vu phenomenon, which seemed peculiar to temporal lobe epilepsy, could also occur totally unassociated with seizures. Wilson searched for an alternative etiology for these nonepileptic déjà vu episodes and pointed out that except for a few cases due to anoxic damage, most of them were simply inexplicable. Wilson also confronted Jackson’s use of the concept of “dis-inhibition” to explain the evocation of the psychic symptoms in temporal lobe seizures. Eventually he reluctantly had to reject this altogether.^25,253

His Harveian Lecture²⁵⁰ emphasized the concept of the epilepsies, the absolute failure of the psychoanalytic approach, and the unity of pathophysiology of the many “epilepsies”: An explosive hyperactivity of the brain and the primacy of the brain in seizure generation and all clinical manifestations. He took the jacksonian concept of “many epilepsies” to embrace the potential for seizures to emanate from many areas of the brain, not just the cortex. By the same token, he felt that all epilepsy was manifestly not the same, and that the gloomy view of the condition that persisted in both lay and professional ranks should be abolished, for it handicapped the sufferer in many aspects of life, both medical and social.²⁵²

During the historical Royal Society’s 1927 discussion on epilepsy, he studiously avoided any detailed consideration of metabolic factors in epilepsy, unlike most other speakers. He simply reiterated his concept of the “epilepsies” and then underlined the primacy of the brain alone in seizure generation: “…a fit was the discharge, the setting free, of accumulated nervous energy in healthy neuro-mechanisms.”²⁵¹ In his Modern Problems in Neurology,²⁵³ Wilson devoted the first four chapters to problems in epileptology, in which he revised concepts of temporal lobe epilepsy mechanisms, discussed the role of inhibition in epilepsy, emphasized the concept of the “epilepsies,” and finally offered his usually optimistic prognosis. The psychic symptoms of temporal lobe epilepsy, he decided, were simply a product of local epileptic irritation of that region of the brain, and he formally abandoned the jacksonian concept of disinhibition. He then widened his conceptual views of the overall condition of “epilepsy” to embrace a broader range of clinical phenomena. The single most important tenet he emphasized above all was that epilepsy is always symptomatic and never a disease per se. He called for great patience in the study of epilepsy: “Research will eventually disclose the cause of those conditions whose etiology currently eludes us.”

In the last years of his life, Wilson was able to finish his two most important and almost identical chapters “The Epilepsies” in Bumke and Foerster’s Handbuch der Neurologie²⁵⁴ and his own personal Textbook of Neurology, finally published posthumously in 1940,²⁵⁵ edited by his brother-in-law Ninian Bruce. His immensely detailed grasp of the literature and documentation of the clinical aspects of epilepsy make it a very important resource in the history of the disease.²⁵ His overall concepts constituted a departure point for the new epileptology that would be ushered in by Lennox to the 1935 London Congress on the use of EEG in the study of epilepsy, an innovation that would change the concept of the condition forever.

W. A. Adie (1886–1935) introduced pyknolepsy to an English audience in his address to the Royal Society of Medicine.¹ Although this form of epilepsy had been reported by Friedmann⁹⁷ and Heilbronner,¹³⁰ Adie emphasized its uniqueness with its many, frequent short-duration attacks; occurrence in the early years of life; explosive onset; and excellent prognosis, and maintained that these features distinguished it from all other forms of epilepsy. In the discussion that followed it was reported that “he was inclined to agree that the disease is only a variety of epilepsy, but its clinical characters are so distinct that it seems worthy of a separate name.” Adie introduced the concept of syndromology, with which epileptology continues now to be engaged in reformulating and revising. His work could only be matched by Herpin¹³² and Janz and Mathes’s early papers¹⁴⁸ that delineated juvenile myoclonic epilepsy.

By the 1930s, a variety of medical, social, and legal issues relating to the care of persons with epilepsy had led to the foundation of the ILAE; the foundation of a dedicated journal, Epilepsia; the formation of a number of charities, institutions, and colonies for persons with epilepsy; and an increasing interest in medical research by philanthropic individuals and organizations. Hughlings Jackson’s concept of the discharging lesion certainly brought the cerebral cortex into focus as the structure most intimately involved with the production of “fits,” but the wide variation in the epilepsies, in their age of onset, semeiology, hereditary nature, and course, seemed to defy an explanation based largely on gross lesions of the cerebral hemispheres. These developments certainly produced a medical culture that fostered the study of the epilepsies that influenced epileptology during the 1930s and 1940s, particularly due to the rise of electroencephalography.

The first investigator to design a laboratory for the simultaneous recording of EEG and motion pictures actually had nothing to do with the study of seizures or epilepsy! In 1935, Alfred Loomis, a Wall Street investment banker turned private scientist, had independently discovered the alpha rhythm in his efforts to improve electrocardiography recordings with additional electrodes. Loomis had been fascinated by hypnotism since childhood and the discovery of “brain rhythms” led him to the study of the EEG changes during hypnosis and sleep. Without any apparent limitations on time, money, or space, Loomis’s EEG lab at his Tuxedo Park home contained a bedroom for subjects to sleep and for the first amplification stage; an amplifier room containing two additional stages as well as electrocardiographic and respiration monitors; and a control room located 66 feet away to house the system of three independent sets of high-speed ink writers and cathode ray oscilloscopes with cameras for photographic recording of the EEG oscillograph trace.^170,171 As subjects were expected to achieve normal sleep during the experiments, the sleeping room was dressed with heavy drapes. Loomis also equipped the rooms with motion cameras with the fastest lenses available. Infrared film had been specially manufactured by the Eastman-Kodak company and was flown in daily from Rochester on dry ice, and the film was developed in two professional-quality darkrooms in the laboratory.⁶⁵

Around this time, Robert Schwab designed a system using two 16-mm cameras to record clinical seizures and corresponding EEG. Both films had special synchronizing marks that were matched and processed into a composite duplicate, which was shown in 1938 at the 96th meeting of the American Psychiatric Association. Hunter and Jasper later reported a method of simultaneously recording the EEG and clinical seizures with a single camera.¹⁴¹ The camera was directed at a full-length mirror hanging above the patient and received the image of the patient and the reflected image from the EEG tracing simultaneously through a system of mirrors mounted at angles above the moving EEG paper.

The use of television in the 1950s made the process less cumbersome. The first use of closed-circuit television (CCTV) for simultaneous recording of the EEG and seizures was reported
in 1966 by Goldensohn.¹¹⁹ At first, the combined split-screen TV images and sound were transferred from the TV to movie film (kinescopes) and later directly to video cassettes.^74,119 Vacuum tube amplifiers in EEG machines were replaced in the 1960s by transistors invented in 1947 by Bardeen, Bratain, and Shockley. The advent of the transistor improved the quality of the routine ink-written EEG record, but it was of much greater importance for the ongoing revolution in computerized handling of all aspects of EEG information related to epilepsy.

Much research in neurophysiology has focused on understanding the cellular electrical activities that generate seizures. Although vacuum tube amplifier technology that could reproduce electrical signals from single neurons had been available since 1906, most laboratories generally took a long time to abandon galvanometers. The Boston physiologist Alexander Forbes was the main contributor to the early development and application of vacuum tube amplification to neurophysiologic research,⁹⁴ as described in an appreciation by Eccles.⁸²

At first, most investigators believed that action potentials of axons and cell bodies summated to form EEG waves. Later, the idea emerged that the relatively slow EEG wave might not consist of “all or none” 0.5- to 1.0-msec action potentials, but rather of graded, slower potentials originating at the synapse. Renshaw et al.²¹² used extracellular microelectrodes that touched single-cell membranes to show probable relationships between slow potentials of single cells that resembled EEG waves. Li and Jasper,¹⁶⁹ also using extracellular microelectrodes, were able to prevent single-cell action potentials from occurring while slower synaptic potentials temporally related to EEG waves persisted, demonstrating that synaptic potentials, but not action potentials, contributed to the generation of EEG waves. Bishop and Clare^20,57 ascribed surface electrical activity to nonpropagated dendritic potentials, and the concept that brain waves were mainly postsynaptic potentials gathered further impetus. Using high-impedance intracellular electrodes for recording in hippocampal neurons, Kandel and Spencer¹⁵⁷ demonstrated temporal relationships between EEG afterdischarges and transmembrane potentials. With the use of intracellular microelectrodes, Goldensohn and Purpura in 1963 were the first to demonstrate the synaptic origin of interictal EEG spikes in the neocortex.¹²⁰ The EEG spikes at the brain surface were found to be summations of depolarizing (excitatory) and hyperpolarizing (inhibitory) postsynaptic potentials (EPSPs and IPSPs) with extreme depolarizations sufficient to prevent firing of the cell. Matsumoto and Ajmone-Marsan in 1964^177,178 described intracellular activity during both ictal and interictal periods and showed that the extreme depolarizations—paroxysmal depolarization shifts (PDSs)—are an essential feature of the spike focus.

Lennox, in summing up the year’s literature for 1944 in Epilepsia, remarked: “War the consumer, has drawn the attention of men from the medical problems of epilepsy in the civilian population, and epilepsy as an aftermath of war has not yet had time to assert itself…”

Indeed, this hugely expensive and exhausting war had slowed advances in many areas of medicine to a crawl. Nevertheless, in some areas there had been progress and some special centers had made significant advances.

For more than a decade and a half, Penfield and his team had been working on the surgical treatment of epilepsy as part of a wider program based on investigating the role of the cerebral cortex of man.^168,200 Penfield and Jasper (Fig. 12) had become experts in applying EEG methods to epilepsy research and practice. Their concept of the centrencephalic system and its role in the mechanisms of what today would be called primary generalized epilepsy^197,198 played a major role in subsequent attempts at seizure classification. In fact, Penfield and Erickson¹⁹⁶ had already made one of the earlier attempts at establishing a framework for classification of specific phenomena¹⁹⁶ based on data obtained from documenting the localized function of various cortical areas. In spite of its obvious limitations, this served to promote further attempts to organize epileptic phenomena with the intention of advancing research.¹⁷⁹

Penfield’s pioneering work attempted to examine the cerebral cortex under direct observation and following stimulation in the operating room. It stands as the first really significant effort to understand the problems posed by abnormal cortical areas involved in epileptic seizures. In a field that has blossomed with the development of modern neuroimaging techniques, the pioneering work in the electrophysiology of the cerebral cortex and the mechanisms of epilepsy of Jasper and Gloor provided an important window into a largely unexplored area.^117,198 The Montreal program, founded by Penfield et al., carried out by a team of exceptional clinicians and scientists, represents a major milestone in mid-20th century epileptology.¹¹⁵

Postwar European epileptology was notable for the early contributions of the Marseille school led by Henri Gastaut (Fig. 13). His program produced a steady stream of publications on many aspects of epilepsy. Through his skills in organizing and financing important meetings that focused on selected aspects of epilepsy, Gastaut initiated a new wave of international interest and cooperation.

Gastaut et al. organized the important third and fourth meetings of the now legendary Colloques de Marseille series, which introduced temporal lobe epilepsy to an international audience. Gastaut’s paper on the “So-called ‘Psychomotor’ and ‘Temporal’ Epilepsy: A Critical Study” was presented as a preliminary report to the Scientific Session of the ILAE meeting in Lisbon in 1953. In this he produced a well-documented, wide-ranging study of this topic and included an extended discussion of the subject by a number of international experts who had attended. The fourth Colloque de Marseille in 1954 discussed the pathologic anatomy of temporal lobe epilepsy and it was followed 3 years later by a meeting in Bethesda, Maryland, in which a large number of international experts covered many aspects of the topic. By now a substantial number of centers in several countries had begun resective surgery programs for this type of epilepsy. Gastaut and the Marseille school had played a significant role in arousing international interest in temporal lobe epilepsy.^9,44,102,104

His 1954 book Epilepsy: Electro-Clinical Correlations¹⁰³ attempted to present a current account of the mechanisms of epileptic seizure generation in the different forms of epilepsy. Synthesizing the rapidly increasing information on neurophysiologic data from his extensive clinical investigation of patients with various forms of epilepsy, Gastaut introduced new and provocative concepts to explain both partial and generalized seizure forms. His ideas pertaining to the generalized epilepsies
were particularly novel. Eight years later, Gastaut collaborated with Roger Broughton¹⁰⁸ to revise the work in light of more recent data. He then initiated the task of encouraging international neurology to attempt to classify seizures, a work that has continued to progress since that time.

Gastaut’s work with Fischer-Williams established the essential electrical and clinical differences between syncope and epilepsy, a problem that had dogged clinical studies in this area for centuries.¹⁰⁵ This contribution was followed by his description of what eventually became known as the Lennox-Gastaut syndrome.¹⁰⁶ Finally, his 1969 classification of epileptic seizures on clinical and EEG criteria (with his dismissal of the concept of “idiopathic epilepsy”) stands as one of the early attempts to marry the clinical and technologic data to form an organized system of epileptology.¹⁰⁷ Gastaut’s unit constituted a powerhouse of European epileptology in the immediate postwar period. His introduction of novel concepts and his research into many facets of this discipline formed the basis for important advances.

Bancaud (1921–1994) and his neurosurgical colleague, Talairach, at the L’ Hôpital St. Anne used specially designed stereotactically implanted electrode arrays to record and plot the paths of various seizure patterns, thus introducing stereoelectroencephalography. With this technique, they demonstrated that seemingly focal seizures could in fact originate from a focus distant from the area of final expression. Bancaud’s concepts regarding the spread of the process of focal epilepsy allowed extensive broadening of current thinking about the origin and spread of focal epileptic seizures.¹⁰

Though some of the older antiepileptic remedies of dubious efficacy had not been completely abandoned, by the beginning of the 20th century, the various bromide salts, particularly potassium bromide, had become the mainstay of the drug therapy of epilepsy. The next effective antiepileptic agent to be recognized was phenobarbital (phenobarbitone). In 1912, Hauptmann,¹²⁸ while using it to tranquilize patients, realized it had suppressed the seizures of those who also happened to suffer from epilepsy. Subsequently, two of its congeners, mephobarbital (N-methylphenobarbitone)²⁶ and primidone (desoxy-phenobarbitone),¹²⁶ were found effective in treating epilepsy.

Up to this point in time, effective antiepileptic drugs had been discovered by chance during their administration to humans for other purposes, or had been tried in the treatment of epilepsy because of chemical structural analogy with antiepileptic molecules. In the late 1930s, however, Putnam and Merritt began to systematically study in experimental animals molecules with structural resemblances to phenobarbital to find new antiepileptic agents. They tested several hydantoin derivatives (in which the central heterocyclic ring of the molecule lacked one of the carbon atoms of the barbiturate ring) and found that phenytoin (diphenylhydantoin) had an apparently promising balance between sedative and antiepileptic properties. It proved to be effective when tried in human epilepsy¹⁸¹ and thereafter came into increasingly widespread use. Friedlander⁹⁵ has recorded in detail the story of its discovery. Other hydantoin derivatives, such as mephenytoin, were later developed and used in humans, but all proved unsatisfactory for reasons of lesser efficacy or toxicity.

The success of the Putnam-Merritt approach led to further experimental animal studies attempting to find other small
heterocyclic molecules with potential antiepileptic properties. Beginning with troxidone (trimethadione),¹⁶⁶ various oxazolidinedione derivatives were shown effective in controlling absence seizures in which barbiturate and hydantoin derivatives were ineffective. Subsequently, succinimide derivatives, in which an oxygen atom replaced one carbon atom in the oxazolidinedione ring, were tested and proved more satisfactory than the oxazolidinediones.²⁵⁶ Carbamazepine, a dibenzazepine derivative and a congener of the antidepressant imipramine, was tested for antiepileptic activity by the pharmaceutical firm Geigy Ltd. in the 1950s and came into increasing use in humans during the following decade.²²¹ The next antiepileptic agent, valproate (used as free acid or sodium or hemisodium salt), was discovered by chance. Initially used in 1961 as a solvent for possible antiepileptic agents in experimental animal studies, it became clear that the solvent, and not the putative agents, was the effective antiepileptic substance.²²² Other agents with some effectiveness against seizures (e.g., sulthiame, clonazepam, and other benzodiazepine derivatives) were discovered and came into some use during the 1960s and 1970s. Additional antiepileptic drugs have since been discovered as the outcome of strategies based on several approaches,²²⁰ random screening of numerous molecules with a wide range of chemical structures (e.g., felbamate), testing structural analogs of known antiepileptic agents (e.g., oxcarbazepine, levetiracetam), and rational attempts to modify known factors believed to facilitate epileptic activity (e.g., vigabatrin, lamotrigine, tiagabine, gabapentin). Reminiscent of ancient dietary recommendations, the ketogenic diet has been used since 1922 with some success in controlling seizures, mainly in children with drug-resistant epilepsy.⁶⁶

Surgery for epilepsy has a history dating back to antiquity, although not always confined to the skull and brain. Trepanation (opening the skull) for seizure relief dates back to antiquity and pre-Columbian times.⁶⁹ In addition, Cooke⁶⁷ had documented surgery for the removal of peripheral lesions thought to cause local irritation, in turn triggering seizures in the area of focal fits. Since seizures were considered equivalent to the orgasm, and onanism or genital irritation were linked by Tissot to seizures, surgery on both male and female genitalia was practiced at various times, particularly after the 18th century.^21,78 Bacon⁷ recommended castration as an extreme method of seizure prevention. Gowers,¹²¹ however, condemned it with authoritative brevity: “Castration has been proposed as a remedial measure, and this has been performed without effect.”

Jackson’s famous footnote¹⁴⁶ to his article on “A Particular Variety of Epilepsy”—“I have suggested that the radical cure of fits in such cases is for the surgeon to cut out that discharging lesion, as well as the tumor, if there be one, producing it”—was the first suggestion of a potential surgical cure.

Surgery for intracranial lesions, guided solely by clinical localization alone, had been practiced early in the final quarter of the 19th century,⁴² and by the time of Jackson’s writing Macewen in Glasgow and Horsley in London had been performing resections of symptomatic lesions.^{137,138,139,156,172,229} Macewen had targeted tumors presenting with seizures, while Horsley was assisted by Hughlings Jackson in the selection of the operative site to remove posttraumatic lesions producing
focal fits. Most importantly, Jackson’s footnote showed his realization of two important principles: The allocation of this special type of seizure to the temporal lobe and the need to remove not only the tumor, but also the epileptogenic cortex.

Early in the 20th century a small number of specialized, mainly European, neurosurgeons were engaged in seizure surgery,⁸⁶ such as Krause in Berlin. Epilepsy surgery, however, began to flourish during the interwar era, the second and third decades. Foerster of Breslau is known as an early pioneer, because of his mentoring relationship with Penfield during the Penfield’s study visit in 1928. Surgery was directed to remove lesions discovered at operative exploration and actual extirpation was achieved by encompassing all visibly abnormal tissue. In 1934, Penfield at the Montreal Neurological Institute introduced the development of a special team to investigate all aspects of preoperative diagnosis, identification and localization of the epileptic focus. In the postwar years, the introduction of comprehensive management programs to care for the patient with epilepsy in all aspects, both medical and social, constituted a major advance in the overall treatment of epilepsy.^87,88

The tremendous impact of EEG on epileptology has been described above, and the impact of this new technique on epilepsy surgery cannot be underestimated. Particularly in North America, which was spared from the destructive effects of World War II, electronics technology saw tremendous advances during the 1940s. These developments allowed the United States and Canada to gain an advantage in applying this novel and productive technology for the investigation of patients with epilepsy surgery by the end of the war.

Evidence for a common pathologic-anatomic substrate for medication-refractory epilepsy, namely, sclerosis of the mesial temporal structures, had been known from postmortem studies since the early 19th century. Yet, the significance of what is now known as “hippocampal sclerosis” and its association with epilepsy was much debated.^31,185,255 Consequently, mesial temporal sclerosis had not been of much neurosurgical interest until the advent of the EEG revealed the central role of this condition in temporal lobe epilepsy and introduced newer concepts in its surgical treatment.⁸⁹ The first major development in the treatment of refractory epilepsy was the discovery by Gibbs et al.¹¹⁴ that EEG recordings of patients with so-called “psychomotor epilepsy” revealed a spike focus over the anterior temporal lobe. This discovery was soon followed by the publication of a series of temporal lobectomies for intractable epilepsy based on EEG findings.⁸ A small series consisting of five patients subjected to anterior temporal lobectomy without the use of EEG was published by Morris,¹⁸⁴ who correctly emphasized the necessity to remove all the medial temporal structures for effective surgery.^24,89 A larger series of temporal lobectomies for intractable epilepsy was published by Penfield and Flanagan¹⁹⁶ that same year. This nearly simultaneous publication of several surgical series, some of which were guided by EEG data, has led to subsequent controversy about the historical priority. It is also unclear whether Jasper believed that the EEG findings were not specific for a localized epileptogenic zone within the temporal lobe as Gastaut¹⁰² has suggested, or whether Penfield, despite Jasper’s opinion, was not convinced of the specificity of the EEG activity to a temporal origin.¹⁵³ In any case, it is clear that the first significant series of temporal resections for intractable temporal lobe epilepsy, guided by EEG both preoperatively and intraoperatively, was produced by Bailey and Gibbs,⁸ who deserve recognition for this important contribution.⁸⁶

Thus, less than a century after Hughlings Jackson had floated the concept of radical neurosurgery “to cut out the discharging lesion,” surgery was proven feasible and was set to take its place in routine epilepsy management. Temporal lobectomy for refractory epilepsy was performed in many centers and interest in this very common form of epilepsy and its surgical treatment intensified. The Marseille Colloquia in 1952 and 1953 generated a great deal of international enthusiasm for temporal lobe epilepsy¹⁰⁴ by delineating this syndrome. In the Bethesda, Maryland, meeting in 1957, a large number of contributors from all over the world presented their data.⁹ As Bailey remarked, Lennox had “…called the psychomotor epilepsies a crossroads, a meeting ground for various disciplines and research-minded men.” It has produced a stream of significant data on the operative treatment of temporal lobe epilepsy, but also on the pathologic etiology and innovative approaches to pre- and postoperative effects of the epilepsy and the surgery.²⁴ Falconer’s concepts of temporal lobe epilepsy and mesial temporal sclerosis⁸⁹ and Taylor’s introduction of the concepts of cortical dysplasias²²⁹ had constituted significant milestones.

Since then, several epilepsy programs have been established in many countries.⁸⁶ The introduction of informative neuroimaging modalities and the use of modern technologies to monitor and record seizures would not only effect radical change in the diagnosis and surgery of epilepsy of focal origin, but along with the radical advances in the genetics of epilepsy, also effect changes in conceptual epileptology at the beginning of the 21st century, seemingly unbelievable to Ford Robertson and his optimistic opinion in the year 1900.