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Epilepsy
Neurobiology of Disease 7, 549 –551 (2000) doi:10.1006/nbdi.2000.0353, available online at http://www.idealibrary.com on
Epilepsy Graham V. Lees and Edward G. Jones Adapted from a Presentation by James McNamara Epilepsy Research Laboratory, Department of Medicine, Duke University Medical Center, 401 Bryan Research Building, Box 3676, Research Drive, Durham, North Carolina 27710
Epilepsy, a brain disorder manifest by recurrent seizures, refers to a complicated constellation of more than 40 distinct disorders. The word epilepsy stems from the Greek word epilambanien meaning “to seize hold of or to attack.” The severity can range from mild episodic attention loss and drowsiness to severe convulsions, associated with a loss of consciousness. Epilepsy affects more than 1% of the population worldwide. In America alone, two and a half million people at any point in time are afflicted with this devastating disease. Ten percent of all Americans, numbering 25 million people, experience a seizure at least once in a lifetime. The annual cost to this country of treating this disorder is in excess of $12 billion. What causes epilepsy? Epilepsy has been termed the sacred disease, in part because as far back as nearly 2000 years ago, possession of evil spirits was thought to be the cause of the disease. Of course, we no longer attribute epilepsy to evil spirits. Scientists have determined that the cause of an epileptic seizure is a misfiring of neurons in the brain. When the normal energy flow between neurons in the brain is disrupted in any way, the brain malfunctions. The effect is similar to an electrical storm, which can “short out” the power to an entire city. An epileptic seizure effectively short-circuits the brain so that it cannot interpret visual, auditory, and sensory signals. Nor can the brain control the muscles. Thus, an epileptic seizure can cause a person to fall down, convulse, and lose consciousness. Epilepsy can arise at any age. While the exact percentage of causal attributes is unknown, it is clear to clinicians that substantial portions of epileptic cases have strong genetic determinants. Another leading cause arises as a consequence of brain injury. These brain traumas most commonly include stroke or head injury following a motor vehicle accident. Progress in understanding the mechanisms of epilepsy during this Decade of the Brain has been astounding. 0969-9961/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
One example lies in the genetics of epilepsy. Not a single gene had been linked to the disease a decade ago. Now researchers have found more than 40 genes that cause epilepsy in mice or humans! There is great diversity within these 40 genes. It is thought that a large portion of the human epilepsies comprises disorders in which the inheritance of two or three susceptibility genes in the same individual is required to produce epilepsy. However, the human epilepsies also include some rare forms in which the mutation of a single gene may occur in just a few families in the entire world. The identification of these genes, which cause the rarer forms of epilepsy, can provide powerful clues to novel antiseizure drug mechanisms and, thus, new forms of effective antiseizure drugs. In other words, the protein coded by the mutant gene can suggest new molecules to be targeted by the antiseizure drugs. These drugs might regulate the structure and function of the molecule to have antiseizure effects. Conversely, as will be explained further, understanding the mechanism by which these drugs act may in turn provide a clue to decoding the epilepsy genes. Even in individuals known to be at a high risk for developing epilepsy, there is currently no effective method of preventing the development of the disease. In addition, once individuals become afflicted with epilepsy, doctors have no way of curing the disease. Rather, current therapies are entirely symptomatic, analogous to the treatment of diabetes with insulin. Like the diabetic, the epileptic can take drugs that inhibit the symptoms of the disease, in this case seizures, but these drugs cannot abolish the problem entirely. There are approximately a dozen drugs in clinical use to inhibit seizures. They fall into three different categories in terms of their targets. Most commonly, the drugs affect the flow of sodium into the cell via voltage-gated sodium ion channels. A sodium ion
549
550 channel is a structure in the cell membrane that is selectively permeable to sodium ions and is opened by changes in voltage across the call membrane. Others affect calcium flow via voltage gated calcium ion channels. The third category of drugs affects some aspect of inhibitory synapses that are activated by the neurotransmitter ␥-aminobutyric acid (GABA). Despite the availability of these dozen or so drugs, at least 25% of patients continue to have seizures. Furthermore, among those in whom seizures are effectively inhibited, substantial numbers experience persistent and undesirable effects from these drugs. In light of this, the current goal of researchers is to identify new classes of antiseizure drugs that act on novel molecular targets and by novel mechanisms that may permit effective treatment of large numbers of individuals unsatisfactorily treated at present. Furthermore, identifying novel epilepsy genes may help identify novel targets. The way in which scientists have discovered new drugs that treat epilepsy owes largely to luck. In the early 1900s, phenobarbital had been synthesized and was being used as a sedative for patients with psychiatric disease. It was serendipitously found to inhibit seizures in those patients who had epilepsy as well as the psychiatric disease being treated. This in turn prompted chemists to modify the structure of phenobarbital. Researchers then used animal models to test these various chemicals that had been synthesized by the organic chemists. About 20 years later, they discovered that phenytoin, a derivative, inhibited electroshock seizures in experimental animals. This led to its use in clinical treatment of epileptic patients. It was not until nearly 50 years later that a group of scientists discovered exactly how phenytoin acts to inhibit a seizure. How does phenytoin inhibit a seizure? Understanding the behavior of a neuron during a seizure provides some useful background to answering this question. Between seizures, neurons fire only once in a relatively brief amount of time. However, during occurrence of the seizure, recordings reveal that the neuron undergoes a strong depolarization and begins to fire at a very high frequency. This pattern of distinctive, high frequency firing differs drastically from the firing of a neuron performing normal brain functions. The dichotomy between the pattern of firing observed very commonly during seizures and uncommonly between seizures can begin to explain how some antiseizure drugs can be selected. The aim is to inhibit high frequency firing but not low-frequency firing to provide a means of more selectively targeting seizure activity. Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
McNamara, Lees, and Jones
Researchers took this information to the laboratory where they applied it directly to a neuron taken from an animal model and placed in a Petri dish. This method gave them optimal control of all of the variables, such as drug concentration. Now that the researchers understood the high-frequency firing pattern of the neuron during a seizure, they could then replicate it artificially by inserting an electrode into the neuron and passing current through it to activate the cell. Despite the passage of a steady current the neuron slowed its frequency discharge and actually stopped firing completely. However, when the drug phenytoin was administered, the neuron slowed its firing frequency much more rapidly. The drug acted specifically on the high-frequency firing, not the low frequency firing. To further explore this theory, researchers used a control neuron, into which they sent a low current, causing the neuron to fire once. Then they increased the current, causing the neuron to fire rapidly, as in a seizure. When they administered phenytoin and repeated the process, the neuron again fired once during the low current. However, during the high-current application, the drug inhibited the rapid firing of that neuron. The drug permitted the normal low-frequency firing, but inhibited the abnormal seizure high-frequency firing. The selective inhibition of the high frequency firing provided a very convenient way of selectively targeting the seizure behavior of a neuron. Phenytoin selectively slows the high frequency firing by acting on a sodium channel. It promotes the stabilization of this sodium channel in a configuration termed “inactivated.” In other words, once the firing of the neuron activates the channel, as in a seizure, the drug encourages the channel to inactivate, thereby stopping the seizure before it starts. It was mentioned earlier that understanding the molecule targeted by the antiseizure drug and the mechanism by which the drug acts on that molecule to limit seizures supplies a candidate mechanism for one of the epilepsy genes. In a way, antiseizure drugs act as detectives because their mechanism of action, i.e., promoting inactivation of a voltage-gated sodium ion channel, predicts the existence of epilepsy genes that must encode for a defective sodium channel. Better still, if the type of epilepsy stems from a rare mutant single gene, then the detective work is all the easier. One such rare mutant gene was discovered in Melbourne, Australia. The type of epilepsy was named “generalized epilepsy with febrile seizures plus.” In this rare form of epilepsy, the affected patients uniformly exhibit febrile seizures. Febrile seizures com-
Epilepsy
FIG. 1. Pie chart demonstrating the proportion of epilepsy genes identified to date as compared with the amount suspected.
monly affect only infants and young children. (Roughly 3% of all children exhibit febrile seizures.) Furthermore, these individuals not only experience febrile seizures, but also grand mal, or tonic– clonic seizures and a host of other forms ranging in severity. This disease is inherited in an autosomal dominant pattern. Because the gene is so specific, these researchers were able to identify it and found it to be a subunit of a voltage-gated sodium ion channel. They affirmed, through research in vitro, that this subunit of the defective gene resulted in defective inactivation of a
551 sodium ion channel. Oddly enough, if researchers had not fortuitously discovered the antiseizure drugs 40 years ago, the discovery of this “epilepsy gene” would trigger a search for drugs that promoted inactivation of a sodium channel. The recent identification of mutant genes underlying two other forms of human epilepsy provides attractive molecular targets for the development of antiseizure drugs with novel mechanisms. One such discovery is of mutant genes that underlie a rare form of seizures affecting newborn infants called “benign familial neonatal convulsions.” This form of epilepsy effects individuals on roughly the third day of life. The seizures typically remit by the third month of life. In approximately 10 to 15% of these cases, the seizures recur later in life. The second discovery is of a mutant gene that encodes for an ion channel activated by the neurotransmitter acetylcholine. This strain of epilepsy shows itself in adolescents and adults. These unfortunate experiments of nature suggest promising new molecular targets for development of antiseizure drugs that may benefit large numbers of patients suffering from epilepsy. Another challenge for the next decade will be the identification of additional epilepsy genes (Fig. 1). It is especially exciting because the theory and techniques to find these genes are already in place. If identified, genes will become powerful tools to direct development of novel and effective therapies for the sacred disease.
Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
Epilepsy Graham V. Lees and Edward G. Jones Adapted from a Presentation by James McNamara Epilepsy Research Laboratory, Department of Medicine, Duke University Medical Center, 401 Bryan Research Building, Box 3676, Research Drive, Durham, North Carolina 27710
Epilepsy, a brain disorder manifest by recurrent seizures, refers to a complicated constellation of more than 40 distinct disorders. The word epilepsy stems from the Greek word epilambanien meaning “to seize hold of or to attack.” The severity can range from mild episodic attention loss and drowsiness to severe convulsions, associated with a loss of consciousness. Epilepsy affects more than 1% of the population worldwide. In America alone, two and a half million people at any point in time are afflicted with this devastating disease. Ten percent of all Americans, numbering 25 million people, experience a seizure at least once in a lifetime. The annual cost to this country of treating this disorder is in excess of $12 billion. What causes epilepsy? Epilepsy has been termed the sacred disease, in part because as far back as nearly 2000 years ago, possession of evil spirits was thought to be the cause of the disease. Of course, we no longer attribute epilepsy to evil spirits. Scientists have determined that the cause of an epileptic seizure is a misfiring of neurons in the brain. When the normal energy flow between neurons in the brain is disrupted in any way, the brain malfunctions. The effect is similar to an electrical storm, which can “short out” the power to an entire city. An epileptic seizure effectively short-circuits the brain so that it cannot interpret visual, auditory, and sensory signals. Nor can the brain control the muscles. Thus, an epileptic seizure can cause a person to fall down, convulse, and lose consciousness. Epilepsy can arise at any age. While the exact percentage of causal attributes is unknown, it is clear to clinicians that substantial portions of epileptic cases have strong genetic determinants. Another leading cause arises as a consequence of brain injury. These brain traumas most commonly include stroke or head injury following a motor vehicle accident. Progress in understanding the mechanisms of epilepsy during this Decade of the Brain has been astounding. 0969-9961/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
One example lies in the genetics of epilepsy. Not a single gene had been linked to the disease a decade ago. Now researchers have found more than 40 genes that cause epilepsy in mice or humans! There is great diversity within these 40 genes. It is thought that a large portion of the human epilepsies comprises disorders in which the inheritance of two or three susceptibility genes in the same individual is required to produce epilepsy. However, the human epilepsies also include some rare forms in which the mutation of a single gene may occur in just a few families in the entire world. The identification of these genes, which cause the rarer forms of epilepsy, can provide powerful clues to novel antiseizure drug mechanisms and, thus, new forms of effective antiseizure drugs. In other words, the protein coded by the mutant gene can suggest new molecules to be targeted by the antiseizure drugs. These drugs might regulate the structure and function of the molecule to have antiseizure effects. Conversely, as will be explained further, understanding the mechanism by which these drugs act may in turn provide a clue to decoding the epilepsy genes. Even in individuals known to be at a high risk for developing epilepsy, there is currently no effective method of preventing the development of the disease. In addition, once individuals become afflicted with epilepsy, doctors have no way of curing the disease. Rather, current therapies are entirely symptomatic, analogous to the treatment of diabetes with insulin. Like the diabetic, the epileptic can take drugs that inhibit the symptoms of the disease, in this case seizures, but these drugs cannot abolish the problem entirely. There are approximately a dozen drugs in clinical use to inhibit seizures. They fall into three different categories in terms of their targets. Most commonly, the drugs affect the flow of sodium into the cell via voltage-gated sodium ion channels. A sodium ion
549
550 channel is a structure in the cell membrane that is selectively permeable to sodium ions and is opened by changes in voltage across the call membrane. Others affect calcium flow via voltage gated calcium ion channels. The third category of drugs affects some aspect of inhibitory synapses that are activated by the neurotransmitter ␥-aminobutyric acid (GABA). Despite the availability of these dozen or so drugs, at least 25% of patients continue to have seizures. Furthermore, among those in whom seizures are effectively inhibited, substantial numbers experience persistent and undesirable effects from these drugs. In light of this, the current goal of researchers is to identify new classes of antiseizure drugs that act on novel molecular targets and by novel mechanisms that may permit effective treatment of large numbers of individuals unsatisfactorily treated at present. Furthermore, identifying novel epilepsy genes may help identify novel targets. The way in which scientists have discovered new drugs that treat epilepsy owes largely to luck. In the early 1900s, phenobarbital had been synthesized and was being used as a sedative for patients with psychiatric disease. It was serendipitously found to inhibit seizures in those patients who had epilepsy as well as the psychiatric disease being treated. This in turn prompted chemists to modify the structure of phenobarbital. Researchers then used animal models to test these various chemicals that had been synthesized by the organic chemists. About 20 years later, they discovered that phenytoin, a derivative, inhibited electroshock seizures in experimental animals. This led to its use in clinical treatment of epileptic patients. It was not until nearly 50 years later that a group of scientists discovered exactly how phenytoin acts to inhibit a seizure. How does phenytoin inhibit a seizure? Understanding the behavior of a neuron during a seizure provides some useful background to answering this question. Between seizures, neurons fire only once in a relatively brief amount of time. However, during occurrence of the seizure, recordings reveal that the neuron undergoes a strong depolarization and begins to fire at a very high frequency. This pattern of distinctive, high frequency firing differs drastically from the firing of a neuron performing normal brain functions. The dichotomy between the pattern of firing observed very commonly during seizures and uncommonly between seizures can begin to explain how some antiseizure drugs can be selected. The aim is to inhibit high frequency firing but not low-frequency firing to provide a means of more selectively targeting seizure activity. Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
McNamara, Lees, and Jones
Researchers took this information to the laboratory where they applied it directly to a neuron taken from an animal model and placed in a Petri dish. This method gave them optimal control of all of the variables, such as drug concentration. Now that the researchers understood the high-frequency firing pattern of the neuron during a seizure, they could then replicate it artificially by inserting an electrode into the neuron and passing current through it to activate the cell. Despite the passage of a steady current the neuron slowed its frequency discharge and actually stopped firing completely. However, when the drug phenytoin was administered, the neuron slowed its firing frequency much more rapidly. The drug acted specifically on the high-frequency firing, not the low frequency firing. To further explore this theory, researchers used a control neuron, into which they sent a low current, causing the neuron to fire once. Then they increased the current, causing the neuron to fire rapidly, as in a seizure. When they administered phenytoin and repeated the process, the neuron again fired once during the low current. However, during the high-current application, the drug inhibited the rapid firing of that neuron. The drug permitted the normal low-frequency firing, but inhibited the abnormal seizure high-frequency firing. The selective inhibition of the high frequency firing provided a very convenient way of selectively targeting the seizure behavior of a neuron. Phenytoin selectively slows the high frequency firing by acting on a sodium channel. It promotes the stabilization of this sodium channel in a configuration termed “inactivated.” In other words, once the firing of the neuron activates the channel, as in a seizure, the drug encourages the channel to inactivate, thereby stopping the seizure before it starts. It was mentioned earlier that understanding the molecule targeted by the antiseizure drug and the mechanism by which the drug acts on that molecule to limit seizures supplies a candidate mechanism for one of the epilepsy genes. In a way, antiseizure drugs act as detectives because their mechanism of action, i.e., promoting inactivation of a voltage-gated sodium ion channel, predicts the existence of epilepsy genes that must encode for a defective sodium channel. Better still, if the type of epilepsy stems from a rare mutant single gene, then the detective work is all the easier. One such rare mutant gene was discovered in Melbourne, Australia. The type of epilepsy was named “generalized epilepsy with febrile seizures plus.” In this rare form of epilepsy, the affected patients uniformly exhibit febrile seizures. Febrile seizures com-
Epilepsy
FIG. 1. Pie chart demonstrating the proportion of epilepsy genes identified to date as compared with the amount suspected.
monly affect only infants and young children. (Roughly 3% of all children exhibit febrile seizures.) Furthermore, these individuals not only experience febrile seizures, but also grand mal, or tonic– clonic seizures and a host of other forms ranging in severity. This disease is inherited in an autosomal dominant pattern. Because the gene is so specific, these researchers were able to identify it and found it to be a subunit of a voltage-gated sodium ion channel. They affirmed, through research in vitro, that this subunit of the defective gene resulted in defective inactivation of a
551 sodium ion channel. Oddly enough, if researchers had not fortuitously discovered the antiseizure drugs 40 years ago, the discovery of this “epilepsy gene” would trigger a search for drugs that promoted inactivation of a sodium channel. The recent identification of mutant genes underlying two other forms of human epilepsy provides attractive molecular targets for the development of antiseizure drugs with novel mechanisms. One such discovery is of mutant genes that underlie a rare form of seizures affecting newborn infants called “benign familial neonatal convulsions.” This form of epilepsy effects individuals on roughly the third day of life. The seizures typically remit by the third month of life. In approximately 10 to 15% of these cases, the seizures recur later in life. The second discovery is of a mutant gene that encodes for an ion channel activated by the neurotransmitter acetylcholine. This strain of epilepsy shows itself in adolescents and adults. These unfortunate experiments of nature suggest promising new molecular targets for development of antiseizure drugs that may benefit large numbers of patients suffering from epilepsy. Another challenge for the next decade will be the identification of additional epilepsy genes (Fig. 1). It is especially exciting because the theory and techniques to find these genes are already in place. If identified, genes will become powerful tools to direct development of novel and effective therapies for the sacred disease.
Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.