SEARCH

SEARCH BY CITATION

Keywords:

  • Epilepsy;
  • Seizures;
  • Epilepsy research;
  • Scientific advances

Summary

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

This paper, based on the 4th Annual Hoyer Lecture presented at the 2006 annual meeting of the American Epilepsy Society, first provides a general view of the current limitations in therapies aimed at achieving the goal of “no seizures, no side effects” for patients living with epilepsy. Some of the seminal discoveries in epilepsy research over the past 100 years are then reviewed, with an emphasis on the pivotal role of basic and clinical/translational science in leading the way to new and effective means for diagnosing and treating for epilepsy. The paper concludes with a view of the future course of epilepsy research. Scientific advances will increasingly rely on the collaboration of multidisciplinary teams of reseachers using the analytic and storage capabilities of machines, and linked together by communication tools such as the Internet and related technologies.

The evolving tradition of the annual Hoyer Lecture is to use the occasion to take stock of where we are in the world of epilepsy, and where we may be headed. Indeed, in 2004, Tom Sutula, in his lecture entitled “Epilepsy After the Decade of the Brain: Misunderstandings, Challenges, and Opportunities,” explored some of the reasons why epilepsy is challenging for healthcare professionals and scientists and how it is often misunderstood by the public (Sutula, 2005). The following year, Jeff Noebels spoke of “New Tools to Cure Epilepsy: Genes, Pixels, Patterns and Prevention” (Noebels, 2006). His lecture focused on advances in science and technology that are beginning to change the way we think about why people develop epilepsy, when the precise causes can be pinpointed in the brain, and how we can more accurately personalize treatment for every patient. In this presentation, I would like to continue this tradition by conveying my own reflections on the “state of the union,” if you will, of the world that those of us working on epilepsy have as such a primary focus of our day-to-day lives.

I have divided my comments into three parts. First, a reflection on the raison d'etre of our work—the person with epilepsy—and the impact that epilepsy has on the patient, his or her loved ones, and the rest of us who are devoted to improving their lives. Next, in anticipation of comments about the directions we are headed in epilepsy research, I will take a brief look back at the progress that has already been made. Finally, some thoughts about the future, which, I will note at the outset, is promising and bright.

The Person with Epilepsy

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

One of the consequences of a life as a professional caring for people with epilepsy is that we listen to countless stories of, and we bear witness to, the impact of seizures and epilepsy on everyday life. It is impossible to fully understand that impact unless you have epilepsy, and one comes closest to an understanding when that person is your child or your partner in life. But medicine teaches us that it is the thinnest of veils that separates those of us who are healthy from those of us who are not, and, in fact, the only difference between ourselves and our patients is our current good fortune.

Case study 1

An otherwise healthy 26-year-old woman was referred by her primary care physician because of a recently witnessed generalized tonic–clonic seizure. In retrospect, she recalled a few episodes of a “funny feeling” in her stomach that were followed by feeling “spacy” and confused. The family history was notable for a cousin with febrile seizures and a niece with epilepsy. The general exam and neurological exam were normal, and a high-resolution MRI scan of the brain was normal. The EEG showed occasional bursts of approximately 4 Hz polyspike and wave, and it was concluded that the patient had an idiopathic generalized epilepsy syndrome.

Speaking with the patient recently, here is what she had to say:

The moment I had my first seizure 3 years ago, at the age of 26, while sitting at an airport restaurant with my husband and my two 1-year old twin boys, my life descended into chaos. The seizure then, and the ones that have happened since, are not the problem—I am unaware during them. The problem is all the time in between my seizures. Every day my mind is filled with the same, recurring questions: Will I make it through the day without one occurring? Will my children be safe? Why did this happen to me in the first place? Will my children develop epilepsy? Why don't I have the same amount of energy that I had before? Will this ever go away?

When we see patients and their families in an office visit, the stories are always unique and distinctive, but the fundamental questions are virtually always the same:

  • 1
    Why did this happen to me?
  • 2
    What is the best treatment for my epilepsy?
  • 3
    Why isn't your therapy working?
  • 4
    When will the seizures go away?

In contemplating these questions, I must admit to the tremendous amount of frustration that I feel in my limited capacity to provide adequate responses to my patients. As an epilepsy specialist, I undoubtedly have a skewed perspective on treatment because I tend to see patients with epilepsy that has not been responsive to initial attempts at treatment. Nonetheless, too often my answers to the four questions above can be summarized as follows:

  • 1
    Why did this happen to me?
    “I am not entirely sure. You likely have a genetic factor given your family history, but the specific cause of your epilepsy is unknown.”
  • 2
    What is the best treatment for my seizures?
    “In addition to being careful with sleep, diet, and other potential factors that can influence the likelihood of seizures, you should be on an antiepileptic drug. We have a number from which to choose, but I cannot predict in advance what drug will be the best for you.”
  • 3
    Why isn't your therapy working?
    “I don't know.”
  • 4
    When will the seizures go away?
    “I don't know.”

To put this into perspective with some other areas of medicine, consider the following case:

Case study 2

A 43-year-old woman came into clinic with a 5-day history of fever, productive cough, pleuritic chest pain, chills, and shortness of breath. The general exam was notable for mild tachypnea, a fever of 39°C and diaphoresis, and the pulmonary exam revealed egophony, crackles, and a pleural friction rub. A chest radiograph showed a left-lower lobe infiltrate consistent with bacterial pneumonia. A sputum sample revealed gram-positive diplococci that were identified as Streptococcus pneumoniae, and an antibiotic sensitivity assay showed the organism resistant to penicillin but sensitive to cephalosporins. The patient was treated with cefalexin and was entirely symptom-free 2 weeks later.

I dream of the day when the approach and the outcome of our care for all patients with epilepsy will be similar to this one.

What will it take to reach this goal?

The story is told of two doctors who are walking along a path next to a river, enjoying the beautiful morning, when all of a sudden they hear the desperate screams of a person struggling in the river, obviously at risk of drowning. Without hesitation, one of the doctors jumps into the fast current, reaches the victim, pulls him to shore, and, with the help of his companion, tends to the man's needs until the ambulance arrives. In a short time, the two resume their peaceful walk, only to be interrupted again by the frantic cries of another person struggling in the water. The same doctor immediately leaps into the water and saves the life of the victim as before. Slightly ruffled, the two friends continue their walk, when, amazingly, they hear a third person thrashing in the water and pleading for help. As the one physician prepares to dive into the river once again, he sees his companion suddenly turn and begin running away. “Don't run!,” he hollers—I'm exhausted and am going to need your help with this one!“Where are you going?” To which the second replies: “I'm going to go to upriver to find out why all these people are falling in the water!”

This tale captures the essence of one of the many gifts that we are offered in choosing the work we do in medicine and science. The opportunity to serve others in a myriad of ways. The nurse or doctor or psychologist who chooses to devote his or her life to the immediacy of taking care of people who are suffering from epilepsy, who is willing to dive into the water whenever called, is the salt of the earth and is directly providing for a fundamental need. At the same time, the scientists among us who are drawn to understanding the causes of epilepsy, who want to know why people are falling into the river in the first place, are providing for an equally great and essential need.

Progress in Epilepsy Research

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

There is simply no question that progress in science will be the main determinant of our moving closer to the day when epilepsy can be effectively treated and cured. To consider where we are currently and to contemplate the future, however, it is wise to take stock of the past. As Goethe said, “He who cannot draw on 3,000 years lives from hand to mouth.”

What, then, is the relatively recent history of epilepsy research? For example, what progress has been made in the past 100 years? To address this, I generated a draft list of what I considered to be the 10 or so most monumental discoveries or advances in epilepsy in the 1900s. My criteria were (1) a scientific discovery, or development of a tool or technique; (2) a result that proved to withstand the test of time; (3) a finding of seminal importance; that is, clearly spawned new directions in epilepsy research; and (4) work specifically tied to the study of epilepsy. This latter criterion excluded great discoveries having more general applications to neuroscience or patient care (e.g., first intracellular recordings, development of MRI scanning). I then sent the list to 16 senior and eminent colleagues who I knew would have well-informed perspectives on our history. This clearly struck a chord, as I received responses from 15 of the 16, and most were almost immediate. Few of my colleagues were shy about providing me with their own interpretation of the past. But it was a very informative exercise, and my list of 10 advances quickly blossomed to 30, and a number of people advised me to stay away from trying to identify the most important work in the last 30 years or so. This was advice I followed, so the list was culled back down to 14 (Table 1).

Table 1.  Seminal advances in epilepsy research during the 1900s
YearInvestigatorsDescription of discoveryReferences
1909CushingObservation that an aura could be elicited in patients with epilepsy when the postcentral gyrus was stimulatedCushing (1909)
1924BergerFirst recording of the EEG in humansBerger (1929)
1935Gibbs, Davis, and LennoxFirst recording of spike and wave in a 21-year-old woman patient of LennoxGibbs et al. (1935)
1937Putnam and MerrittDemonstration of the effect of phenytoin on electric shock thresholdsPutnam and Merritt (1937)
1941Jasper and KershmanUse of EEG to localize epileptic abnormalities and identification of the temporal lobe as the origin of psychomotor seizuresJasper (1941), Jasper and Kershman (1941)
1947LennoxDescription of heritability of epilepsy through the study of twin pairsLennox (1947)
1950MorrisReport of temporal lobe resections involving amygdala and hippocampus for the treatment of psychomotor epilepsy (work popularized by Penfield and Flanigan the same year)Morris (1950), Penfield and Flanigin (1950)
1954Hunt et al.Report of complete resolution of seizures by treatment of an infant with pyridoxineHunt et al. (1954)
1959Enomoto and Ajmone-MarsanRecording of brief slow-potential shifts with burst of high-voltage spikes, later designated “periodic depolarization shifts” by Matsumoto and Ajmone-Marsan in 1964Enomoto and Ajmone-Marsan (1959), Matsumoto and Ajmone-Marsan (1964)
1963CrandallFirst report of chronic depth electrode recordings in humans, marking the beginning of the modern era of video-EEG telemetryCrandall et al. (1963)
1967GoddardObservation of the “kindling” effectGoddard (1967)
1971Bhagavan et al.First description of seizures induced by monosodium glutamate, followed by Olney et al.—First description of seizures and hippocampal damage induced by kainic acidBhagavan et al. (1971), Olney et al. (1974)
1972YamamotoFirst demonstration of epileptiform activity in the hippocampal slice preparationYamamoto (1972)
1973Meldrum et al.Demonstration that prolonged status causes neuronal injury, even when systemic effects are controlledMeldrum and Brierley (1973)

There are a number of additional major discoveries in the past 30 years, including the studies by Nelson and Ellenberg showing an increased risk of developing epilepsy in subgroups of children experiencing at least one febrile seizure (Nelson and Ellenberg, 1976), the discoveries by Jeff Noebels, Mark Leppert, Sam Berkovic, and others of specific gene mutations causing epilepsy (Noebels and Sidman, 1979; Leppert et al., 1989; Steinlein et al., 1995), work by Solomon Moshe and Yehezkal Ben-Ari demonstrating that the immature brain is susceptible to injury (Moshe et al., 1983; Ben-Ari et al., 1984), and much, much more. But one additional force in the latter half of the 20th century deserves special recognition, and that is the prodigious work of David Prince. In addition to making his own seminal discoveries related to the nature of epileptogenic foci, inhibitory circuits, and mechanisms of lesion-induced epileptogenesis, Dr. Prince has also trained a veritable army of talented and productive epilepsy researchers who span the globe and have been the leaders of the field in recent decades. Readers are encouraged to visit http://neurotree.org to gain more of an appreciation of the impact of this extraordinary individual.

Given the tremendous advances over the course of 100 years, it is remarkable to think how each of these seminal discoveries, and many others, have impacted the way we understand the nature of epilepsy and the manner in which we care for patients. But why is there still such a profound knowledge gap? Why are we still so limited in our ability to answer the most basic questions asked by our patients? The answer relates to the complexity and diversity of the epilepsies, as well as the complexity of the brain itself (Table 2).

Table 2.  Overarching themes/concepts regarding the challenge of understanding the neurobiology of epilepsy
• Epilepsy is associated with an extraordinarily broad spectrum of conditions and ontogeny
• Epilepsy involves the most complex entity in the known universe
• Seizures are, fundamentally, manifestations of abnormal network properties; we currently lack the tools for analyzing complex, biological networks
• Seizures result from a stochastic process; our understanding of the underlying mechanisms that contribute to the lowering of the seizure threshold in humans remains extremely rudimentary; e.g,
 ○ fever (primarily in the immature brain)
 ○ sleep deprivation
 ○ hormonal milieu
 ○ stress
 ○ The validity and even reliability of our models remains very limited

Many former leaders in epilepsy have emphasized the challenge of bridging the knowledge gap and advocated for a plan for action. For example, Lennox, in his 1946 monograph on “Science and Seizures” (Lennox, 1941), devoted a chapter to the subject of “A Campaign Against Epilepsy,” where he posed the question “What is a reasonable program designed to improve the condition and position of persons with seizures?” He answered this by suggesting there are three aspects of this question: Education of the public, treatment of the patient, and attainment of new knowledge. In the section with the subheading “The Utopia of Research,” Lennox started with the sentence “Medical research is the hope of the future.” He went on to talk about the potential of understanding the genetic basis of epilepsy and the prospects of altering brain chemistry, and he finished with a call for more funding to support research.

In 1978, the NIH published a “Plan for Nationwide Action on Epilepsy,” produced by a nine-member “Commission for the Control of Epilepsy and Its Consequences,” led by Richard Masland and Kiffin Penry (United States, 1977). In it, there is a 15-page summary, with two additional volumes, describing 74 specific recommendations. Among other things, this “Call to Action” emphasized the need for research focused on epidemiology and vital statistics, genetics, prevention, toxic and metabolic factors, surgical treatment, drug research, and others.

Most readers are likely aware of the more recent calls to action. The first was the historic White House-initiated conference, “Curing Epilepsy: Focus on the Future,” held in March of 2000, and hosted by NINDS and cosponsored by the Epilepsy Foundation, the American Epilepsy Society, Citizens United for Research in Epilepsy, and the National Association of Epilepsy Research Centers. At that conference, a number of investigators felt it was important to define a set of benchmarks that could be used to help set research priorities and to measure progress over subsequent years (see Table 3; Jacobs et al., 2001; and http://www.ninds.nih.gov/funding/research/epilepsyweb/epilepsybenchmarks.htm). The second conference of this kind, entitled “Curing Epilepsy: Translating Discoveries into Therapies,” was held in March of 2007. Time was again taken at the meeting to allow participants to consider the current state of epilepsy research and set targets for research in coming years. An updated set of Benchmarks is currently under development and will be presented at the Annual Meeting of the American Epilepsy Society in December 2007.

Table 3.  Benchmarks for epilepsy research (2000)
I. Understanding basic mechanisms of epileptogenesis
 A. Discover the range of anatomical, physiological, and molecular substrates associated with the epilepsies; define unambiguous markers of epileptogenicity
 B. Continue the progress of identifying the genes predisposing to epilepsy
 C. Validate and apply models of epileptogenesis and epilepsy as biological test systems for novel therapy
II. Create and implement new therapies aimed at the prevention of epilepsy in patients at risk (antiepileptogenesis therapy in humans)
III. Create and implement new therapies free of side effects that are aimed at the cessation of seizures in patients with epilepsy

Future Prospects in Epilepsy Research

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

What of the future? What will be the pathways to discovery in epilepsy research? How should we rethink the quest for cures? Experience and common sense suggest it is foolhardy to try and predict what the most likely discoveries will be in the next 50 years, let alone the next 5 years. However, I believe it is safe to predict that the manner in which we explore the science of epilepsy will evolve considerably over the coming years in a rather fundamental way amazingly. Specifically, it will be through the formation of larger and more complex research networks that will link together many individuals, all relying heavily on machines and technology, working toward common goals.

This is not to say that the creativity of the individual investigator, or small groups of investigators, will become any less important in the advancement of science. The retrospective look at the progress of epilepsy research in the past century makes it clear that individual scientists, those with focused and imaginative minds, will continue to have a significant role, if not the predominant role, in leading us forward. And, to that end, the epilepsy research community must continue to encourage funding of the very best investigator-initiated projects. We also must ensure that academia continues to reward the talents of the individual, even when the person may be insufferably narrow and even irritating in the minds of some, and we need to identify the most talented, uniquely creative minds among our students, and inspire them to do everything possible to direct their imaginations toward exploring the unknown rather than merely tinkering with what is currently known.

What of the other end of the spectrum, the creativity that emerges from groups of individuals, something that might be called collective or pooled creativity? We are already well along the way in a new era of science, for example, where the NIH and universities are recognizing the need to fuel transdisciplinary and translational investigation—the latest Clinical and Translational Science Award initiative from NIH is one especially prominent example (see http://www.ncrr.nih.gov/clinical_research_resources/clinical_and_translational_science_awards/). Success in this enterprise is based primarily on the existence of highly efficient, highly functioning networks of individuals working together on common problems or goals. E-mail, the Internet, cell phones, Sharepoint, desktop videoconferencing, and so forth are helping to shape these networks. In fact, it has now become somewhat typical for authors on a scientific paper to have never met one another in person, despite the fact that the level of their intellectual exchange was as deep as if their labs were down the hall from one another.

Of course, it is remarkable to consider the rate at which the scope of pooled creativity is increasing. Most scientists are aware of Moore's Law, named after Gordon Moore, cofounder of Intel. Moore's Law has been remarkably accurate in predicting the doubling of computational power every 10 years, with a proportionate decrease in cost. The futurist Ray Kurzweil has put this increase in computational power in terms of the level of function of organic nervous systems (Kurzweil, 1999). Thus, the computational speed of a standard, $1,000 desktop computer achieved the processing ability (in terms of nodal points and speed) of the brain of Drosophila melanogaster, the fruit fly, in 1998, and just this year the equivalent desktop machine has now surpassed the network capabilities of the mouse. Kurzweil then goes on to predict that in roughly 2018, this $1,000 desktop computer will match the processing ability of a human brain. But he does not stop there. In 2070 or so, give or take a decade, this single machine will equal the processing capacity of all human beings on the planet!

Even more remarkable is the fact that these predictions have not taken into account the existence of the Internet. True, processing speeds and bandwidth remain limiting factors, but who could have ever predicted the extent to which the Internet has already enabled massive numbers of not just individual computers but human brains to network together. A striking example of this is what occurred in the spring of 2006 to Howard Kaloogian, candidate from the 50th congressional district in Southern California, who posted a picture on his Website that he claimed was a typical street scene in downtown Baghdad and that he cited as evidence that Iraq was much more calm and stable than what many people have been led to believe. All it took was a blogger to post the seemingly innocuous statement: “I am no photographic expert, but to me, this does not appear to be a photo of Baghdad (or even Iraq) at all.” The blogging network quickly sprang into action, and within hours and a few hundred postings, a group of ad hoc collaborators, drawing on expertise from throughout the world, was able to confirm, to the undoubted chagrin of Kaloogian and his staff, that the photo was actually of a street scene in the Istanbul suburb of Bakirkoy, and a blogger submitted a comparative photo as proof! (see http://www.dailykos.com/story/2006/3/28/152755/284 and http://www.dailykos.com/story/2006/3/29/11569/6885 for an extraordinary electronic dialogue).

The future impact of the linking together of millions and soon billions of nodal points of machines and human brains, each with their own unique strengths and perspectives, is incalculable. But there is no doubt that it will be a major, driving force behind the evolving nature of creativity within the domain of epilepsy research. In fact, there are a number of examples of these evolving networks that have sprung up just in the past year or so, and I will mention just a few.

The Epilepsy Microarray Consortium, which grew out of an NINDS-sponsored workshop on microarrays in 2002, is a collaborative effort led by Dr. Raymond Dingledine and involves seven institutions in the United States and Europe. The project aims to test the hypothesis that similar transcriptional events underlie epileptogenesis in diverse rat models. This effort is a response to Cure Benchmark I.A.3, which called for the establishment of a collaborative network that enables investigators to compare results of gene-chip analyses arising from different models of epileptogenesis and epilepsy.

Another example is the network of investigators in the United States and Europe brought together through an NINDS funding initiative aimed at advancing the development of models of epileptogenesis. Spearheaded by Jim Stables at NINDS, this effort is linked to Cure Benchmark I.C.1: “Design a strategy for validating models of epileptogenesis, and determine the efficacy of a limited number of proposed antiepileptic treatments in validated models of epileptogenesis.”

A third example comes from the studies on seizure detection and seizure prediction being carried out by Brian Litt and his colleagues at The University of Pennsylvania and collaborators elsewhere. The multidisciplinary nature of the group at Penn is truly extraordinary, and includes dozens of scientists with expertise in basic mechanisms of epilepsy, human electrophysiology, bioengineering, computational neuroscience, and statistics. Furthermore, they have partnered with colleagues in Europe and other parts of the world to create an international effort to tackle an exceedingly complex area of epilepsy research, but one that is certain to bring enormous benefit to people with epilepsy in the not so distant future.

The final example comes from the growing number of investigators who are focusing on the genetics of epilepsy. The initial completion of the human genome project at the turn of the century has provided us with the technology and tools to now begin to address the complex genetics of epilepsy, and at last count there were more than 20 teams of scientists around the world carrying out these sorts of large-scale studies. In 2002, a number of investigators in the United States met at the annual meeting at the AES to consider how we might work together to help advance work in this area further. Our motivation came in large part from the realization that the major obstacle in this next phase of genetics research would be in trying to characterize the phenotype of very large numbers of patients with epilepsy, a task that could not be accomplished by individual investigators or even single research groups. After a great deal of planning and organization, the Epilepsy Phenome/Genome Project, a large-scale study aimed at understanding the genetic factors underlying a specific set of human epilepsies, as well as the genetic factors influencing pharmacoresponsiveness, has been approved for funding by NINDS and is now underway. This effort involves 25 coinvestigators (and more than 50 other physicians, research nurses, informatics specialists, and others) based at 14 different institutions, and organized around the various scientific disciplines required for a study of this scale. The plan is to collect detailed phenotypic information and blood samples on 3,750 patients with epilepsy and 3,000 controls over the next 5 years. For more information on the project, see http://www.epgp.org/.

Importantly, none of these recent examples of multidisciplinary, translational, team-driven science, let alone the much larger number of single investigator-initiated projects, would be possible without the enormous support provided to the epilepsy research community by the NIH. As shown in Fig. 1, for the last three years the funding from NIH for epilepsy research has exceeded $100 million annually; this represents more than a 30% increase over the commitment in 2000. More than 85% of this funding comes from the NINDS alone. The long-term impact of this investment is incalculable, but there is no question that the NINDS remains the single most important resource in the world for advancing epilepsy research. For this reason, all of us must continue to work closely with the AES, the Epilepsy Foundation, and other organizations to publicize the impact that NINDS is having in improving the lives of people with epilepsy, and to advocate for even more funding of basic and clinical research.

image

Figure 1. Grant support for epilepsy research by the NINDS and other institutes within NIH between 2000 and 2006.

Download figure to PowerPoint

Conclusion

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

I began this piece with some of the stories that characterize the experience of living with epilepsy, and I admitted the sense of frustration that I feel in our inability to answer the most basic questions that our patients ask of us, and the current limits to therapy. The story of the two physicians emphasized the important role that all of us have in improving the lives of people living with epilepsy, but I hope it is clear that our only hope for the future is progress in understanding the fundamental nature of seizures and epilepsy, and translating these discoveries into therapies. The progress in epilepsy research over the last 100 years has been extraordinary, and with the exponential expansion in our ability to bring together scientists and clinicians from many disciplines and throughout the world, the progress to come over the coming decades is truly unimaginable.

So, despite the dissatisfaction that readers may share with me in our limited ability to reach the goal of “no seizures, no side effects” in many of our patients; despite the enormity of the knowledge gap in epilepsy; despite the limits in funding for science in our nation at this moment; and despite the seemingly endless work that needs to be done, it is worth reflecting, for a moment, on the true nature of the work in which we are involved, and what we will accomplish.

This perspective is conveyed well by a parable attributed to the Italian psychiatrist Roberto Assagioli, and which I learned from my colleague and dear friend Rachel Naomi Remen:

A traveler in the 14th century journeyed to a village where laborers were working at what appeared to be a huge building project, and he came across three stonecutters. He asked the first, “What are you doing?” to which the stonecutter replied bitterly, “What does it look like I'm doing? I'm cutting these huge boulders of granite into stones 1 cubit by 1 cubit by 3/4 cubit. It's the same work I've been doing for years, it pays for my food and a place to sleep, and I'll probably do this miserable work for the rest of my life.” The traveler went to the second stonecutter and asked, “What are you doing?” to which the stonecutter replied, “I am cutting this granite into blocks 1 cubit by 1 cubit by 3/4 cubit. It's hard work, but this is the way I earn a living for my family. The money I make buys clothes for my children and food so they can grow strong. And my wife and I enjoy a home filled with warmth and love.” And the traveler went to the third stonecutter and asked, “What are you doing?” to which the man replied joyously, “I am building a great cathedral. One that will stand for a thousand years, and will provide the people in my village and those living for hundreds of miles in the countryside a place to come and pray.”

And so it should be for all of us.

Acknowledgments

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References

Supported by NIH grant NS053998. The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this report is consistent with those guidelines. The author reports no conflicts of interest.

References

  1. Top of page
  2. The Person with Epilepsy
  3. Progress in Epilepsy Research
  4. Future Prospects in Epilepsy Research
  5. Conclusion
  6. Acknowledgments
  7. References
  • Ben-Ari Y, Tremblay E, Berger M, Nitecka L. (1984) Kainic acid seizure syndrome and binding sites in developing rats. Brain Res 316:284288.
  • Berger H. (1929) Über das elektroenkephalogramm des menschen. Archiv für Psychiatrie und Nervenkrankheiten 87:527570.
  • Bhagavan HN, Coursin DB, Stewart CN. (1971) Monosodium glutamate induces convulsive disorders in rats. Nature 232:275276.
  • Crandall PH, Walter RD, Rand RW. (1963) Clinical applications of studies on stereotactically implanted electrodes in temporal-lobe epilepsy. J Neurosurg 20:827840.
  • Cushing H. (1909) A note upon the faradic stimulation of the postcentral gyrus in conscious patients. Brain 32:4453.
  • Enomoto TF, Ajmone-Marsan C. (1959) Epileptic activation of single cortical neurons and their relationship with electroencephalographic discharges. Electroencephalogr Clin Neurophysiol Suppl 11:199218.
  • Gibbs F, Davis H, Lennox W. (1935) The EEG in epilepsy and in conditions of impaired consciousness. Arch Neurol Psychiatry 34:11341148.
  • Goddard GV. (1967) Development of epileptic seizures through brain stimulation at low intensity. Nature 214:10201021.
  • Hunt AD Jr, Stokes J Jr, Mc CW, Stroud HH. (1954) Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 13:140145.
  • Jacobs MP, Fischbach GD, Davis MR, Dichter MA, Dingledine R, Lowenstein DH, Morrell MJ, Noebels JL, Rogawski MA, Spencer SS, Theodore WH. (2001) Future directions for epilepsy research. Neurology 57:15361542.
  • Jasper H. (1941) Electroencephalography. In PenfieldW, EricksonT (Eds) Epilepsy and cerebral localization. Charles C. Thomas, Springfield , IL , pp. 380454.
  • Jasper H, Kershman J. (1941) Electroencephalographic classification of the epilepsies. Arch Neurol Psychiatry 45:903943.
  • Kurzweil R. (1999) The age of spiritual machines. Viking/Penguin Books, New York .
  • Lennox W. (1941) Science and seizures: new light on epilepsy and migraine. Harper, New York .
  • Lennox W. (1947) Sixty-six twin pairs affected by seizures. Res Publ Assoc Res Nerv Ment Dis 26:1134.
  • Leppert M, Anderson V, Quattlebaum T, Stauffer D, O'Connel P, Nakamura Y, Lalouel J, White R. (1989) Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337:647648.
  • Matsumoto J, Ajmone-Marsan C. (1964) Cortical cellular phenomena in experimental epilepsy: interictal manifestations. Exp Neurol 9:286304.
  • Meldrum B, Brierley J. (1973) Prolonged epileptic seizures in primates: ischemic cell change and its relation to ictal physiological events. Arch Neurol 28:1017.
  • Morris A. (1950) The surgical treatment of psychomotor epilepsy. Med Ann Dist Col 19:121131.
  • Moshe SL, Albala BJ, Ackermann RF, Engel J, Jr. (1983) Increased seizure susceptibility of the immature brain. Brain Res 283:8185.
  • Nelson K, Ellenberg J. (1976) Predictors of epilepsy in children who have experienced febrile seizures. N Eng J Med 295:10291033.
  • Noebels JL, Sidman RL. (1979) Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204:13341336.
  • Noebels JL. (2006) The Judith Hoyer Lecture: genes, pixels, patterns, and prevention. Epilepsy Behav 9:379385.
  • Olney JW, Rhee V, Ho OL. (1974) Kainic acid: a powerful neurotoxic analogue of glutamate. Brain Res 77:507512.
  • Penfield W, Flanigin H. (1950) Surgical treatment of temporal lobe seizures. Arch Neurol Psychiatry 64:491500.
  • Putnam T, Merritt H. (1937) Experimental determination of the anticonvulsant properties of some phenyl derivatives 85:525526.
  • United States. (1977) Plan for nationwide action on epilepsy. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda .
  • Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Scheffer IE, Berkovic SF. (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 11:201203.
  • Sutula TP. (2005) Epilepsy after the decade of the brain: misunderstandings, challenges, and opportunities. Epilepsy Behav 6:296302.
  • Yamamoto C. (1972) Intracellular study of seizure-like afterdischarges elicited in thin hippocampal sections in vitro. Exp Neurol 35:154164.