Epilepsy Research: Its Scope and Challenge

What kinds of things are being studied?
Research related to epilepsy is remarkably broad and comprehensive, with programs in numerous university centers worldwide. Ongoing studies involve many scientific disciplines and areas of exploration. For example, neuroscientists study seizure-like activity of cells in a culture dish. Neurologists, radiologists, and physicists investigate new ways to view brain function in animals and humans. Nurses and physicians test experimental treatments for epilepsy.

Why is it so hard to find answers?
Research into epilepsy is especially challenging. The complexity of the brain limits our understanding of normal brain function, let alone how brain disturbances lead to epilepsy. To complicate matters further, the many different types of epilepsy have unique causes and consequences. This is because seizures, the defining symptom of epilepsy, may result from many different forms of abnormal brain function. Because there are literally hundreds of ways to induce seizures in the uninjured brain, figuring out the precise mechanisms in any specific form of epilepsy is a formidable undertaking.

The many ways in which seizures can be produced also creates challenges for developing experimental models to study the different epilepsies. How can researchers be sure that the brain disturbance causing seizures in an animal being studied is the same kind of disturbance as in humans with a particular form of epilepsy? Despite the difficulty, however, research into epilepsy (and into nervous system function in general) has progressed at an astonishing pace over the past few decades.

What are laboratory scientists working on?
Laboratory research (so-called basic science) aims to answer many questions related to epilepsy. Currently, we do not understand how an injury to the brain, a defect in brain development, or a genetic abnormality leads to a specific form of epilepsy. In addition to studies of how specific changes in the brain eventually produce epilepsy (a process known as epileptogenesis), related investigations in many laboratories are directed at understanding how brief or prolonged seizures directly alter brain function. These include changes in gene expression, "rewiring" of brain connections, and the death or birth of specific brain cells. In terms of seizures themselves, researchers are studying how they start, spread, and stop; why certain types of seizures occur at specific ages or in response to distinct stimuli; and how antiepileptic medications work on brain cells to block seizures.

To investigate these questions, scientists rely on many different animal models of epilepsy. That is, they study laboratory animals with spontaneous or provoked seizures to gain insight into the mechanisms underlying epilepsy in humans. Seizures involve interactions and connections between many brain areas. Therefore, mammals with intact nervous system function are typically more useful for studies of acute seizures or epileptogenesis than are experiments on cells grown in Petri dishes. Most animal studies use rodents (mainly rats and mice) because they are easy to work with, relatively inexpensive, and possess brain structures and responses to injury that are sufficiently similar to humans to allow useful conclusions to be drawn.

What are clinical researchers working on?
Clinical research involves scientific studies of people-both healthy ones and those with medical disorders. Clinical research related to epilepsy concentrates on the causes, diagnosis, and treatment of the different forms of epileptic disorders. The testing of new antiepileptic medications comprises a large portion of clinical epilepsy studies. Non-medicinal therapies are also being investigated, including new forms of brain surgery and methods of electrical brain stimulation.

Brain imaging: Tools for viewing the structure and functioning of the brain ("neuroimaging"), such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET), are playing a rapidly expanding role in epilepsy diagnosis. Researchers are using these imaging tools in combination with electroencephalography (EEG) to improve the detection of brain abnormalities and to more precisely determine the locations where seizures begin.

Genetics and brain development: Many recent advances in understanding the causes of certain epilepsies have arisen from research into human genetics. Through these studies, we now appreciate the importance of heredity for many different types of epilepsy. Moreover, intensive studies of large families in which epilepsy is passed on for several generations have recently revealed the first "epilepsy genes." These genes have mutations (inherited or spontaneous changes in the DNA sequence or genetic code) that lead to seizure development. Some of these gene mutations also cause the brain to form abnormally. Research into brain development is particularly relevant to the epilepsies because seizure disorders often begin in childhood. As the technology used to diagnose epilepsy is improving, abnormalities of brain development are being found more often, even in people whose epilepsy does not begin until early adulthood.

Other current areas of interest in clinical epilepsy research include the study of electrical or magnetic brain waves (neurophysiology), neuropsychological research into localizing brain function and understanding how it is disturbed by seizures, and investigations of the interactions between epilepsy and functions such as sleep or hormonal cycles.

How do basic science and clinical research complement one another?
The main research questions related to epilepsy, such as understanding how brain injuries cause epilepsy or developing new treatments, will likely take a great deal of time and effort to answer. In the era we are entering, however, the potential for rapid research progress leading to better clinical care is unprecedented. Our expectations have been (and should be) raised because of scientific advances in medicine and biology. Scientific findings in the laboratory are now being applied more and more rapidly to patients with neurological disorders. This is made possible by our ability to combine basic science and clinical research.

Let's consider the "ion channel story" as an example. Ion channels are molecules on the surface of brain cells that control neural activity. A gene for one of these channels has been found to cause epilepsy in a certain strain of mice, which has seizures resembling human staring spells (as in absence seizures). Researchers studying human families with inherited epilepsy have searched for and found mutations in the same gene in some of these families. Other families with the same type of epilepsy do not have this mutation. However, scientists have found a mutation involving a related type of ion channel on a different chromosome in several of these families. To better understand how this gene mutation affects brain cell function, scientists developed a mouse strain that carries the human gene mutation. The laboratory researchers are now able to study these mice and find out how brain cell excitability is altered-in other words, how the mutation leads to epilepsy.

This scenario sounds as though it may be far into the future, but in fact it is already evolving in many labs around the world, where work is under way to unravel several different epilepsy genes. Other causes of epilepsy are also being studied. Thus, laboratory and clinical research into epilepsy build upon one another. Both types of work are necessary if we are to understand how the brain functions normally, how epilepsy develops, and how epilepsy can be prevented or cured.

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