The major advances in epilepsy in the 20th century and what we can expect (hope for) in the future

The management of many of these cases of chronic convulsive disease is a task of difficulty, requiring the utmost patience and perseverance on the part of both the patient and the physician. The old power of casting them out has gone from the earth, and it is only the study of their origin and history, and careful experiment in their treatment, that we can hope to regain over them such power as may still be possible to man. 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. Although the condition of many sufferers is still gloomy enough, it is not now without hope, and to them also, we may surely trust the progress of the recent past is the dawn of a brighter day. W. R. Gowers, M.D., F.R.C.P., September, 1881(Gowers, 1885) In the preceding quotation, Gowers briefly summarized major 19th century epilepsy advances. Still to come in that century were animal research convulsion models and establishment of the discipline of neurosurgery. Two books summarized epilepsy in that time period: from Britain (Turner, 1907) and from the United States (U.S.) (Spratling, 1904). Both authors were involved in the worldwide system of colonies established to provide lifelong care for epileptics in an isolated and protective environment. In 1898, in the U.S., William Letchworth, L.L.D. and Frederick Peterson, M.D., organized the National Association for the Study of Epilepsy and the Care and Treatment of Epileptics, for “any person interested in the scientific study of epilepsy, or in the study of ways and means to improve the condition of epileptics, or in sociological subjects generally” (Letchworth, 1901). The Association became the American affiliate of the International League Against Epilepsy (ILAE), when the latter was founded in Budapest, Hungary in August, 1909. The Association ceased to exist in 1925. In 1903, Lundborg described progressive myoclonic epilepsy. Gowers (1907) published The Borderlands of Epilepsy. Cerebrospinal fluid (CSF) examination was used diagnostically. In 1895, Wilhelm Roentgen discovered the x-ray, and by 1896 Pean and Mergier demonstrated skull lesions but not brain imaging. Sherrington (1906) published Integrative Action of the Nervous System. The 1906 Nobel Prize went to Golgi and Cajal for identifying neurons and synapses. Adrenalin was studied prior to neurotransmitter identification. In 1912, phenobarbital was synthesized and replaced bromide (Hauptmann, 1912). World War I interrupted the U.S. supply of phenobarbital, creating major treatment problems, as documented in Rusk’s autobiography (Rusk, 1972) and by Grinker (1920), who had used phenobarbital since 1913. A U.S. Army World War I Division of Neurology and Psychiatry, headed by Pearce Bailey, examined military recruits—leading to epilepsy epidemiologic data—and treated and rehabilitated injured soldiers. Neurodiagnostic studies became available in 1918 when Walter Dandy described pneumoventriculography and (in 1919) pneumoencephalography. Some U.S. institutions started developing clinical neurology as a full-time discipline. The Boston City Hospital (BCH) Neurological Unit, Harvard Medical School, became the dominant epilepsy force in 1920 when Stanley Cobb began research on experimental convulsions and recruited staff, who would make key contributions for the next two decades. William Lennox arrived in 1921, and made epilepsy his life work. Lennox’s forte was in thoroughly summarizing the epilepsy literature as a stimulus for other researchers. His first monograph (Lennox & Cobb, 1928), and ultimately the two-volume book Epilepsy and Related Disorders (Lennox & Lennox, 1960), were signal publications. His research was on effects of starvation, ketogenic diet, and altered cerebral oxygen in seizures. Much of his work resulted in negative findings. A 1928 Rockefeller Foundation endowment established a full-time neurology unit at BCH, which then served as a model for creation of academic center Neurology Departments (White, 1984). Dandy used hemispherectomy for glioblastoma, a procedure not utilized significantly for epilepsy until the 1990s. By 1929, Egar Moniz had introduced arteriography. Dale and Dudley identified acetylcholine, a neurotransmitter studied in epileptiform activity. Berger (1929) reported human brain waves, later replicated by Adrian and Mathews (1934). Frederick Gibbs joined BCH full time in 1929; with his wife, Erna Leonhardt, he collaborated with Lennox and Hallowell Davis to study electroencephalography (EEG) of epilepsy patients using a single-channel Western Union undulator. In 1935, they published the first description of three Hertz spike and wave activity correlating with petit mal seizures. They recruited an electronics expert from the Massachusetts Institute of Technology, Albert Grass, who built a three-channel EEG machine, which led to the formation of Grass Instruments Company, for years the major EEG machine manufacturer. The BCH group described the three most common seizure types: petit mal, psychomotor, and grand mal. The Gibbses eventually moved to the University of Illinois and collaborated with Percival Bailey on temporal lobe epilepsy surgery. In 1928, H. Houston Merritt and Tracy Putnam joined BCH. In 1938, they discovered that phenytoin (then called diphenylhydantoin) increased the seizure threshold of electrically induced cat convulsions. They proceeded to clinical trials and found good seizure control (Merritt & Putnam, 1938). Parke-Davis marketed Dilantin that same year, since the Federal Food and Drug Act of 1906 required only accurate labeling. Merritt and Putnam (1945) continued to screen more than 600 Parke-Davis compounds, but none was as effective as phenytoin. Phenytoin became immediately popular in the U.S., but had delayed European use, possibly because of difficulty obtaining it due to World War II. Victor Horsley in 1886 localized and removed an epileptogenic lesion at the National Hospital, London. In Germany, Fedor Krause and Otfrid Foerster further refined surgical technique. Wilder Penfield studied technique with Foerster, returning in 1928 to Montreal, Canada. In November 1928, working with William Cone, Penfield used the Foerster method on an epilepsy patient. In 1934, Penfield founded the Montreal Neurological Institute (MNI), which uniquely combined a 50-bed neurologic disorders hospital with a brain research center. Epilepsy was the main theme of “The Neuro.” In 1939 Herbert Jasper established the MNI EEG laboratory. Work at the MNI included not only surgery but also many areas of epilepsy including: neurochemistry; the thalamic intralaminar system; cortical localization of language, spatial, auditory and visual perception; the role of the amygdala particularly in amnesia; brain tumors; and cerebral circulation. Epilepsy and the Functional Anatomy of the Brain (Penfield & Jasper, 1954) became an important source for epilepsy syndrome descriptions, their EEG correlates, and surgical management. In the 1930s, eugenics became an issue. Genetics was incompletely understood, but in some cases seizures appeared to be familial. Castration and sterilization were considered as potential treatments. In 1936, the American Neurological Association Committee for the Investigation of Eugenical Sterilization published a report (Myerson et al., 1936), indicating sterilization should be voluntary, done only with patient consent, and under supervision of a trained board. The report indicated that in special or selective cases, sterilization might be indicated in epilepsy—but that for epileptics with infrequent seizures and an “intact personality,” sterilization should not be performed. It would be some time before sterilization for epilepsy would be eliminated worldwide. Sulfanilamide was a major 1930s medical advance, but in 1937 a U.S. sulfanilamide preparation containing diethylene glycol caused more than 70 deaths, leading to new regulations for the preparation, safety, testing, labeling, distribution, and marketing of drugs. In 1938, at the American Psychiatric Association meeting, Robert Schwab showed moving pictures of seizures using two cameras operating simultaneously. Television in the 1950s and closed-circuit television monitoring would ultimately lead to epilepsy monitoring units. Lennox stayed at BCH until the early 1940s, moved briefly to Boston Psychopathic Hospital, and in 1944 moved to Boston Children’s Hospital and established the Seizure Unit. He died in 1960. The Lennox family also made significant epilepsy contributions. His wife, Emma Buchtel Lennox, helped found the Epilepsy Society of Massachusetts. His daughter, Margaret Lennox Buchthal, a neurophysiologist at Copenhagen University where her husband Fritz Buchthal did early work on phenytoin blood levels, was Editor-in-Chief of Epilepsia from 1969 to 1973. From 1944 to 1946, the RK Richards group demonstrated that trimethadione prevented pentylenetetrazol (PTZ) induced rat seizures and was effective for human absence seizures (Richards & Everett, 1946). The team at the University of Utah, with L. Goodman, J. Toman, E. Swinyard, and later D. Woodbury, developed a laboratory battery to screen compounds for potential anticonvulsant activity, which continued to be used for the rest of the century. The screen was based on the observation that drugs such as phenytoin first reduce duration and then abolish extensor component of the tonic phase of maximal electroshock seizures (MES) but do not prevent PTZ-induced threshold seizures. Conversely, trimethadione and antiabsence drugs prevent PTZ-induced seizures but are ineffective against MES. From a social perspective, the new antiepileptic drugs (AEDs) were invaluable. Phenytoin permitted seizure control and allowed discharge of colony residents to reenter society. Public advertisement campaigns included pamphlets like “The Ghost is Out of the Closet” and educational film strips, which were widely used at that time period in both schools and movie houses. Anatomic studies early in the century attempted to elucidate the role of cortical and subcortical centers in the genesis of the tonic and clonic seizure components, mainly from observation of motor effects derived from a particular stimulation. Electrophysiology became a major tool, with study of discharges and after discharges, recruiting responses, and spreading depression (Purpura, 1953). Moruzzi and Magoun demonstrated the reticular activating system. Despite the horrors of World War II, compassion did prevail. In Germany, the leader of the Bethel Epilepsiezentrum and the Hospital Mara in Bielefeld, Germany, was able to protect the residents from destruction. As a result of World War II, the Declaration of Helsinki, defining human research, was adopted in 1946. Juhn Wada survived World War II as a medical student in Japan. At the Hokkaido Imperial University Hospital Department of Neurology and Psychiatry, his work with psychiatric electroshock led to the recognition of the need for cognitive side effect prevention. He obtained sodium amytal from the U.S. Army Hospital in Sapporo, and despite concerns, injected the left carotid of a status epilepticus patient—with resultant seizure cessation and loss of motor and speech function. He immediately recognized the value this procedure might have for cerebral speech lateralization. Jean Talairach and Jean Bancaud continued their work on stereotactic surgery through World War II in the Paris underground sewers, and developed a stereotactic human brain atlas allowing implanted depth electrodes to define the extent and location of epileptogenic regions. In December, 1946, a joint meeting of the ILAE, the American League Against Epilepsy (renamed the American Epilepsy Society in 1954), and the Association for Research in Nervous and Mental Diseases was held in New York. The published proceedings (Association for Research in Nervous and Mental Disease, 1946) summarized the state of epilepsy and served as a stimulus to reactivate the groups and as a nidus for future work worldwide. Transistors and oscilloscopes were developed in the 1940s and researchers no longer had to use smoked drums for recording experiments. In 1949 Roberts and Frankel found an unknown ninhydrin-positive substance in chromatographed fresh human brain tissue, which was identified the following year as γ-aminobutyric acid (GABA), the inhibitory neurotransmitter. In 1947, George Dawson recorded evoked responses from the human scalp in response to somatosensory stimuli. Corpus callosum section was introduced for seizures. At the end of World War II, Henri Gastaut began recording EEGs on a one-channel Marey roller. In 1946 he studied with Grey Walter in Bristol and discovered photic stimulation as an EEG seizure activator. Returning to Marseille, he created the Timone Hospital EEG Laboratory with a four-channel Grass EEG. He became a founder of the International EEG Federation. In 1949, he traveled to study with Penfield and Jasper in Montreal, and studied the role of thalamic reticular structures in the genesis of Metrazol-induced generalized paroxysmal EEG discharges and developed the concept of centrencephalic seizures. He returned to make the Marseille School the dominant epilepsy force for several decades. In 1953 he became head of the Marseille Hospital Neurobiological Laboratories. In 1958 he the for of with epilepsy. In he created the to provide to with epilepsy. 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