**6. Epilepsy in the twentieth century**

Before the end of the 19th century, in 1898, William Letchworth (1823-1910) and Frederick Peterson (1859-1938) will organize the National Association for the Study of Epilepsy and the Care and Treatment of Epileptics in the US (Letchworth, 1901). At the beginning of the 20th century, William Spartling will be the first to use the term 'epileptologist' for a

Hallmarks in the History of Epilepsy: From Antiquity Till the Twentieth Century 145

lesions on an epilepsy patient (Penfield & Steelman, 1947). The concept of eugenics will become an issue in the control of epilepsy; in 1936, the American Neurological Association Committee for the Investigation of Eugenical Sterilization will publish a report (Myerson et al., 1936) stating that sterilization of epileptics should be voluntary, conducted under

Kluver and Bucy will show, in 1939, that changes in behavior in monkeys may be associated with temporal lobe lessions (Kluver & Bucy, 1997), whereas in 1941 Jasper and Kershmann will prove that the temporal lobe is the site of origin of psychomotor seizures (Jasper & Kershmann, 1941). Percival Bailey (1892-1973) is the first to attempt temporal lobetomies for psychomotor seizures and the first to use electo-corticography for intra-operative

In 1946, a new anti-epileptic drug trimethadione was reported by Richards and Evertt to prevent pentylenetetrazol induced seizures (Richards & Everett, 1946). Other important advances in the field of epileptology were the development of a stereotactic human brain atlas by Talairach and Bancaud and the discovery of γ-aminobutiric acid (GABA) by Roberts

The beginning of the 1950's is marked by the establishment of the National Institute of Neurological Diseases and Blindness (NINDB). William Penfield will perfect and establish his surgical procedures as a treatment of choice in intractable epilepsy, especially of neocortical regions (Penfield & Baldwin, 1952; Penfield & Flanigin, 1950; Penfield & Steelman, 1947), whereas one should also mention the method of hemispherectomy introduced by Roland Krynauw in 1950 (Krynauw, 1950). Bailey and Gibbs in 1951 will employ the EEG as a guide to perform temporal lobe surgery (Bailey & Gibbs, 1951), whereas in 1953, Murray Falconer in London introduced the en bloc anterior temporal lobe resection and the term mesial temporal sclerosis (Falconer et al., 1953). In 1954, Penfield will publish with Herbert Jasper, an eminent neurophysiologist, one of the great classics in neurology, *Epilepsy and the Functional Anatomy of the Human Brain* (Penfield & Jasper, 1954). An important and influential figure in the field of Epileptology who become active during this period was Henri Gastaut. He was the founder of International EEG Federation and, in 1953, became head of the Marseille Hospital Neurobiological laboratories. His contribution in the study of epileptology was monumental; he defined five major human EEG paterns (lambda waves, pi rhythm, mu rhythm, rolandic spikes and posterior theta rhythm) (Naquet, 1996a, 1996b). During this decade, new drugs will come up such as carbamazepine in 1953 (Schindler & Häfliger, 1954), ethosuximide in 1958 (Vossen, 1958), sodium valproate

In 1961, the International Bureau for Epilepsy (IBE) was established. In 1966, Surgeon General William Stewart will create the Surgeon General's Public Health Service Advisory Committee on the Epilepsies, whereas, in 1969, the Society for Neuroscience was established. Important advances will be made in the field of neuroscience and in the physiology of synapses by Eccles, Kandel, Spencer, Speckman, Purpura, Meldrum and others. During this period important EEG studies will be conducted in animals mainly by Prince and his research team demonstrating the spikes and waves associated with synchronous paroxysmal depolarizing bursts occuring in cortical neurons (Matsumoto & Marsan, 1964a, 1964b; Prince, 1968a; Prince & Futamachi, 1968), and the spike-wave complex (Prince, 1968b)*.* In 1968, Murray Alexander Falconer (1910-1977) will recognize the importance of hippocambal sclerosis in temporal lobe epilepsy (Falconer, 1968). James Kiffin

supervision and only with patient consent.

and Frankel in 1949 (Roberts & Frankel, 1950).

localization (Bailey & Gibbs, 1951).

in 1963 (Meunier et al., 1963).

physician specializing in epilepsy. Cajal will describe neurons and synapses, a hallmark finding in the history of Neurology; in 1906, he will receive the Nobel prize for his discoveries.

In 1903, the first description of progressive myoclonic epilepsy by Herman Bernhard Lundborg (1868-1943) will be published (Lundborg, 1903), whereas Gowers will publish his famous book *The Borderlands of Epilepsy* (Gowers, 1903)

In 1912, Kaufmann will notice the electric changes in the brain during experimentally induced seizures (Kaufman, 1912), whereas in the same year Alfred Hauptmann (1881-1948) will synthesize phenobarbital, one of the first anti-epileptic drugs (Hauptmann, 1912). Two years later Napoleon Cybulski (1854 - 1919) and Jelenska-Macieszyna (Cybulski & Jelenska-Macieszyna, 1914) will publish the first fotographs of electroencephalography, whereas Walter Dandy (1886-1946) will describe in 1918 and 1919 pneumoventriculography and pneumoencephalography (Dandy, 1918, 1919a, 1919b). During the 1920's, William Gordon Lennox (1884–1960) and Cobb will focus on the effects of starvation, ketogenic diet and altered cerebral oxygen in seizures and they will publish their first monograph (Lennox & Cobb, 1928).

Fig. 4. Alfred Hauptmann (1881-1948)

In 1929, Hans Berger (1873-1941) will report human brain waves (Berger, 1929), confirmed later by Adrian and Matthews (Adrian & Mathews, 1934). In 1932, Berger reported sequential postictal EEG changes after a generalized tonicoclonic seizure, and in 1933 he published the first example of interictal changes and a minor epileptic seizure with 3/s rhytmic waves in the EEG (Berger, 1932, 1933). His work on epileptic EEG will be completed by Frederic Andrews Gibbs (1903–1992) and Erna Gibbs (1904-1987) who in collaboration with William G. Lennox will establish the correlation between EEG findings and epileptic convulsions (Gibbs et al., 1935; Gibbs et al., 1937; Gibbs et al., 1936). During the same period, H. Houston Merritt (1902 – 1979) and Tracy Putnam (1894-1975) will discover phenytoin and its effect on the control of epileptic seizures publishing their results in a series of papers (Merrit & Putnam, 1938a, 1938b, 1939, 1940). Phenytoin will become the first-line medication for the prevention of partial and tonic-clonic seizures and for acute cases of epilepsies or status epilepticus. Important advances will also be made on the fields of epileptic surgery by Wilder Penfield (1891-1976) who applied the Foerster method of removing epileptogenic

physician specializing in epilepsy. Cajal will describe neurons and synapses, a hallmark finding in the history of Neurology; in 1906, he will receive the Nobel prize for his

In 1903, the first description of progressive myoclonic epilepsy by Herman Bernhard Lundborg (1868-1943) will be published (Lundborg, 1903), whereas Gowers will publish his

In 1912, Kaufmann will notice the electric changes in the brain during experimentally induced seizures (Kaufman, 1912), whereas in the same year Alfred Hauptmann (1881-1948) will synthesize phenobarbital, one of the first anti-epileptic drugs (Hauptmann, 1912). Two years later Napoleon Cybulski (1854 - 1919) and Jelenska-Macieszyna (Cybulski & Jelenska-Macieszyna, 1914) will publish the first fotographs of electroencephalography, whereas Walter Dandy (1886-1946) will describe in 1918 and 1919 pneumoventriculography and pneumoencephalography (Dandy, 1918, 1919a, 1919b). During the 1920's, William Gordon Lennox (1884–1960) and Cobb will focus on the effects of starvation, ketogenic diet and altered cerebral oxygen in seizures and they will publish their first monograph (Lennox &

In 1929, Hans Berger (1873-1941) will report human brain waves (Berger, 1929), confirmed later by Adrian and Matthews (Adrian & Mathews, 1934). In 1932, Berger reported sequential postictal EEG changes after a generalized tonicoclonic seizure, and in 1933 he published the first example of interictal changes and a minor epileptic seizure with 3/s rhytmic waves in the EEG (Berger, 1932, 1933). His work on epileptic EEG will be completed by Frederic Andrews Gibbs (1903–1992) and Erna Gibbs (1904-1987) who in collaboration with William G. Lennox will establish the correlation between EEG findings and epileptic convulsions (Gibbs et al., 1935; Gibbs et al., 1937; Gibbs et al., 1936). During the same period, H. Houston Merritt (1902 – 1979) and Tracy Putnam (1894-1975) will discover phenytoin and its effect on the control of epileptic seizures publishing their results in a series of papers (Merrit & Putnam, 1938a, 1938b, 1939, 1940). Phenytoin will become the first-line medication for the prevention of partial and tonic-clonic seizures and for acute cases of epilepsies or status epilepticus. Important advances will also be made on the fields of epileptic surgery by Wilder Penfield (1891-1976) who applied the Foerster method of removing epileptogenic

famous book *The Borderlands of Epilepsy* (Gowers, 1903)

discoveries.

Cobb, 1928).

Fig. 4. Alfred Hauptmann (1881-1948)

lesions on an epilepsy patient (Penfield & Steelman, 1947). The concept of eugenics will become an issue in the control of epilepsy; in 1936, the American Neurological Association Committee for the Investigation of Eugenical Sterilization will publish a report (Myerson et al., 1936) stating that sterilization of epileptics should be voluntary, conducted under supervision and only with patient consent.

Kluver and Bucy will show, in 1939, that changes in behavior in monkeys may be associated with temporal lobe lessions (Kluver & Bucy, 1997), whereas in 1941 Jasper and Kershmann will prove that the temporal lobe is the site of origin of psychomotor seizures (Jasper & Kershmann, 1941). Percival Bailey (1892-1973) is the first to attempt temporal lobetomies for psychomotor seizures and the first to use electo-corticography for intra-operative localization (Bailey & Gibbs, 1951).

In 1946, a new anti-epileptic drug trimethadione was reported by Richards and Evertt to prevent pentylenetetrazol induced seizures (Richards & Everett, 1946). Other important advances in the field of epileptology were the development of a stereotactic human brain atlas by Talairach and Bancaud and the discovery of γ-aminobutiric acid (GABA) by Roberts and Frankel in 1949 (Roberts & Frankel, 1950).

The beginning of the 1950's is marked by the establishment of the National Institute of Neurological Diseases and Blindness (NINDB). William Penfield will perfect and establish his surgical procedures as a treatment of choice in intractable epilepsy, especially of neocortical regions (Penfield & Baldwin, 1952; Penfield & Flanigin, 1950; Penfield & Steelman, 1947), whereas one should also mention the method of hemispherectomy introduced by Roland Krynauw in 1950 (Krynauw, 1950). Bailey and Gibbs in 1951 will employ the EEG as a guide to perform temporal lobe surgery (Bailey & Gibbs, 1951), whereas in 1953, Murray Falconer in London introduced the en bloc anterior temporal lobe resection and the term mesial temporal sclerosis (Falconer et al., 1953). In 1954, Penfield will publish with Herbert Jasper, an eminent neurophysiologist, one of the great classics in neurology, *Epilepsy and the Functional Anatomy of the Human Brain* (Penfield & Jasper, 1954). An important and influential figure in the field of Epileptology who become active during this period was Henri Gastaut. He was the founder of International EEG Federation and, in 1953, became head of the Marseille Hospital Neurobiological laboratories. His contribution in the study of epileptology was monumental; he defined five major human EEG paterns (lambda waves, pi rhythm, mu rhythm, rolandic spikes and posterior theta rhythm) (Naquet, 1996a, 1996b). During this decade, new drugs will come up such as carbamazepine in 1953 (Schindler & Häfliger, 1954), ethosuximide in 1958 (Vossen, 1958), sodium valproate in 1963 (Meunier et al., 1963).

In 1961, the International Bureau for Epilepsy (IBE) was established. In 1966, Surgeon General William Stewart will create the Surgeon General's Public Health Service Advisory Committee on the Epilepsies, whereas, in 1969, the Society for Neuroscience was established. Important advances will be made in the field of neuroscience and in the physiology of synapses by Eccles, Kandel, Spencer, Speckman, Purpura, Meldrum and others. During this period important EEG studies will be conducted in animals mainly by Prince and his research team demonstrating the spikes and waves associated with synchronous paroxysmal depolarizing bursts occuring in cortical neurons (Matsumoto & Marsan, 1964a, 1964b; Prince, 1968a; Prince & Futamachi, 1968), and the spike-wave complex (Prince, 1968b)*.* In 1968, Murray Alexander Falconer (1910-1977) will recognize the importance of hippocambal sclerosis in temporal lobe epilepsy (Falconer, 1968). James Kiffin

Hallmarks in the History of Epilepsy: From Antiquity Till the Twentieth Century 147

The most important evolution, however, in the field of epileptology during the last twenty years was the connection between genetic factors and epilepsy; in 1989 Leppert was the first to identify the link between chromosome 20 and idiopathic human epilepsy syndrome in a family with benign familial neonatal convulsions (Leppert et al., 1989). The growing evidence on the connection between various genes and epilepsies is the cutting edge of modern epilepsy research, and in the next decades new exciting discoveries are going to

The fascinating history of epilepsy is connected with the history of humanity; early reports on epilepsy go back to the ancient assyrian and babylonian texts, scanning a period of almost 4,000 years. The first hallmark in the history of epilepsy are the Hippocratic texts which set in doubt the divine origin of the disease. Major advances in the understanding of epilepsy will come much later, during the 18th and 19th century; theories on epilepsy during this period are formulated on a solid scientific basis and epileptics are for the first time treated as patients and not as lunatics or possessed. During this period, experimental studies were conducted as well as advances made in the pathology of the disease and the connection of epilepsy with various psychiatric symptoms. The work of John Hughlings Jackson was preceded by a plethora of studies by Dutch, German, English and French physicians who evolved scientific thought and performed thorough studies on epilepsy. The advent of the 20th century led to the in-depth understanding of the mechanisms of the disease, the development of effective drugs and neuro-imaging methods. Last but not least, one should mention the important advances in the molecular biology of the disease and the

Abbas, Ali Ibn. (1523). Theorica, In: *Liber totius medicine necessaria continens quem* 

Abulcasim (1519). *Liber theoricae nec non practicae alsaharavii, qui vulgo acararius dicitur*, fol. 34,

Adrian, E.D., & Mathews, B.H.C. (1934). The berger rhythm: Potential changes from the

Africanus, C. (1536-1539). De communibus medico etc. Ix, 7 vol. 2, In: *Opera omnia*, p. 247,

Albertoni, P. (1882). Untersuchungen über die wirkung einiger arzneimittel auf die

Aretaeus (1856a). Cure of the paroxysm of the epileptics, chapter v, on acute diseases book i,

Aretaeus (1856b). On epilepsy, chapter iv, on chronic diseases, book i., In: F. Adams (Ed.), *The extant works of aretaeus, the cappadocian.*, p. 297, The Sydenham society, London.

*sapientissimus haly filius abbas .... Edidit, regique inscripsit, unde et regalis, dispositionis* 

occipital lobes in man. *Brain,* Vol. *57,* No. 4, (December 1934), pp 355-385, ISSN

erregbarkeit des grosshirns nebst beitragen zur therapie der epilepsie, . *Arc Exp* 

In: F. Adams (Ed.), *The extant work of aretaeus*, p. 399-400, The Sydenham Society,

change epileptology (Baulac & Baulac, 2010).

connection of various genes with various forms of epilepsy.

*nomen assumpsit*, IX, 6, fol 103, Lyon.

*Path Pharm,* Vol. *15,* No. 3-4, pp 248-288,

**7. Conclusions** 

**8. References** 

Augsburg.

1460-2156

Basel.

London.

Penry (1929-1996), in 1969, will publish his treatise *Basic Mechanisms of the Epilpsies* and afterwards *Antiepileptic Drugs, Neurosurgical Management of the Epilepsis, Complex Partial Seizures and their Treatment* and *Antiepileptic Drugs Mechanisms of Action.* Although carbamazepine and valproate were available in Europe during the 60s, no other drug was licensed in the US.

Fig. 5. Henri Gastaut (1915 -1995)

In 1970, Penry and Cereghino were employed in designing clinical trials for anti-epileptic drugs (AEDs). Carbamazepine was the first drug to be licensed by the FDA based on the results of clinical trials. Charles Pippenger (1939- ) developed methods for measuring blood levels of AEDs (Painter et al., 1978), whereas Fritz Dreifuss (1926-1997) worked on videomonitoring of absence seizures and helped in the classification of various epileptic conditions (Penry et al., 1975). An important development in the field of neuroscience was that of Erwin Neher (1944- ), who invented the patch clamp method to measure the flow of current through single-ion channels (Neher et al., 1978). Prince *et al* will make the first studies of cellular phenomena of epileptic events in the human cortex (Schwartzkroin & Prince, 1978; Wong & Prince, 1978, 1981). Meldrum will prove that the assumption connecting brain damage from seizures as a result of hypoxia, is wrong (Meldrum & Horton, 1973a, 1973b; Meldrum et al., 1973); he demonstrated that the excessive excitatory activity is responsible for the brain cellular loss.

The advent of the new decade, the 1908s, was marked by huge advances in the fields of neuro-imaging techniques, such as the CT, MRI, PET-scanning, and video-EEG monitoring. Epileptics are being evaluated psychologically and socially and before 1990, Quality of Life tools were developed. During the 1990s, the decade of the brain, the Global Campaign Against Epilepsy, launched in 1997 by the WHO, ILAE and IBE brought epilepsy out of the Shadows improving diagnosis, treatment, prevention and social acceptability. Various changes regarding the epileptic brain damage will also be studied, such as the mossy fiber sprouting and synaptic reorganization (Houser et al., 1990; Sutula et al., 1989; Sutula et al., 1988) (Tauck & Nadler, 1985). In 1993, Gabapentin (Neurontin) marketed in the US as the first AED which is not metabolized in the liver.

The most important evolution, however, in the field of epileptology during the last twenty years was the connection between genetic factors and epilepsy; in 1989 Leppert was the first to identify the link between chromosome 20 and idiopathic human epilepsy syndrome in a family with benign familial neonatal convulsions (Leppert et al., 1989). The growing evidence on the connection between various genes and epilepsies is the cutting edge of modern epilepsy research, and in the next decades new exciting discoveries are going to change epileptology (Baulac & Baulac, 2010).
