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Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.
Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.
Vijay M. Thadani,
Dr. Thadani is Professor of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He reports no conflict of interest.
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of epilepsy care and research. Epilepsy is a disease whose earliest descriptions date back to Egypt and Mesopotamia 3,000 years ago. A modern understanding of epilepsy as an electrical disorder of the brain dates back perhaps 150 years. The last 25 years have seen considerable progress in diagnosis and treatment, but in the Western world, the prevalence of epilepsy has held steady at around 1%, and a quarter of those patients have seizures that are not controlled, in spite of appropriate therapy.
While generalized and focal seizures remain the cornerstones of classification, the most recent theoretical advance is the network concept of epilepsy. By definition, a network must have nodes and connections. In generalized forms of epilepsy, these are recognized to be diffuse groupings of neurons and the fiber tracts that connect them. They are widely distributed and conducive to the rapid and bilateral spread of electrical abnormalities throughout the brain. In focal epilepsies, the abnormal electrical activity in the network is more constrained by traditional anatomic landmarks, but this does not preclude the possibility of secondary generalization. The elucidation of such networks by intracranial EEG and fMRI studies is a major triumph of the last 25 years.
All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
Looking Ahead
As they say, it is difficult to make predictions, especially about the future, but one can anticipate not only the identification of more gene mutations that cause epilepsy, but their correction with CRISPR/Cas9 and related technologies. Likewise, we can anticipate new antiepileptic drugs, but whether they will be broad-spectrum blockbusters like the cannabis derivatives are thought to be, or designer molecules tailored to specific types of seizures and epilepsy remains to be seen. In tuberous sclerosis, for example, drugs like tacrolimus that inhibit the mTOR pathway not only suppress abnormal cell proliferation, but also help with seizure control. Likewise, a small minority of epilepsies, now recognized to be autoimmune, will be treated with targeted immune suppression. A major goal is the discovery of drugs that will prevent the development of epilepsy or cure it in its early stages, as opposed to merely controlling the seizures.
Imaging of epileptic foci and networks of seizure spread will continue to improve with higher field strength MRI scans. EEG, MRI, and fMRI will probably coalesce, and PET scans will play a larger role. Combined images will guide epilepsy surgeons with regard to the boundaries of resections. The nature of EEG recording will also change. Until recently, owing to the properties of available amplifiers, we have looked at electrical oscillations between 1 Hz and 70 Hz. However, much higher frequencies are increasingly recognized as important in defining the epileptogenic zone and network. Epilepsy surgery that takes high-frequency oscillations into account will optimize the removal of epileptogenic lesions and the disruption of epileptic networks, while minimizing injury to normal brain functions.
Resective surgery may itself be rendered obsolete by cerebral stimulation, now in its infancy. Implanted devices such as Neuropace have shown promise in detecting seizures and delivering a counter-shock to abort them. Biologic stimulation is also on the horizon. In animal models, transplantation of GABA-producing cells has cured epilepsy, and optogenetic techniques may soon make it possible to activate particular classes of neurons that can turn off epileptic activity.
One can also anticipate a shift in treatment away from the exclusive emphasis on seizure control. We increasingly recognize that epilepsy is much more than seizures, and that patients with epilepsy may also have depression, impaired memory, and anxiety related to their illness. In the long run, the psychosocial problems of patients with epilepsy cannot be separated from social problems as a whole. Will, for example, the new, and doubtless expensive, treatments for epilepsy be made available to all who need them, or will we be obliged to work in a two-tier system? As health care providers, we can be cautiously optimistic regarding the medical aspects of epilepsy, but we will have to think in quite unanticipated ways to ensure equitable outcomes.