Epilepsy & Seizures

An analysis of health care expenditures faced by elderly patients with epilepsy over a 12-year period in the United States found rising annual costs over time that approached a mean of $20,000, according to researchers from the Medical University of South Carolina, Charleston.

Alain Lekoubou, MD, and his colleagues estimated health care expenditures during 2003-2014 for patients aged 65 years and older with and without epilepsy by extrapolating data from the Medical Expenditure Panel Survey Household Component to more than 37 million elderly individuals in the United States. The investigators published their findings in Epilepsia.

Thinkstock Photos

[email protected]

SOURCE: Lekoubou A et al. Epilepsia. 2018 June 19. doi: 10.1111/epi.14455.

An analysis of health care expenditures faced by elderly patients with epilepsy over a 12-year period in the United States found rising annual costs over time that approached a mean of $20,000, according to researchers from the Medical University of South Carolina, Charleston.

Alain Lekoubou, MD, and his colleagues estimated health care expenditures during 2003-2014 for patients aged 65 years and older with and without epilepsy by extrapolating data from the Medical Expenditure Panel Survey Household Component to more than 37 million elderly individuals in the United States. The investigators published their findings in Epilepsia.

Thinkstock Photos

[email protected]

SOURCE: Lekoubou A et al. Epilepsia. 2018 June 19. doi: 10.1111/epi.14455.

An analysis of health care expenditures faced by elderly patients with epilepsy over a 12-year period in the United States found rising annual costs over time that approached a mean of $20,000, according to researchers from the Medical University of South Carolina, Charleston.

Alain Lekoubou, MD, and his colleagues estimated health care expenditures during 2003-2014 for patients aged 65 years and older with and without epilepsy by extrapolating data from the Medical Expenditure Panel Survey Household Component to more than 37 million elderly individuals in the United States. The investigators published their findings in Epilepsia.

Thinkstock Photos

[email protected]

SOURCE: Lekoubou A et al. Epilepsia. 2018 June 19. doi: 10.1111/epi.14455.

Click here to read Neurology Board Review: Epilepsy

Neurology Board Review: Epilepsy is a resource developed by leading clinical educators for studying for board certification and maintenance of certification exams.

After reading the article, Click Here to Access the Board Review Questions

About the Authors

Shavonne L. Massey, MD
Clinical Instructor
Departments of Neurology and Pediatrics
Children’s Hospital of Philadelphia
University of Pennsylvania
Philadelphia, Pennsylvania

Hannah C. Glass, MDCM, MAS
Associate Professor
Departments of Neurology, Pediatrics, and
Epidemiology & Biostatistics
University of California, San Francisco
San Francisco, California

Click here to read Neurology Board Review: Epilepsy

After reading the article, Click Here to Access the Board Review Questions

Click here to read Neurology Board Review: Epilepsy

Neurology Board Review: Epilepsy is a resource developed by leading clinical educators for studying for board certification and maintenance of certification exams.

After reading the article, Click Here to Access the Board Review Questions

About the Authors

Shavonne L. Massey, MD
Clinical Instructor
Departments of Neurology and Pediatrics
Children’s Hospital of Philadelphia
University of Pennsylvania
Philadelphia, Pennsylvania

Hannah C. Glass, MDCM, MAS
Associate Professor
Departments of Neurology, Pediatrics, and
Epidemiology & Biostatistics
University of California, San Francisco
San Francisco, California

Click here to read Neurology Board Review: Epilepsy

After reading the article, Click Here to Access the Board Review Questions

Click here to read Neurology Board Review: Epilepsy

Neurology Board Review: Epilepsy is a resource developed by leading clinical educators for studying for board certification and maintenance of certification exams.

After reading the article, Click Here to Access the Board Review Questions

About the Authors

Shavonne L. Massey, MD
Clinical Instructor
Departments of Neurology and Pediatrics
Children’s Hospital of Philadelphia
University of Pennsylvania
Philadelphia, Pennsylvania

Hannah C. Glass, MDCM, MAS
Associate Professor
Departments of Neurology, Pediatrics, and
Epidemiology & Biostatistics
University of California, San Francisco
San Francisco, California

Click here to read Neurology Board Review: Epilepsy

After reading the article, Click Here to Access the Board Review Questions

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.

MALMO, SWEDEN – Children who experience a febrile seizure in conjunction with a vaccination have developmental outcomes comparable with those of children who have non–vaccine-related febrile seizures and healthy controls who’ve never had a febrile seizure, according to the first prospective case-control cohort study to examine the issue.

This finding has important implications for clinical practice, Lucy Deng, MD, observed at the annual meeting of the European Society for Paediatric Infectious Diseases.

“Febrile seizures associated with a vaccine can decrease parent and provider confidence in vaccine safety,” the pediatrician noted. Based upon her study results, however, physicians now can offer a truly evidence-based message of reassurance.

Bruce Jancin/MDedge News

[email protected]

MALMO, SWEDEN – Children who experience a febrile seizure in conjunction with a vaccination have developmental outcomes comparable with those of children who have non–vaccine-related febrile seizures and healthy controls who’ve never had a febrile seizure, according to the first prospective case-control cohort study to examine the issue.

This finding has important implications for clinical practice, Lucy Deng, MD, observed at the annual meeting of the European Society for Paediatric Infectious Diseases.

“Febrile seizures associated with a vaccine can decrease parent and provider confidence in vaccine safety,” the pediatrician noted. Based upon her study results, however, physicians now can offer a truly evidence-based message of reassurance.

Bruce Jancin/MDedge News

[email protected]

MALMO, SWEDEN – Children who experience a febrile seizure in conjunction with a vaccination have developmental outcomes comparable with those of children who have non–vaccine-related febrile seizures and healthy controls who’ve never had a febrile seizure, according to the first prospective case-control cohort study to examine the issue.

This finding has important implications for clinical practice, Lucy Deng, MD, observed at the annual meeting of the European Society for Paediatric Infectious Diseases.

“Febrile seizures associated with a vaccine can decrease parent and provider confidence in vaccine safety,” the pediatrician noted. Based upon her study results, however, physicians now can offer a truly evidence-based message of reassurance.

Bruce Jancin/MDedge News

[email protected]

Vijay M. Thadani, MD, PhD

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, MD, PhD

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, MD, PhD

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.

LOS ANGELES—Among patients with intractable focal epilepsy who have failed one or more epilepsy surgeries, reoperation may provide long-term seizure control, according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Patients with prior epilepsy surgery are less likely to achieve seizure freedom, however, compared with patients undergoing initial epilepsy surgery, the researchers said.

“It is possible to achieve long-term seizure control in patients with failed prior epilepsy surgery,” said Ruta Yardi, MD, a researcher at the Cleveland Clinic, and colleagues. “A lesional MRI, specific prior postoperative pathology, and fewer prior resections seem to predict better outcomes.” These results may be helpful in identifying candidates for reoperation, the investigators said.

Epilepsy surgery is the most effective treatment option for patients with medically refractory focal epilepsy, but initial surgeries may not be successful, Dr. Yardi and colleagues said. A small percentage of patients who do not benefit from a first surgery may be evaluated for another resection. Data for how outcomes vary with successive surgeries are limited, however, the researchers said.

To assess longitudinal seizure outcomes following reoperations in patients with intractable focal epilepsy and identify prognostic factors that influence these outcomes, Dr. Yardi and colleagues retrospectively studied 898 patients (448 female; about a third pediatric) who underwent epilepsy surgery at the Cleveland Clinic between 1995 and 2016. The investigators analyzed baseline characteristics, known predictors of seizure outcome, surgical data, pathology, and postoperative seizure recurrence. The primary outcome was complete seizure freedom (ie, Engel Class IA) at last follow-up.

The researchers analyzed the data using Kaplan–Meier survival curves and univariate and multivariate hazard modeling. The analysis included 788 patients without prior surgery, 92 patients with one prior surgery, and 18 patients with two or more prior surgeries. Two years after the most recent epilepsy surgery, 58% of patients with no prior surgery were seizure-free, compared with 49% of patients who had one prior surgery and 39% of patients who had two or more prior surgeries. Patients with more than one surgery were more likely to have an Engel outcome score of greater than Class I.

Variables that correlated with better seizure outcome in the univariate analysis included female gender; a lesional initial MRI; no history of generalization; and mesial temporal sclerosis, malformations of cortical development, or tumor on pathology. In the multivariate model, gender, history of generalization, and number of prior surgeries remained statistically significant.

—Jake Remaly

LOS ANGELES—Among patients with intractable focal epilepsy who have failed one or more epilepsy surgeries, reoperation may provide long-term seizure control, according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Patients with prior epilepsy surgery are less likely to achieve seizure freedom, however, compared with patients undergoing initial epilepsy surgery, the researchers said.

“It is possible to achieve long-term seizure control in patients with failed prior epilepsy surgery,” said Ruta Yardi, MD, a researcher at the Cleveland Clinic, and colleagues. “A lesional MRI, specific prior postoperative pathology, and fewer prior resections seem to predict better outcomes.” These results may be helpful in identifying candidates for reoperation, the investigators said.

Epilepsy surgery is the most effective treatment option for patients with medically refractory focal epilepsy, but initial surgeries may not be successful, Dr. Yardi and colleagues said. A small percentage of patients who do not benefit from a first surgery may be evaluated for another resection. Data for how outcomes vary with successive surgeries are limited, however, the researchers said.

To assess longitudinal seizure outcomes following reoperations in patients with intractable focal epilepsy and identify prognostic factors that influence these outcomes, Dr. Yardi and colleagues retrospectively studied 898 patients (448 female; about a third pediatric) who underwent epilepsy surgery at the Cleveland Clinic between 1995 and 2016. The investigators analyzed baseline characteristics, known predictors of seizure outcome, surgical data, pathology, and postoperative seizure recurrence. The primary outcome was complete seizure freedom (ie, Engel Class IA) at last follow-up.

The researchers analyzed the data using Kaplan–Meier survival curves and univariate and multivariate hazard modeling. The analysis included 788 patients without prior surgery, 92 patients with one prior surgery, and 18 patients with two or more prior surgeries. Two years after the most recent epilepsy surgery, 58% of patients with no prior surgery were seizure-free, compared with 49% of patients who had one prior surgery and 39% of patients who had two or more prior surgeries. Patients with more than one surgery were more likely to have an Engel outcome score of greater than Class I.

Variables that correlated with better seizure outcome in the univariate analysis included female gender; a lesional initial MRI; no history of generalization; and mesial temporal sclerosis, malformations of cortical development, or tumor on pathology. In the multivariate model, gender, history of generalization, and number of prior surgeries remained statistically significant.

—Jake Remaly

LOS ANGELES—Among patients with intractable focal epilepsy who have failed one or more epilepsy surgeries, reoperation may provide long-term seizure control, according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Patients with prior epilepsy surgery are less likely to achieve seizure freedom, however, compared with patients undergoing initial epilepsy surgery, the researchers said.

“It is possible to achieve long-term seizure control in patients with failed prior epilepsy surgery,” said Ruta Yardi, MD, a researcher at the Cleveland Clinic, and colleagues. “A lesional MRI, specific prior postoperative pathology, and fewer prior resections seem to predict better outcomes.” These results may be helpful in identifying candidates for reoperation, the investigators said.

Epilepsy surgery is the most effective treatment option for patients with medically refractory focal epilepsy, but initial surgeries may not be successful, Dr. Yardi and colleagues said. A small percentage of patients who do not benefit from a first surgery may be evaluated for another resection. Data for how outcomes vary with successive surgeries are limited, however, the researchers said.

To assess longitudinal seizure outcomes following reoperations in patients with intractable focal epilepsy and identify prognostic factors that influence these outcomes, Dr. Yardi and colleagues retrospectively studied 898 patients (448 female; about a third pediatric) who underwent epilepsy surgery at the Cleveland Clinic between 1995 and 2016. The investigators analyzed baseline characteristics, known predictors of seizure outcome, surgical data, pathology, and postoperative seizure recurrence. The primary outcome was complete seizure freedom (ie, Engel Class IA) at last follow-up.

The researchers analyzed the data using Kaplan–Meier survival curves and univariate and multivariate hazard modeling. The analysis included 788 patients without prior surgery, 92 patients with one prior surgery, and 18 patients with two or more prior surgeries. Two years after the most recent epilepsy surgery, 58% of patients with no prior surgery were seizure-free, compared with 49% of patients who had one prior surgery and 39% of patients who had two or more prior surgeries. Patients with more than one surgery were more likely to have an Engel outcome score of greater than Class I.

Variables that correlated with better seizure outcome in the univariate analysis included female gender; a lesional initial MRI; no history of generalization; and mesial temporal sclerosis, malformations of cortical development, or tumor on pathology. In the multivariate model, gender, history of generalization, and number of prior surgeries remained statistically significant.

—Jake Remaly

LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.

Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.

Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.

LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.

Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.

Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.

LOS ANGELES—Treatment for as long as four years with adjunctive perampanel is safe and effective for adolescents with secondarily generalized seizures or primary generalized tonic-clonic seizures, according to a post hoc study presented at the 70th Annual Meeting of the American Academy of Neurology. “These post hoc results are encouraging, given the refractory nature of these seizure types,” said the investigators.

Perampanel has regulatory approval for the treatment of partial seizures with or without secondarily generalized seizures, and for the adjunctive treatment of primary generalized tonic-clonic seizures in patients age 12 and younger with epilepsy. Phase II and III randomized, double-blind, placebo-controlled trials indicated that adjunctive perampanel (at doses of 12 mg/day or less) was effective and tolerable in patients with these types of seizures in idiopathic generalized epilepsy. The participants who completed these studies were eligible to enter one of four open-label extension studies.

Jesus Eric Piña-Garza, MD, a pediatric neurologist at the Children’s Hospital at TriStar Centennial in Nashville, and colleagues used data from these open-label extension studies to assess the long-term efficacy and safety of adjunctive perampanel in patients from ages 12 to 17 with secondarily generalized seizures or primary generalized tonic-clonic seizures.

First Anti-CGRP Monoclonal Antibody Gains FDA Approval

The FDA approved Aimovig (erenumab-aooe) for the preventive treatment of migraine in adults. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that blocks the activity of calcitonin gene-related peptide (CGRP). The treatment is given by once-monthly self-injections. Aimovig’s effectiveness was evaluated in three placebo-controlled clinical trials. The first included 955 patients with episodic migraine. Over six months, treated patients had, on average, one to two fewer monthly migraine days than controls. The second study included 577 patients with episodic migraine. Over three months, treated patients had, on average, one fewer migraine day per month than controls. The third study evaluated 667 patients with chronic migraine. Over three months, treated patients had, on average, 2.5 fewer monthly migraine days than controls. Aimovig is marketed by Amgen.

FDA Approves Gilenya for Pediatric Use

The FDA has approved Gilenya (fingolimod) for the treatment of children and adolescents between the ages of 10 and 18 with relapsing forms of multiple sclerosis (MS), making it the first disease-modifying therapy indicated for these young patients. The approval extends the age range for the drug, which was previously approved for patients age 18 and older with relapsing MS. Gilenya was granted Breakthrough Therapy status in December 2017 for this pediatric indication. The approval was supported by PARADIGMS, a double-blind, randomized, multicenter phase III safety and efficacy study of Gilenya versus interferon beta-1a. In this study, oral Gilenya reduced the annualized relapse rate by approximately 82% for as long as two years, compared with interferon beta-1a intramuscular injections in adolescents with relapsing MS. Gilenya is marketed by Novartis.

FDA Approves Treatment for CIDP

The FDA has approved Hizentra (immune globulin subcutaneous [human] 20% liquid) as the first subcutaneous immunoglobulin (SCIg) for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment. The approval was based on the phase III PATH study, which was the largest controlled clinical study of patients with CIDP to date. The percentage of patients experiencing CIDP relapse or withdrawal for any other reason during SCIg treatment was significantly lower with Hizentra (38.6% on low-dose Hizentra [0.2 g/kg weekly], 32.8% on high-dose Hizentra [0.4 g/kg weekly]) than with placebo (63.2%). Treated patients reported fewer systemic adverse reactions per infusion, compared with IVIg treatment (2.7% vs 9.8%, respectively). Approximately 93% of infusions caused no adverse reactions. Hizentra is marketed by CSL Behring.

DBS Device Approved for Refractory Epilepsy

The FDA granted premarket approval for Medtronic’s deep brain stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures in patients age 18 or older who are refractory to three or more antiepileptic drugs. The approval is based on the blinded phase and seven-year follow-up data from the SANTE trial, which included 110 patients. The median total seizure frequency reduction from baseline was 40.4% in implanted patients versus 14.5% for the placebo group at three months and 75% at seven years with ongoing open-label therapy. Twenty subjects (18%) had at least one six-month seizure-free period between implant and year seven, including eight subjects (7%) who were seizure-free for the preceding two years. Seizure severity and quality-of-life scales showed statistically significant improvement from baseline to year seven. No significant cognitive declines or worsening of depression were noted.

FDA Issues Warning About Lamictal

The FDA recently warned that Lamictal (lamotrigine), frequently used for treating seizures and bipolar disorder, can cause a rare but serious immune system reaction called hemophagocytic lymphohistiocytosis (HLH), which can be life-threatening. HLH typically presents as a persistent fever, usually greater than 101° F, and can lead to severe problems with blood cells and vital organs. Health care professionals should be aware that prompt recognition and early treatment are important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms, such as rash and fever, are not specific. HLH also may be confused with other serious immune-related adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS). The FDA is requiring a change to the drug’s prescribing information and drug labeling.

First Anti-CGRP Monoclonal Antibody Gains FDA Approval

The FDA approved Aimovig (erenumab-aooe) for the preventive treatment of migraine in adults. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that blocks the activity of calcitonin gene-related peptide (CGRP). The treatment is given by once-monthly self-injections. Aimovig’s effectiveness was evaluated in three placebo-controlled clinical trials. The first included 955 patients with episodic migraine. Over six months, treated patients had, on average, one to two fewer monthly migraine days than controls. The second study included 577 patients with episodic migraine. Over three months, treated patients had, on average, one fewer migraine day per month than controls. The third study evaluated 667 patients with chronic migraine. Over three months, treated patients had, on average, 2.5 fewer monthly migraine days than controls. Aimovig is marketed by Amgen.

FDA Approves Gilenya for Pediatric Use

The FDA has approved Gilenya (fingolimod) for the treatment of children and adolescents between the ages of 10 and 18 with relapsing forms of multiple sclerosis (MS), making it the first disease-modifying therapy indicated for these young patients. The approval extends the age range for the drug, which was previously approved for patients age 18 and older with relapsing MS. Gilenya was granted Breakthrough Therapy status in December 2017 for this pediatric indication. The approval was supported by PARADIGMS, a double-blind, randomized, multicenter phase III safety and efficacy study of Gilenya versus interferon beta-1a. In this study, oral Gilenya reduced the annualized relapse rate by approximately 82% for as long as two years, compared with interferon beta-1a intramuscular injections in adolescents with relapsing MS. Gilenya is marketed by Novartis.

FDA Approves Treatment for CIDP

The FDA has approved Hizentra (immune globulin subcutaneous [human] 20% liquid) as the first subcutaneous immunoglobulin (SCIg) for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment. The approval was based on the phase III PATH study, which was the largest controlled clinical study of patients with CIDP to date. The percentage of patients experiencing CIDP relapse or withdrawal for any other reason during SCIg treatment was significantly lower with Hizentra (38.6% on low-dose Hizentra [0.2 g/kg weekly], 32.8% on high-dose Hizentra [0.4 g/kg weekly]) than with placebo (63.2%). Treated patients reported fewer systemic adverse reactions per infusion, compared with IVIg treatment (2.7% vs 9.8%, respectively). Approximately 93% of infusions caused no adverse reactions. Hizentra is marketed by CSL Behring.

DBS Device Approved for Refractory Epilepsy

The FDA granted premarket approval for Medtronic’s deep brain stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures in patients age 18 or older who are refractory to three or more antiepileptic drugs. The approval is based on the blinded phase and seven-year follow-up data from the SANTE trial, which included 110 patients. The median total seizure frequency reduction from baseline was 40.4% in implanted patients versus 14.5% for the placebo group at three months and 75% at seven years with ongoing open-label therapy. Twenty subjects (18%) had at least one six-month seizure-free period between implant and year seven, including eight subjects (7%) who were seizure-free for the preceding two years. Seizure severity and quality-of-life scales showed statistically significant improvement from baseline to year seven. No significant cognitive declines or worsening of depression were noted.

FDA Issues Warning About Lamictal

The FDA recently warned that Lamictal (lamotrigine), frequently used for treating seizures and bipolar disorder, can cause a rare but serious immune system reaction called hemophagocytic lymphohistiocytosis (HLH), which can be life-threatening. HLH typically presents as a persistent fever, usually greater than 101° F, and can lead to severe problems with blood cells and vital organs. Health care professionals should be aware that prompt recognition and early treatment are important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms, such as rash and fever, are not specific. HLH also may be confused with other serious immune-related adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS). The FDA is requiring a change to the drug’s prescribing information and drug labeling.

First Anti-CGRP Monoclonal Antibody Gains FDA Approval

The FDA approved Aimovig (erenumab-aooe) for the preventive treatment of migraine in adults. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that blocks the activity of calcitonin gene-related peptide (CGRP). The treatment is given by once-monthly self-injections. Aimovig’s effectiveness was evaluated in three placebo-controlled clinical trials. The first included 955 patients with episodic migraine. Over six months, treated patients had, on average, one to two fewer monthly migraine days than controls. The second study included 577 patients with episodic migraine. Over three months, treated patients had, on average, one fewer migraine day per month than controls. The third study evaluated 667 patients with chronic migraine. Over three months, treated patients had, on average, 2.5 fewer monthly migraine days than controls. Aimovig is marketed by Amgen.

FDA Approves Gilenya for Pediatric Use

The FDA has approved Gilenya (fingolimod) for the treatment of children and adolescents between the ages of 10 and 18 with relapsing forms of multiple sclerosis (MS), making it the first disease-modifying therapy indicated for these young patients. The approval extends the age range for the drug, which was previously approved for patients age 18 and older with relapsing MS. Gilenya was granted Breakthrough Therapy status in December 2017 for this pediatric indication. The approval was supported by PARADIGMS, a double-blind, randomized, multicenter phase III safety and efficacy study of Gilenya versus interferon beta-1a. In this study, oral Gilenya reduced the annualized relapse rate by approximately 82% for as long as two years, compared with interferon beta-1a intramuscular injections in adolescents with relapsing MS. Gilenya is marketed by Novartis.

FDA Approves Treatment for CIDP

The FDA has approved Hizentra (immune globulin subcutaneous [human] 20% liquid) as the first subcutaneous immunoglobulin (SCIg) for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment. The approval was based on the phase III PATH study, which was the largest controlled clinical study of patients with CIDP to date. The percentage of patients experiencing CIDP relapse or withdrawal for any other reason during SCIg treatment was significantly lower with Hizentra (38.6% on low-dose Hizentra [0.2 g/kg weekly], 32.8% on high-dose Hizentra [0.4 g/kg weekly]) than with placebo (63.2%). Treated patients reported fewer systemic adverse reactions per infusion, compared with IVIg treatment (2.7% vs 9.8%, respectively). Approximately 93% of infusions caused no adverse reactions. Hizentra is marketed by CSL Behring.

DBS Device Approved for Refractory Epilepsy

The FDA granted premarket approval for Medtronic’s deep brain stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures in patients age 18 or older who are refractory to three or more antiepileptic drugs. The approval is based on the blinded phase and seven-year follow-up data from the SANTE trial, which included 110 patients. The median total seizure frequency reduction from baseline was 40.4% in implanted patients versus 14.5% for the placebo group at three months and 75% at seven years with ongoing open-label therapy. Twenty subjects (18%) had at least one six-month seizure-free period between implant and year seven, including eight subjects (7%) who were seizure-free for the preceding two years. Seizure severity and quality-of-life scales showed statistically significant improvement from baseline to year seven. No significant cognitive declines or worsening of depression were noted.

FDA Issues Warning About Lamictal

The FDA recently warned that Lamictal (lamotrigine), frequently used for treating seizures and bipolar disorder, can cause a rare but serious immune system reaction called hemophagocytic lymphohistiocytosis (HLH), which can be life-threatening. HLH typically presents as a persistent fever, usually greater than 101° F, and can lead to severe problems with blood cells and vital organs. Health care professionals should be aware that prompt recognition and early treatment are important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms, such as rash and fever, are not specific. HLH also may be confused with other serious immune-related adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS). The FDA is requiring a change to the drug’s prescribing information and drug labeling.