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Milestones in epilepsy*

2009; Wiley; Volume: 50; Issue: 3 Linguagem: Inglês

10.1111/j.1528-1167.2009.02050.x

1528-1167

Edward Reynolds,

Genomics and Rare Diseases

After 45 years in clinical, academic, and political epileptology, including an increasing interest in the history of epilepsy, I have reached an age where it is possible to look back and reflect on possible advances in our understanding and practice of epileptology during the period of my career and to view them in the context of the much longer history of our subject. This commentary, therefore, reflects my personal view of milestones in the history of epilepsy, which is inevitably influenced by my own personal journey in epileptology, some aspects of which are discussed elsewhere (see de Toffol & Genton, 2008). I have had the great privilege of working with James Kinnier Wilson on the oldest detailed description of epilepsy in existence, a Babylonian text in the British Museum, London, from the second millennium B.C. (Kinnier Wilson & Reynolds, 1990). James is the son of the famous King’s neurologist, Samuel Alexander Kinnier Wilson, who described Wilson’s disease. He is an Assyriologist at Cambridge and can translate cuneiform scripts, which I am unable to do. Being the son of a doctor he has always been interested in medical texts and drew my attention to this account of epilepsy, which is one chapter in a Babylonian textbook of medicine made up of 40 such tablets or texts. The amazing thing to me is the accurate account of so many seizure types that we recognize today—for example, tonic–clonic, absence, complex partial, Jacksonian, or even gelastic seizures. The Babylonians, however, had no understanding of pathology or of brain function, and each seizure type was thought to be the result of an invasion of the body by a particular demon. The first line of the text states: If epilepsy falls once upon a person or falls many times, it is the result of possession by a demon or a departed spirit. The Babylonians apparently had no doubt about whether a single seizure is epilepsy. Every attack, whether single or multiple, was the result of possession. Here is a remarkable account, for example, of a left-sided focal motor attack, in which progression to loss of consciousness makes it harder to drive out the demon: If at the time of his possession, while he is sitting down, his left eye moves to the side, a lip puckers, saliva flows from his mouth, and his hand, leg and trunk on the left side jerk like a newly slaughtered sheep, it is miqtu. If at the time of the possession his mind is consciously aware, the demon can be driven out; if at the time of possession his mind is not so aware, the demon cannot be driven out. The Babylonians were describing exactly the same disorder that we see today, and their account is surely a milestone in the history of epilepsy. Recently, Kinnier Wilson and I translated a Babylonian account of psychoses associated with epilepsy (Reynolds & Kinnier Wilson, 2008). The next milestone must surely be the Greek account of “The sacred disease” by the school of Hippocrates in the fifth century B.C. Hippocrates describes in some detail the prevailing supernatural view of epilepsy, no doubt inherited from the Babylonians and probably other cultures. However, he rejects this interpretation and for the first time suggests a natural causation mediated through disorder of the function of the brain: “The brain is the seat of this disease, as it is of other very violent diseases” (Hippocrates, 1985). Unfortunately, the Hippocratic concept of a treatable brain disorder had little influence on the prevailing supernatural view, as is well described in the scholarly history of epilepsy from the Greeks to the late 19th century by Temkin (1971). It was not until the 17th and 18th centuries that the concept of epilepsy as a brain disorder began to take root in Europe, as illustrated, for example, by “An essay of the pathology of the brain and nervous stock: in which convulsive diseases are treated of,” by Thomas Willis (1684). During these two centuries the major issue and debate was what to include within the concept of epilepsy—that is, all periodic “convulsive diseases” or only those with a rather restricted kind of motor convulsion with or without loss of consciousness? Therefore, many treatises on “convulsive diseases” appeared, which included hysteria, tetanus, tremors, rigors, and other paroxysmal movement disorders. The latter were gradually separated off from epilepsy in the 19th century, as illustrated by the distinguished Lumleian Lectures on “convulsive diseases” by Robert Bentley Todd (1849) and by John Hughlings Jackson (1890). At the same time, in the late 19th century, another kind of separation began of “nervous disorders.” Disorders of brain function associated with brain lesions, discovered by the new discipline of neuropathology, were separated from “mental disorders” associated with the new psychodynamic psychiatry of Freud and others, in which no brain pathology was detected. This process continued well into the 20th century, leading to varying degrees of separation of neurology from psychiatry with rather indistinct or controversial boundaries. There also began, in the second half of the 19th century, a parallel and equally long-running debate concerning the distinction between pure primary idiopathic epilepsy, in which the brain is macroscopically normal, from secondary symptomatic epilepsy, which is associated with many different brain pathologies. This debate continues today and is at the heart of current controversies concerning modern ILAE classifications of the epilepsies (Reynolds & Rodin, 2009). Also in the 19th century, with the development of the concept of functional localization in the brain (Ferrier, 1876) and the discovery, for example, of the motor cortex (Fritsch & Hitzig, 1870), the concept of “epileptiform” or “partial” seizures arose as models for the study of “generalized” seizures (Jackson, 1870, 1890). By meticulously studying the clinical features of unilateral epileptiform motor seizures, Jackson was able to conclude (as was later confirmed experimentally) that the motor cortex was concerned with movements rather than individual muscles, another milestone. Paroxysmal episodes of an intellectual, emotional, or behavioral kind, including hysteria or “hystero-epilepsy” (Gowers, 1881), were more difficult to classify and localize. It was not until the discovery of the human electroencephalogram in the 20th century (Berger, 1929) that the concepts of temporal lobe or frontal epilepsy were gradually clarified, and psychological concepts of hysteria evolved. As the concept of a brain disorder gradually took hold between the 17th and 19th centuries, it was widely believed that epilepsy must have a vascular basis attributable to either acute anemia or acute congestion of the brain. Even Jackson accepted that epilepsy had a vascular basis in his early writings in the 1860s (Temkin, 1971; Reynolds & Trimble, 2009). Earlier, however, Todd had challenged this view and was the first to develop an electrical theory of brain function and of epilepsy in his Lumleian Lectures (Todd, 1849). Todd was an anatomist, physiologist, and pathologist as well as an outstanding physician with an interest in disorders of the nervous system. He was aware of the great new discoveries in electromagnetism through his contact with his contemporary in London, Michael Faraday, the greatest electrical scientist of all time. Influenced by Faraday, Todd conceived of “nervous force” as a polar force, analogous to electricity but mediated by unknown molecular and nutritional mechanisms. He, therefore, preferred the term “nervous polarity.” Applying Faraday’s concept of “disruptive discharge,” he viewed seizures as the result of electrical discharges in the brain. According to Todd: “These periodic evolutions of the nervous force which give rise to the complete epileptic paroxysm may be compared to the electrical phenomenon described by Faraday under the name “disruptive discharge.” This is the origin of our use of the word “discharge” in epilepsy today (Reynolds, 2004a, 2004b, 2007). It is to Todd, therefore, that the credit is due for a major milestone in our understanding of epilepsy. However, as illustrated in Table 1 it took more than 80 years for his electrical concepts of brain function and epilepsy to take root. His views were supported by the work of Caton with his discovery of electrical potentials in the brains of animals in the 1870s, and of Berger with his discovery of the human electroencephalograph in the 1920s. In 1935, at the second International Neurological Congress in London, vascular theories of epilepsy were finally laid to rest and electrical theories widely embraced, due to the work of Berger, Lennox, Penfield, and others (Reynolds, 2005). Incidentally, at that same Congress in London, the International League Against Epilepsy was reborn following its demise during the World War I—soon after its original birth in Budapest in 1909, the centenary of which we are now celebrating. Finally there is a wonderful symmetry in the story of the evolution of our ideas of the electrical basis of brain function and of epileptic discharges, summarized in Table 1. Hodgkin and Huxley won the Nobel Prize in 1963 for their discovery of the ionic basis of Todd’s “nervous polarity” or neurotransmission; the relevant ions of sodium and potassium, central to their hypothesis, were the very ones that Humphrey Davy had discovered in the first decade of the 1800s. Sir Humphrey Davy (1778–1829) was the leading British scientist and Director of the Royal Institution in London in the early part of the 19th century. It was he who took on as a laboratory assistant the relatively uneducated Michael Faraday, who then rose to succeed and surpass him in the fields of chemistry and physics (especially electromagnetism), and who so influenced Todd who applied his ideas to the brain (Reynolds, 2004a,b). This brings me a little nearer to our own time, especially as I was born in 1935. It is premature and more difficult to judge progress since then, but I have a few comments based on my own experience. One of my earliest interests was in chronic antiepileptic drug toxicity (Reynolds, 1975). Figure 1 illustrates the considerable delay experienced in recognizing chronic toxic effects of the older drugs. Although we are now more vigilant, we are still experiencing some surprises with the newer drugs—for example, retinopathy seen with vigabatrin or polycystic ovarian syndrome with valproate. It turned out that some of these problems were exacerbated by polytherapy, and so I turned my attention, with the help of David Chadwick, Simon Shorvon, and others, to monotherapy, assisted by the newly developed techniques for antiepileptic drug monitoring. Since our first studies with phenytoin and carbamazepine in the mid-1970s (Reynolds et al., 1976; Shorvon et al., 1978), many others have confirmed our observation that 70–80% of newly diagnosed adults and children can be controlled with carefully monitored monotherapy with a variety of different drugs (Perucca, 1997). This finding inevitably led to comparative monotherapy studies between the various standard drugs, to ask the question: which drug(s) should we be using in newly diagnosed patients? In an Medical Research Council (MRC)-supported multicenter prospective randomized pragmatic study, my colleagues and I could not demonstrate any clear differences in efficacy between phenobarbitone, phenytoin, carbamazepine, and sodium valproate, in sample sizes of up to 120 on each drug (Heller et al., 1995; de Silva et al., 1996). Time scale of recognition of chronic toxic effects of phenobarbitone, phenytoin and primidone. From Reynolds, 1975. In the last 20 years 10 new antiepileptic drugs have come on to the market in the United Kingdom. Trials have revealed remarkable similarity in effectiveness between newer drugs and the older drugs, whether for partial seizures (using carbamazepine as the standard drug), or for generalized and unclassifiable seizures (using valproate as the standard drug) (Marson et al., 2007a, 2007b). Do any or all of these newer drugs represent a milestone in the treatment of epilepsy? I have my doubts, unless any one of them can be shown to have opened up some remarkable new metabolic lead in our understanding of epilepsy. Certainly we have greater choice, slightly better targeting, and the possibility of less toxicity in some patients. But against those advantages, we have much confusion, polytherapy is on the rise, and there are much greater economic costs. It is a sobering thought that nearly a century after Hauptmann reported the effectiveness of phenobarbitone in epilepsy in 1912, it is still the most widely used drug in the world! I think the introduction of phenobarbitone was a milestone, probably more so than the bromides that preceded it and those drugs that followed. The above-referenced monotherapy studies have revealed a much more optimistic view of prognosis for the majority of patients than prevailed 40 years ago (e.g., Rodin, 1968), and have raised very interesting questions about why a minority of patients progress to intractability (Reynolds et al., 1983). These are not entirely new questions, as Gowers (1881) wondered how to “arrest” the process of epilepsy, and even Hippocrates observed that epilepsy could become too “inveterate” for the treatments available. When these fundamental questions are eventually answered, a new milestone in epilepsy will have been achieved. What else has changed during my 45 years in clinical epileptology? Diagnosis has certainly improved and Table 2 illustrates some of the advances since the 1960s. But are any of these milestones in our understanding of epilepsy? Again I have my doubts. What they do represent is steady progress in the sophistication and precision of applying our existing knowledge and understanding to the diagnosis and management of our patients. The modern era is also marked by an expansion of interest in basic mechanisms underlying seizures and epilepsies, stimulated by developments in genetics, molecular biology, neurophysiology, functional imaging, and numerous newer chemical techniques for exploring the concepts of excitation, inhibition, modulation, neurotransmission, and so on. At this time, it is very difficult to say that any of these represents a major milestone in our understanding of epilepsy. Every advance seems to add to the enormous complexity of the nervous system and the probability that multiple elusive genetic–molecular–metabolic mechanisms contribute to the wide range of epilepsies. Indeed, there is some evidence that epilepsy, which can occur in all mammalian species, does so more frequently as brains have become more complex. Perhaps the very complexity of the human brain increases vulnerability? Despite scientific advances in the 19th and 20th centuries, epilepsy has remained a profound social problem compounded by the deeply rooted historical concepts of a supernatural or sacred disorder described earlier. The birth of the International League Against Epilepsy (ILAE) in 1909, and of the International Bureau of Epilepsy (IBE) in 1966, was definitely a milestone in the history of epilepsy. Both organizations have contributed to steady progress, especially in economically more advanced countries; in the establishment of specialized services; and in the erosion of ignorance, fear, misunderstanding, and stigma, and in associated legal and social penalties. But even in these more developed countries, there is still a considerable distance to travel. However, epilepsy is a global problem and here I am encouraged by the progress of the Global Campaign Against Epilepsy, a partnership between ILAE, IBE, and the World Health Organization (WHO), and which is bringing public and political awareness and improved services to the developing world where the needs are much greater. I am proud of the fact that epilepsy is the first neurologic disorder to be given the highest priority by WHO and to be given its own Campaign. The address of Dr. Gro Harlem Brundtland, Director General of WHO, at the launch of the second phase of the ILAE/IBE/WHO Global Campaign in 2001, was certainly a milestone in the social history of epilepsy and should be read by all concerned (see Reynolds, 2002). One spin-off of the Campaign has been the continuing growth in the League and the Bureau in the last decade. Both now have approximately 100 chapters, involving every continent; as we used to say about the British Empire, the sun now never sets on the League or the Bureau. Where will the milestones come from in the future? Table 3 summarizes a few speculative suggestions. We need to think more of curing instead of controlling the disorder, of arresting epilepsy, to use Gowers’ term, rather than suppressing seizures; and of course, we need to concentrate more on prevention. For all these purposes, we need to focus more on interseizure events, on natural history, and on processes of intractability as well as remission. At the metabolic level, we should give more emphasis to energy metabolism, rather than the current focus on neurotransmission and signaling. Of course, genetics is important. But in the end, we must still answer the question of how genetic predisposition leads to changes in energy metabolism, neuronal stability, and seizure threshold. One area that intrigues me involves the processes of synchronization in the brain, which undoubtedly are relevant to epilepsy. It seems that synchronization is a widespread phenomenon in nature and in the universe (Strogatz, 2003). Because epilepsy is the most universal medical disorder on the planet, perhaps a universal phenomenon lies at the heart of it? Hopefully the pace of discovery is accelerating, but as described above it is never as fast as we like to think it is. We should be motivated, however, not only by the personal and global needs of people with epilepsy but also because our search will continue to shed light on the function of that microuniverse within our skulls, which we call our brain. I have many people to thank for their support and encouragement over my 45 years in epileptology—so many, in fact, that it is impossible to mention them individually. They include many colleagues within the various institutions and disciplines of King’s College; many within the International League, the International Bureau, and the WHO; and many trustees and staff, donors, and supporters of The Fund for Epilepsy. I am also very grateful to many junior colleagues who have educated me, and to so many patients who have motivated me. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure: I have no conflicts of interest to disclose.