American Neurological Association (ANA): Annual Meeting 2011

SAN DIEGO – Triptans are routinely prescribed to migraine patients who have a history of cardiovascular disease, according to evidence from a large medical claims database study.

Serotonin (5-HT) receptor agonists are among the most commonly prescribed medications for migraine patients, but are contraindicated in patients who have a history, signs, or symptoms of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes; any other underlying cardiovascular disease; or uncontrolled hypertension, according to package inserts.

Daisy S. Ng-Mak, Ph.D., of Merck Sharp & Dohme and her colleagues randomly selected 10 representative health plans from MedAssurant Inc.’s MORE² (Medical Outcomes for Research on Economics and Effectiveness) registry, which contains records from more than 77 million people of all ages. Of 2.5 million records from the registry for patients aged 18-64 years, they found that 8% of 121,286 migraine patients had a cardiovascular contraindication, such as a history of MI or stroke or documented prescriptions for cardiovascular disease.*

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well."

Among those patients, 22% had received a prescription for a triptan during 2009, the authors reported at the annual meeting of the American Neurological Association.

Dr. Ng-Mak and her coauthors identified migraine patients through chart diagnoses, prescription claims, or treatment of at least two headaches at least a week apart. They similarly found cardiovascular contraindications by either diagnosis or prescription claim data.

Among patients aged 18-49 years with such a cardiovascular contraindication, 24% received a triptan prescription.

"Especially ... concerning," the authors noted, was the fact that 21% of older migraine patients with cardiac contraindications at the time of the study had received a triptan prescription."

These 50- to 64-year-olds "may be exposed to other risks" that heighten cardiac concerns, Dr. Ng-Mak said.

In an interview following the meeting, Dr. Ng-Mak said she found the findings "quite eye catching."

"We really don’t know why we saw this high percentage – a shocking percentage – of patients with cardiac contraindications [who were] receiving triptans," she said.

Dr. Juline Bryson, a neurologist and headache specialist at St. Luke’s/Roosevelt Medical Center in New York City, said that "overfamiliarity" may be to blame.

In the 20 years since the introduction of sumatriptan, the drug class has greatly expanded and has been widely accepted as efficacious therapy for migraine, she said.

"We may be getting so comfortable with prescribing triptans these days that we almost think of them like Aleve or Advil," said Dr. Bryson, who was not affiliated with the database study. In brief, 10-minute visits, primary care physicians may not be taking the time to carefully consider the patient’s history when they decide to quickly prescribe something for migraine pain.

Another neurologist unaffiliated with the study, Dr. Matthew S. Robbins, said that patients often arrive at the Montefiore Headache Center in New York City with a history of taking triptans that long predates their cardiovascular history.

When the patient was "young and healthy" many years before, he or she may have received a triptan prescription for migraines, was satisfied, and kept requesting it, he speculated. At some point along the way, a cardiovascular condition developed, but physicians kept refilling the triptan prescription without realizing that the drug was now contraindicated.

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well," said Dr. Robbins, a neurologist at Montefiore.

A separate study – the U.S. population–based AMPP (American Migraine Prevalence and Prevention) study – found that 10% of 5,591 individuals with episodic migraine reported that they had experienced a major cardiovascular event, such as stroke or MI, or a cardiovascular procedure.

The analysis examined five areas of unmet need among persons with episodic migraine, including cardiovascular event history, reported Dawn C. Buse, Ph.D., director of behavioral medicine at the Montefiore Headache Center.

More than 40% of episodic migraine patients met criteria for at least one type of unmet need related to acute headache medications, including dissatisfaction with treatment (15.2%), moderate to severe headache-related disability (19.2%), excessive use of opioids or barbiturates (13%), and two or more visits a year to an emergency department or urgent care center for headache (2.3%).

According to Dr. Buse, "these data demonstrate that despite the existing armamentarium of acute headache therapies, many individuals with headache are not receiving satisfactory results. This is likely due to a range of factors, which may include limited access to care, cost barriers, and limitations of existing acute treatments for migraine."

In this portion of the study, patients with cardiovascular disease were not asked whether they were taking triptans, but in a previous report from AMPP, widespread triptan use was seen in migraineurs (Headache 2010;50:256-63).

That study found triptan use in 8.5% of patients with a history of MI, in 7% of those with a history of stroke, in 9% of patients who had undergone heart surgery, in 16% of patients with transient ischemic attacks, and in 18% of patients with a history of claudication.

Merck Sharp & Dohme funded the use of the registry data for this study.* The AMPP study was funded through a research grant to the National Headache Foundation from Ortho-McNeil Neurologics, with additional support provided by Allergan Pharmaceuticals, NuPathe Inc., and Merck Sharp & Dohme. Some of the AMPP investigators, including Dr. Buse, have received research support from Allergan and NuPathe.

* Correction, 11/15/2011: An earlier version of this story incorrectly stated the number and ages of patients who have records in the MORE² registry, as well as how the use of the registry data was funded.

SAN DIEGO – Triptans are routinely prescribed to migraine patients who have a history of cardiovascular disease, according to evidence from a large medical claims database study.

Serotonin (5-HT) receptor agonists are among the most commonly prescribed medications for migraine patients, but are contraindicated in patients who have a history, signs, or symptoms of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes; any other underlying cardiovascular disease; or uncontrolled hypertension, according to package inserts.

Daisy S. Ng-Mak, Ph.D., of Merck Sharp & Dohme and her colleagues randomly selected 10 representative health plans from MedAssurant Inc.’s MORE² (Medical Outcomes for Research on Economics and Effectiveness) registry, which contains records from more than 77 million people of all ages. Of 2.5 million records from the registry for patients aged 18-64 years, they found that 8% of 121,286 migraine patients had a cardiovascular contraindication, such as a history of MI or stroke or documented prescriptions for cardiovascular disease.*

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well."

Among those patients, 22% had received a prescription for a triptan during 2009, the authors reported at the annual meeting of the American Neurological Association.

Dr. Ng-Mak and her coauthors identified migraine patients through chart diagnoses, prescription claims, or treatment of at least two headaches at least a week apart. They similarly found cardiovascular contraindications by either diagnosis or prescription claim data.

Among patients aged 18-49 years with such a cardiovascular contraindication, 24% received a triptan prescription.

"Especially ... concerning," the authors noted, was the fact that 21% of older migraine patients with cardiac contraindications at the time of the study had received a triptan prescription."

These 50- to 64-year-olds "may be exposed to other risks" that heighten cardiac concerns, Dr. Ng-Mak said.

In an interview following the meeting, Dr. Ng-Mak said she found the findings "quite eye catching."

"We really don’t know why we saw this high percentage – a shocking percentage – of patients with cardiac contraindications [who were] receiving triptans," she said.

Dr. Juline Bryson, a neurologist and headache specialist at St. Luke’s/Roosevelt Medical Center in New York City, said that "overfamiliarity" may be to blame.

In the 20 years since the introduction of sumatriptan, the drug class has greatly expanded and has been widely accepted as efficacious therapy for migraine, she said.

"We may be getting so comfortable with prescribing triptans these days that we almost think of them like Aleve or Advil," said Dr. Bryson, who was not affiliated with the database study. In brief, 10-minute visits, primary care physicians may not be taking the time to carefully consider the patient’s history when they decide to quickly prescribe something for migraine pain.

Another neurologist unaffiliated with the study, Dr. Matthew S. Robbins, said that patients often arrive at the Montefiore Headache Center in New York City with a history of taking triptans that long predates their cardiovascular history.

When the patient was "young and healthy" many years before, he or she may have received a triptan prescription for migraines, was satisfied, and kept requesting it, he speculated. At some point along the way, a cardiovascular condition developed, but physicians kept refilling the triptan prescription without realizing that the drug was now contraindicated.

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well," said Dr. Robbins, a neurologist at Montefiore.

A separate study – the U.S. population–based AMPP (American Migraine Prevalence and Prevention) study – found that 10% of 5,591 individuals with episodic migraine reported that they had experienced a major cardiovascular event, such as stroke or MI, or a cardiovascular procedure.

The analysis examined five areas of unmet need among persons with episodic migraine, including cardiovascular event history, reported Dawn C. Buse, Ph.D., director of behavioral medicine at the Montefiore Headache Center.

More than 40% of episodic migraine patients met criteria for at least one type of unmet need related to acute headache medications, including dissatisfaction with treatment (15.2%), moderate to severe headache-related disability (19.2%), excessive use of opioids or barbiturates (13%), and two or more visits a year to an emergency department or urgent care center for headache (2.3%).

According to Dr. Buse, "these data demonstrate that despite the existing armamentarium of acute headache therapies, many individuals with headache are not receiving satisfactory results. This is likely due to a range of factors, which may include limited access to care, cost barriers, and limitations of existing acute treatments for migraine."

In this portion of the study, patients with cardiovascular disease were not asked whether they were taking triptans, but in a previous report from AMPP, widespread triptan use was seen in migraineurs (Headache 2010;50:256-63).

That study found triptan use in 8.5% of patients with a history of MI, in 7% of those with a history of stroke, in 9% of patients who had undergone heart surgery, in 16% of patients with transient ischemic attacks, and in 18% of patients with a history of claudication.

Merck Sharp & Dohme funded the use of the registry data for this study.* The AMPP study was funded through a research grant to the National Headache Foundation from Ortho-McNeil Neurologics, with additional support provided by Allergan Pharmaceuticals, NuPathe Inc., and Merck Sharp & Dohme. Some of the AMPP investigators, including Dr. Buse, have received research support from Allergan and NuPathe.

* Correction, 11/15/2011: An earlier version of this story incorrectly stated the number and ages of patients who have records in the MORE² registry, as well as how the use of the registry data was funded.

SAN DIEGO – Triptans are routinely prescribed to migraine patients who have a history of cardiovascular disease, according to evidence from a large medical claims database study.

Serotonin (5-HT) receptor agonists are among the most commonly prescribed medications for migraine patients, but are contraindicated in patients who have a history, signs, or symptoms of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes; any other underlying cardiovascular disease; or uncontrolled hypertension, according to package inserts.

Daisy S. Ng-Mak, Ph.D., of Merck Sharp & Dohme and her colleagues randomly selected 10 representative health plans from MedAssurant Inc.’s MORE² (Medical Outcomes for Research on Economics and Effectiveness) registry, which contains records from more than 77 million people of all ages. Of 2.5 million records from the registry for patients aged 18-64 years, they found that 8% of 121,286 migraine patients had a cardiovascular contraindication, such as a history of MI or stroke or documented prescriptions for cardiovascular disease.*

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well."

Among those patients, 22% had received a prescription for a triptan during 2009, the authors reported at the annual meeting of the American Neurological Association.

Dr. Ng-Mak and her coauthors identified migraine patients through chart diagnoses, prescription claims, or treatment of at least two headaches at least a week apart. They similarly found cardiovascular contraindications by either diagnosis or prescription claim data.

Among patients aged 18-49 years with such a cardiovascular contraindication, 24% received a triptan prescription.

"Especially ... concerning," the authors noted, was the fact that 21% of older migraine patients with cardiac contraindications at the time of the study had received a triptan prescription."

These 50- to 64-year-olds "may be exposed to other risks" that heighten cardiac concerns, Dr. Ng-Mak said.

In an interview following the meeting, Dr. Ng-Mak said she found the findings "quite eye catching."

"We really don’t know why we saw this high percentage – a shocking percentage – of patients with cardiac contraindications [who were] receiving triptans," she said.

Dr. Juline Bryson, a neurologist and headache specialist at St. Luke’s/Roosevelt Medical Center in New York City, said that "overfamiliarity" may be to blame.

In the 20 years since the introduction of sumatriptan, the drug class has greatly expanded and has been widely accepted as efficacious therapy for migraine, she said.

"We may be getting so comfortable with prescribing triptans these days that we almost think of them like Aleve or Advil," said Dr. Bryson, who was not affiliated with the database study. In brief, 10-minute visits, primary care physicians may not be taking the time to carefully consider the patient’s history when they decide to quickly prescribe something for migraine pain.

Another neurologist unaffiliated with the study, Dr. Matthew S. Robbins, said that patients often arrive at the Montefiore Headache Center in New York City with a history of taking triptans that long predates their cardiovascular history.

When the patient was "young and healthy" many years before, he or she may have received a triptan prescription for migraines, was satisfied, and kept requesting it, he speculated. At some point along the way, a cardiovascular condition developed, but physicians kept refilling the triptan prescription without realizing that the drug was now contraindicated.

"I have had to refuse to refill the prescriptions over the severe protest of the patient, because [the drug had] worked so well," said Dr. Robbins, a neurologist at Montefiore.

A separate study – the U.S. population–based AMPP (American Migraine Prevalence and Prevention) study – found that 10% of 5,591 individuals with episodic migraine reported that they had experienced a major cardiovascular event, such as stroke or MI, or a cardiovascular procedure.

The analysis examined five areas of unmet need among persons with episodic migraine, including cardiovascular event history, reported Dawn C. Buse, Ph.D., director of behavioral medicine at the Montefiore Headache Center.

More than 40% of episodic migraine patients met criteria for at least one type of unmet need related to acute headache medications, including dissatisfaction with treatment (15.2%), moderate to severe headache-related disability (19.2%), excessive use of opioids or barbiturates (13%), and two or more visits a year to an emergency department or urgent care center for headache (2.3%).

According to Dr. Buse, "these data demonstrate that despite the existing armamentarium of acute headache therapies, many individuals with headache are not receiving satisfactory results. This is likely due to a range of factors, which may include limited access to care, cost barriers, and limitations of existing acute treatments for migraine."

In this portion of the study, patients with cardiovascular disease were not asked whether they were taking triptans, but in a previous report from AMPP, widespread triptan use was seen in migraineurs (Headache 2010;50:256-63).

That study found triptan use in 8.5% of patients with a history of MI, in 7% of those with a history of stroke, in 9% of patients who had undergone heart surgery, in 16% of patients with transient ischemic attacks, and in 18% of patients with a history of claudication.

Merck Sharp & Dohme funded the use of the registry data for this study.* The AMPP study was funded through a research grant to the National Headache Foundation from Ortho-McNeil Neurologics, with additional support provided by Allergan Pharmaceuticals, NuPathe Inc., and Merck Sharp & Dohme. Some of the AMPP investigators, including Dr. Buse, have received research support from Allergan and NuPathe.

* Correction, 11/15/2011: An earlier version of this story incorrectly stated the number and ages of patients who have records in the MORE² registry, as well as how the use of the registry data was funded.

SAN DIEGO – Several new antiepileptic drugs and devices aimed at preventing or suppressing seizure have achieved results with better management of side effects than is seen with existing therapeutic agents, according to Dr. Jacqueline A. French.

"You may hear many people saying that we have made no progress whatsoever" in epilepsy therapy, said Dr. French, professor of neurology and codirector of epilepsy research and clinical trials at New York University.

Indeed, about a third of patients were considered "treatment resistant" during the era of bromide therapy for epilepsy, and about the same proportion of patients are considered "treatment resistant" today, Dr. French said at the annual meeting of the American Neurological Association.

However, she explained that far better management of side effects has been achieved, resulting in better overall management and fewer total seizures in today’s patients.

One measure of that success is the increasingly challenging task of finding patients who experience four or more seizures a month, thereby qualifying for clinical trials, Dr. French noted.

In the pipeline today are what she called "evolutionary" drugs – new twists on mechanisms found in existing therapeutic agents that enhance their safety, tolerability, or potency – and "revolutionary" drugs characterized by novel mechanisms.

The following are among the potential options on the horizon for clinical practice.

Evolutionary Drugs

Clobazam, marketed as Frisium or Urbanol, a benzodiazepine widely used in Canada and Europe, is under consideration by the Food and Drug Administration after submission of a study involving Lennox-Gastaut syndrome. Dr. French said the agent is believed to produce less tachyphylaxis than others in its class.

Brivaracetam, an analogue of levetiracetam, is hoped to exceed the potency of its predecessor while reducing side effects of irritability and depression. The first study of the agent in a small group of expert sites was "extremely promising," but a second, global trial failed. A third trial is underway, Dr. French said, to clarify results.

Eslicarbazepine is a third-generation version of carbamazepine, "the drug we love to hate," she said. Approved in Europe, this agent has a short half-life and is dosed once daily. Its improved side effect profile is the main draw, especially with regard to body weight, cholesterol, glucose, and hepatic effects.

Revolutionary Drugs

Ezogabine (Potiga), a novel potassium channel blocker, selectively activates the KCNQ channel, resulting in "stabilization of hyperexcitable neuronal cells." In clinical trials in patients with partial-onset seizures, the drug showed "no plateau of efficacy," but adverse events have limited its dosage.

Perampanel is the first drug to be submitted to the FDA based on an excitation mechanism rather than membrane inhibition or stabilization. The drug is a highly selective, noncompetitive, antiglutamate receptor antagonist. "It’s pretty close to getting to the clinic," she said at the meeting.

VX-765 is "something completely different," said Dr. French: an interleukin-converting enzyme inhibitor developed at the behest of researchers based on their hypothesis that modulation of proinflammatory cytokines might play a major role in seizure suppression. One human proof-of-concept trial has been completed, and another trial will be launched soon. As in animal studies, seizures were reduced following a delay period in the initial human study, she said.

Devices

Medtronic's deep brain stimulator, a device currently under FDA review, produces shocks at regular, timed intervals following implantation in the thalamus. "Patients can self-trigger the device if they feel a seizure coming on," she said. In studies, both actively treated and sham groups had a reduction in seizures early on, but efficacy improved over time in the treated group, and the device is believed by proponents to be most efficacious as long as 2 years after implantation.

NeuroPace's responsive neurostimulator system, or RNS, a "smart" device, countershocks the epileptic focus, and is similarly believed to lead to "better and better and better" seizure control over months of use, Dr. French said.

NeuroVista's seizure advisory system is another implantable device, this one acting on a complex algorithm of input from the brain to warn patients in advance of impending seizures. Should a patient receive a signal from the device, he or she might have an hour to prepare for a seizure, reducing safety concerns and heightening patients’ sense of empowerment over the disease.

Dr. French is president of the Epilepsy Study Consortium, which receives funding and provides consultation to a large number of pharmaceutical companies, including those represented in her talk. As a nonprofit organization, the Epilepsy Study Consortium’s members receive no personal compensation from pharmaceutical companies.

SAN DIEGO – Several new antiepileptic drugs and devices aimed at preventing or suppressing seizure have achieved results with better management of side effects than is seen with existing therapeutic agents, according to Dr. Jacqueline A. French.

"You may hear many people saying that we have made no progress whatsoever" in epilepsy therapy, said Dr. French, professor of neurology and codirector of epilepsy research and clinical trials at New York University.

Indeed, about a third of patients were considered "treatment resistant" during the era of bromide therapy for epilepsy, and about the same proportion of patients are considered "treatment resistant" today, Dr. French said at the annual meeting of the American Neurological Association.

However, she explained that far better management of side effects has been achieved, resulting in better overall management and fewer total seizures in today’s patients.

One measure of that success is the increasingly challenging task of finding patients who experience four or more seizures a month, thereby qualifying for clinical trials, Dr. French noted.

In the pipeline today are what she called "evolutionary" drugs – new twists on mechanisms found in existing therapeutic agents that enhance their safety, tolerability, or potency – and "revolutionary" drugs characterized by novel mechanisms.

The following are among the potential options on the horizon for clinical practice.

Evolutionary Drugs

Clobazam, marketed as Frisium or Urbanol, a benzodiazepine widely used in Canada and Europe, is under consideration by the Food and Drug Administration after submission of a study involving Lennox-Gastaut syndrome. Dr. French said the agent is believed to produce less tachyphylaxis than others in its class.

Brivaracetam, an analogue of levetiracetam, is hoped to exceed the potency of its predecessor while reducing side effects of irritability and depression. The first study of the agent in a small group of expert sites was "extremely promising," but a second, global trial failed. A third trial is underway, Dr. French said, to clarify results.

Eslicarbazepine is a third-generation version of carbamazepine, "the drug we love to hate," she said. Approved in Europe, this agent has a short half-life and is dosed once daily. Its improved side effect profile is the main draw, especially with regard to body weight, cholesterol, glucose, and hepatic effects.

Revolutionary Drugs

Ezogabine (Potiga), a novel potassium channel blocker, selectively activates the KCNQ channel, resulting in "stabilization of hyperexcitable neuronal cells." In clinical trials in patients with partial-onset seizures, the drug showed "no plateau of efficacy," but adverse events have limited its dosage.

Perampanel is the first drug to be submitted to the FDA based on an excitation mechanism rather than membrane inhibition or stabilization. The drug is a highly selective, noncompetitive, antiglutamate receptor antagonist. "It’s pretty close to getting to the clinic," she said at the meeting.

VX-765 is "something completely different," said Dr. French: an interleukin-converting enzyme inhibitor developed at the behest of researchers based on their hypothesis that modulation of proinflammatory cytokines might play a major role in seizure suppression. One human proof-of-concept trial has been completed, and another trial will be launched soon. As in animal studies, seizures were reduced following a delay period in the initial human study, she said.

Devices

Medtronic's deep brain stimulator, a device currently under FDA review, produces shocks at regular, timed intervals following implantation in the thalamus. "Patients can self-trigger the device if they feel a seizure coming on," she said. In studies, both actively treated and sham groups had a reduction in seizures early on, but efficacy improved over time in the treated group, and the device is believed by proponents to be most efficacious as long as 2 years after implantation.

NeuroPace's responsive neurostimulator system, or RNS, a "smart" device, countershocks the epileptic focus, and is similarly believed to lead to "better and better and better" seizure control over months of use, Dr. French said.

NeuroVista's seizure advisory system is another implantable device, this one acting on a complex algorithm of input from the brain to warn patients in advance of impending seizures. Should a patient receive a signal from the device, he or she might have an hour to prepare for a seizure, reducing safety concerns and heightening patients’ sense of empowerment over the disease.

Dr. French is president of the Epilepsy Study Consortium, which receives funding and provides consultation to a large number of pharmaceutical companies, including those represented in her talk. As a nonprofit organization, the Epilepsy Study Consortium’s members receive no personal compensation from pharmaceutical companies.

SAN DIEGO – Several new antiepileptic drugs and devices aimed at preventing or suppressing seizure have achieved results with better management of side effects than is seen with existing therapeutic agents, according to Dr. Jacqueline A. French.

"You may hear many people saying that we have made no progress whatsoever" in epilepsy therapy, said Dr. French, professor of neurology and codirector of epilepsy research and clinical trials at New York University.

Indeed, about a third of patients were considered "treatment resistant" during the era of bromide therapy for epilepsy, and about the same proportion of patients are considered "treatment resistant" today, Dr. French said at the annual meeting of the American Neurological Association.

However, she explained that far better management of side effects has been achieved, resulting in better overall management and fewer total seizures in today’s patients.

One measure of that success is the increasingly challenging task of finding patients who experience four or more seizures a month, thereby qualifying for clinical trials, Dr. French noted.

In the pipeline today are what she called "evolutionary" drugs – new twists on mechanisms found in existing therapeutic agents that enhance their safety, tolerability, or potency – and "revolutionary" drugs characterized by novel mechanisms.

The following are among the potential options on the horizon for clinical practice.

Evolutionary Drugs

Clobazam, marketed as Frisium or Urbanol, a benzodiazepine widely used in Canada and Europe, is under consideration by the Food and Drug Administration after submission of a study involving Lennox-Gastaut syndrome. Dr. French said the agent is believed to produce less tachyphylaxis than others in its class.

Brivaracetam, an analogue of levetiracetam, is hoped to exceed the potency of its predecessor while reducing side effects of irritability and depression. The first study of the agent in a small group of expert sites was "extremely promising," but a second, global trial failed. A third trial is underway, Dr. French said, to clarify results.

Eslicarbazepine is a third-generation version of carbamazepine, "the drug we love to hate," she said. Approved in Europe, this agent has a short half-life and is dosed once daily. Its improved side effect profile is the main draw, especially with regard to body weight, cholesterol, glucose, and hepatic effects.

Revolutionary Drugs

Ezogabine (Potiga), a novel potassium channel blocker, selectively activates the KCNQ channel, resulting in "stabilization of hyperexcitable neuronal cells." In clinical trials in patients with partial-onset seizures, the drug showed "no plateau of efficacy," but adverse events have limited its dosage.

Perampanel is the first drug to be submitted to the FDA based on an excitation mechanism rather than membrane inhibition or stabilization. The drug is a highly selective, noncompetitive, antiglutamate receptor antagonist. "It’s pretty close to getting to the clinic," she said at the meeting.

VX-765 is "something completely different," said Dr. French: an interleukin-converting enzyme inhibitor developed at the behest of researchers based on their hypothesis that modulation of proinflammatory cytokines might play a major role in seizure suppression. One human proof-of-concept trial has been completed, and another trial will be launched soon. As in animal studies, seizures were reduced following a delay period in the initial human study, she said.

Devices

Medtronic's deep brain stimulator, a device currently under FDA review, produces shocks at regular, timed intervals following implantation in the thalamus. "Patients can self-trigger the device if they feel a seizure coming on," she said. In studies, both actively treated and sham groups had a reduction in seizures early on, but efficacy improved over time in the treated group, and the device is believed by proponents to be most efficacious as long as 2 years after implantation.

NeuroPace's responsive neurostimulator system, or RNS, a "smart" device, countershocks the epileptic focus, and is similarly believed to lead to "better and better and better" seizure control over months of use, Dr. French said.

NeuroVista's seizure advisory system is another implantable device, this one acting on a complex algorithm of input from the brain to warn patients in advance of impending seizures. Should a patient receive a signal from the device, he or she might have an hour to prepare for a seizure, reducing safety concerns and heightening patients’ sense of empowerment over the disease.

Dr. French is president of the Epilepsy Study Consortium, which receives funding and provides consultation to a large number of pharmaceutical companies, including those represented in her talk. As a nonprofit organization, the Epilepsy Study Consortium’s members receive no personal compensation from pharmaceutical companies.

SAN DIEGO – Neurocardiogenic injury was surprisingly common in a series of patients treated for status epilepticus in a retrospective review conducted by investigators at the Mayo Clinic in Rochester, Minn.

Among 46 patients treated for 55 episodes of status epilepticus between 1999 and 2011, at least 8 (17%) experienced possible neurocardiogenic injury, Dr. Sara Hocker reported at the annual meeting of the American Neurological Association.

"I think we underestimate these cases because we don’t typically get troponin [levels] or echocardiograms in these patients," Dr. Hocker said in an interview at the meeting, where she presented the findings in poster form.

Patients included in the review were a mean age of 50 (within a standard deviation of 17.9 years) at the time of generalized convulsive or nonconvulsive status epilepticus. In 49 episodes, anesthetic coma was induced, and patients required anesthetic agents for an average 9.6 days.

At the onset of an episode, only 18 patients had troponin levels measured, with a mean of 0.1 and a standard deviation of 0.19 ng/mL.

Electrocardiogram findings at the onset of status epilepticus included ST elevation (7%), ST depression (5%), T wave inversion (5%), LVH (7%), and nonspecific ST changes (55%). Cardiac arrhythmias required intervention in more than 22% of cases, and included asystole (12%), ventricular tachycardia/fibrillation/flutter (8%), paroxysmal supraventricular tachycardia (2%), sinus bradycardia (46%), and sinus tachycardia (75%).

A non–ST elevation myocardial infarction was diagnosed in one patient, and pulmonary edema was present in more than one-third of patients.

Among 20 patients evaluated with echocardiography during status epilepticus, 8 had possible stress-induced cardiomyopathy that resolved following the episode.

"Neurologists and cardiologists are absolutely aware of catecholamine surge causing neurocardiogenic injury in massive neurologic insults like subarachnoid [hemorrhage] or acute hydrocephalus, or seizures," Dr. Hocker said.

"However, I think when we see patients with status, the majority of us, even neurointensivists, are surprised to see massive cardiogenic injury or any cardiogenic injury. It’s not the first thing we think of, and we don’t screen for it," she noted.

She said further review of the cases is underway to determine preexisting risk factors.

In the meantime, practice has changed at the Mayo Clinic to require echocardiograms in status epilepticus patients until more is known about neurocardiogenic injury in these patients.

"Is it worth it going forward to screen these patients carefully? Will it change outcomes? I don’t think we know enough at this point to say," Dr. Hocker said.

For institutions without easy access to echocardiograms in an intensive setting, bedside ultrasounds may be prudent "to decide whether to order a full echo or not," she advised.

Dr. Hocker reported no relevant disclosures related to her study.

SAN DIEGO – Neurocardiogenic injury was surprisingly common in a series of patients treated for status epilepticus in a retrospective review conducted by investigators at the Mayo Clinic in Rochester, Minn.

Among 46 patients treated for 55 episodes of status epilepticus between 1999 and 2011, at least 8 (17%) experienced possible neurocardiogenic injury, Dr. Sara Hocker reported at the annual meeting of the American Neurological Association.

"I think we underestimate these cases because we don’t typically get troponin [levels] or echocardiograms in these patients," Dr. Hocker said in an interview at the meeting, where she presented the findings in poster form.

Patients included in the review were a mean age of 50 (within a standard deviation of 17.9 years) at the time of generalized convulsive or nonconvulsive status epilepticus. In 49 episodes, anesthetic coma was induced, and patients required anesthetic agents for an average 9.6 days.

At the onset of an episode, only 18 patients had troponin levels measured, with a mean of 0.1 and a standard deviation of 0.19 ng/mL.

Electrocardiogram findings at the onset of status epilepticus included ST elevation (7%), ST depression (5%), T wave inversion (5%), LVH (7%), and nonspecific ST changes (55%). Cardiac arrhythmias required intervention in more than 22% of cases, and included asystole (12%), ventricular tachycardia/fibrillation/flutter (8%), paroxysmal supraventricular tachycardia (2%), sinus bradycardia (46%), and sinus tachycardia (75%).

A non–ST elevation myocardial infarction was diagnosed in one patient, and pulmonary edema was present in more than one-third of patients.

Among 20 patients evaluated with echocardiography during status epilepticus, 8 had possible stress-induced cardiomyopathy that resolved following the episode.

"Neurologists and cardiologists are absolutely aware of catecholamine surge causing neurocardiogenic injury in massive neurologic insults like subarachnoid [hemorrhage] or acute hydrocephalus, or seizures," Dr. Hocker said.

"However, I think when we see patients with status, the majority of us, even neurointensivists, are surprised to see massive cardiogenic injury or any cardiogenic injury. It’s not the first thing we think of, and we don’t screen for it," she noted.

She said further review of the cases is underway to determine preexisting risk factors.

In the meantime, practice has changed at the Mayo Clinic to require echocardiograms in status epilepticus patients until more is known about neurocardiogenic injury in these patients.

"Is it worth it going forward to screen these patients carefully? Will it change outcomes? I don’t think we know enough at this point to say," Dr. Hocker said.

For institutions without easy access to echocardiograms in an intensive setting, bedside ultrasounds may be prudent "to decide whether to order a full echo or not," she advised.

Dr. Hocker reported no relevant disclosures related to her study.

SAN DIEGO – Neurocardiogenic injury was surprisingly common in a series of patients treated for status epilepticus in a retrospective review conducted by investigators at the Mayo Clinic in Rochester, Minn.

Among 46 patients treated for 55 episodes of status epilepticus between 1999 and 2011, at least 8 (17%) experienced possible neurocardiogenic injury, Dr. Sara Hocker reported at the annual meeting of the American Neurological Association.

"I think we underestimate these cases because we don’t typically get troponin [levels] or echocardiograms in these patients," Dr. Hocker said in an interview at the meeting, where she presented the findings in poster form.

Patients included in the review were a mean age of 50 (within a standard deviation of 17.9 years) at the time of generalized convulsive or nonconvulsive status epilepticus. In 49 episodes, anesthetic coma was induced, and patients required anesthetic agents for an average 9.6 days.

At the onset of an episode, only 18 patients had troponin levels measured, with a mean of 0.1 and a standard deviation of 0.19 ng/mL.

Electrocardiogram findings at the onset of status epilepticus included ST elevation (7%), ST depression (5%), T wave inversion (5%), LVH (7%), and nonspecific ST changes (55%). Cardiac arrhythmias required intervention in more than 22% of cases, and included asystole (12%), ventricular tachycardia/fibrillation/flutter (8%), paroxysmal supraventricular tachycardia (2%), sinus bradycardia (46%), and sinus tachycardia (75%).

A non–ST elevation myocardial infarction was diagnosed in one patient, and pulmonary edema was present in more than one-third of patients.

Among 20 patients evaluated with echocardiography during status epilepticus, 8 had possible stress-induced cardiomyopathy that resolved following the episode.

"Neurologists and cardiologists are absolutely aware of catecholamine surge causing neurocardiogenic injury in massive neurologic insults like subarachnoid [hemorrhage] or acute hydrocephalus, or seizures," Dr. Hocker said.

"However, I think when we see patients with status, the majority of us, even neurointensivists, are surprised to see massive cardiogenic injury or any cardiogenic injury. It’s not the first thing we think of, and we don’t screen for it," she noted.

She said further review of the cases is underway to determine preexisting risk factors.

In the meantime, practice has changed at the Mayo Clinic to require echocardiograms in status epilepticus patients until more is known about neurocardiogenic injury in these patients.

"Is it worth it going forward to screen these patients carefully? Will it change outcomes? I don’t think we know enough at this point to say," Dr. Hocker said.

For institutions without easy access to echocardiograms in an intensive setting, bedside ultrasounds may be prudent "to decide whether to order a full echo or not," she advised.

Dr. Hocker reported no relevant disclosures related to her study.

SAN DIEGO – Like pivotal puzzle pieces, new genetic and molecular clues to the etiology of epilepsy are bringing into focus processes that have long perplexed clinicians and researchers.

New genetic findings and the unmasking of epileptogenic molecular seizure responses were among the advances outlined by speakers at the meeting’s presidential symposium.

Photo credit: Dr. Samuel F. Berkovic

Dr. Samuel F. Berkovic, codiscoverer of the first epilepsy gene in 1995, announced that "the impact of the new genetics is here now for clinical neurologists," bringing abundant opportunities for translational research and the possibility of unraveling causation within families burdened by epilepsy.

Population studies, twin studies, and multiplex family studies now point to a far greater impact of genetics on the development of epilepsy than ever suspected, said Dr. Berkovic, director of the Epilepsy Research Centre and laureate professor of medicine at the University of Melbourne.

"Most patients who walk into my clinic or yours don’t [speak of] a family history," he said.

Instead, "fairy stories" such as minor birth injuries or "a fall from a swing" are often cited as explanations for a family member’s seizures.

Incomplete family histories, de novo mutagenesis, and complex genetic inherence patterns all contribute to an underappreciation of the genetic underpinnings of many forms of epilepsy, not only among family members, but by clinicians as well, Dr. Berkovic explained.

His center’s study of more than 300 twins with epilepsy has now detected a concordance rate of 0.73 for generalized epilepsy among monozygous twins.

"That’s about as high as it gets in any complex disease," he said.

Monozygous concordance rates for focal epilepsy (0.34) and febrile epilepsy (0.60) were also much higher than anticipated, he said.

Epilepsy due to a single genetic mutation has proved to be rare, but "the smart money is going to be downstream, ... [with] a whole array of variants acting on common pathways."

Several unexpected findings have already surfaced in the search for genetic clues to epilepsy, including a link between mutations in the GLUT-1 gene (a glucose transporter to the brain) and paroxysmal exercise-induced dystonia and a wide spectrum of idiopathic generalized epilepsies, particularly those with absence seizures.

Unexpected deletions or duplications of gene copies have also been a fruitful avenue of study in epilepsy that includes intellectual disability or autism, Dr. Berkovic said.

Genetic investigations have become essential in such cases, producing a "hit rate on the order of 10%, somewhat of a big surprise," he said.

Studies from Dr. Berkovic’s group also revealed that the de novo mutation in the SCN1A gene found in 80% of individuals with Dravet syndrome likely occurs as early as the two-cell stage of embryonic development, since the mutation was present in a variety of tissue samples – lymphocytes, hair, buccal cells, and neuronal cells of one twin and not the other in studied pairs.

Deletion of chromosome 15q has been found to knock out seven genes and has been linked to autism, intellectual disability, and schizophrenia. Ironically, it is linked to merely a mild form of genetic generalized epilepsy.

At the opposite end of the spectrum are de novo mutations that cause profoundly severe epileptic encephalopathies in early childhood. These have now been identified as the cause of "at least a third if not half of these previously unsolved cases," he said.

"Diagnosis can be made rapidly in the clinic and one can get on with the business of counseling the families and doing the best one can with a terrible genetic burden," he said.

New technology that permits the sequencing of 20,000 genes for less than $1,000 is leading to the rapid discovery of genes underlying rare forms of epilepsy, such as the identification of the GOSR2 gene responsible for progressive myoclonic epilepsy (Am. J. Hum. Genet. 2011;88:657-63).

Genetic advances with massive parallel sequencing are "just astonishing," he said, pointing to the discovery of 50 new recessive genes for myogenic disorders.

Dr. James O. McNamara, chairman of neurobiology at Duke University Medical Center in Durham, N.C., shared Dr. Berkovic’s enthusiasm.

"This is an incredibly exciting time for the epilepsies," he marveled, embarking on a talk about a promising suspect in the search for the molecular link between complicated febrile seizures and subsequent development of mesial temporal lobe epilepsy.

Dr. McNamara reviewed a series of animal studies showing that activation of the tyrosine receptor kinase TrkB immediately following status epilepticus is both necessary and sufficient to produce temporal lobe epilepsy later in life.

Increased activity of TrkB in synapses ipsilateral to the amygdala within the hippocampus was "fleeting," he emphasized, peaking at 6-24 hours and no longer present after a week following status epilepticus (J. Neurosci. 2010;30:6188-96).

The identification of a "critical period" for molecular events setting the stage for future seizures raises the enticing possibility of designing a brief intervention to halt the process, Dr. McNamara said.

Dr. McNamara and his team put this theory to the test by introducing a TrkB inhibitor to genetically engineered mice soon after they had experienced an episode of status epilepticus. This prevented subsequent seizures or sharply reduced their frequency.

"Can we identify a drug – a.k.a. ‘magic bullet’ – to inhibit TrkB or causal downstream signaling pathway [in humans]? I think that globally in this field there is progress that invites optimism," Dr. McNamara said.

Such an intervention could potentially prevent development of a life-altering form of epilepsy using a short-term strategy.

"Limiting drug treatment to a week or two following status epilepticus minimizes unwanted effects inherent in lifelong drug exposure," he noted.

How early would one need to intervene following status epilepticus?

"That is an incredibly important question," he said in response to an audience query about timing. "We hope that [the National Institute for Neurological Disorders and Stroke] will continue its support so we can answer that."

Dr. Berkovic reported receiving honoraria from UCB Pharma and Wolters Kluwer. Dr. McNamara disclosed that he is a consultant for Pappas Ventures and founder and member of the board of directors of NeurOp.

Courtesy Dr. Samuel F. Berkovic

SAN DIEGO – Like pivotal puzzle pieces, new genetic and molecular clues to the etiology of epilepsy are bringing into focus processes that have long perplexed clinicians and researchers.

New genetic findings and the unmasking of epileptogenic molecular seizure responses were among the advances outlined by speakers at the meeting’s presidential symposium.

Photo credit: Dr. Samuel F. Berkovic

Dr. Samuel F. Berkovic, codiscoverer of the first epilepsy gene in 1995, announced that "the impact of the new genetics is here now for clinical neurologists," bringing abundant opportunities for translational research and the possibility of unraveling causation within families burdened by epilepsy.

Population studies, twin studies, and multiplex family studies now point to a far greater impact of genetics on the development of epilepsy than ever suspected, said Dr. Berkovic, director of the Epilepsy Research Centre and laureate professor of medicine at the University of Melbourne.

"Most patients who walk into my clinic or yours don’t [speak of] a family history," he said.

Instead, "fairy stories" such as minor birth injuries or "a fall from a swing" are often cited as explanations for a family member’s seizures.

Incomplete family histories, de novo mutagenesis, and complex genetic inherence patterns all contribute to an underappreciation of the genetic underpinnings of many forms of epilepsy, not only among family members, but by clinicians as well, Dr. Berkovic explained.

His center’s study of more than 300 twins with epilepsy has now detected a concordance rate of 0.73 for generalized epilepsy among monozygous twins.

"That’s about as high as it gets in any complex disease," he said.

Monozygous concordance rates for focal epilepsy (0.34) and febrile epilepsy (0.60) were also much higher than anticipated, he said.

Epilepsy due to a single genetic mutation has proved to be rare, but "the smart money is going to be downstream, ... [with] a whole array of variants acting on common pathways."

Several unexpected findings have already surfaced in the search for genetic clues to epilepsy, including a link between mutations in the GLUT-1 gene (a glucose transporter to the brain) and paroxysmal exercise-induced dystonia and a wide spectrum of idiopathic generalized epilepsies, particularly those with absence seizures.

Unexpected deletions or duplications of gene copies have also been a fruitful avenue of study in epilepsy that includes intellectual disability or autism, Dr. Berkovic said.

Genetic investigations have become essential in such cases, producing a "hit rate on the order of 10%, somewhat of a big surprise," he said.

Studies from Dr. Berkovic’s group also revealed that the de novo mutation in the SCN1A gene found in 80% of individuals with Dravet syndrome likely occurs as early as the two-cell stage of embryonic development, since the mutation was present in a variety of tissue samples – lymphocytes, hair, buccal cells, and neuronal cells of one twin and not the other in studied pairs.

Deletion of chromosome 15q has been found to knock out seven genes and has been linked to autism, intellectual disability, and schizophrenia. Ironically, it is linked to merely a mild form of genetic generalized epilepsy.

At the opposite end of the spectrum are de novo mutations that cause profoundly severe epileptic encephalopathies in early childhood. These have now been identified as the cause of "at least a third if not half of these previously unsolved cases," he said.

"Diagnosis can be made rapidly in the clinic and one can get on with the business of counseling the families and doing the best one can with a terrible genetic burden," he said.

New technology that permits the sequencing of 20,000 genes for less than $1,000 is leading to the rapid discovery of genes underlying rare forms of epilepsy, such as the identification of the GOSR2 gene responsible for progressive myoclonic epilepsy (Am. J. Hum. Genet. 2011;88:657-63).

Genetic advances with massive parallel sequencing are "just astonishing," he said, pointing to the discovery of 50 new recessive genes for myogenic disorders.

Dr. James O. McNamara, chairman of neurobiology at Duke University Medical Center in Durham, N.C., shared Dr. Berkovic’s enthusiasm.

"This is an incredibly exciting time for the epilepsies," he marveled, embarking on a talk about a promising suspect in the search for the molecular link between complicated febrile seizures and subsequent development of mesial temporal lobe epilepsy.

Dr. McNamara reviewed a series of animal studies showing that activation of the tyrosine receptor kinase TrkB immediately following status epilepticus is both necessary and sufficient to produce temporal lobe epilepsy later in life.

Increased activity of TrkB in synapses ipsilateral to the amygdala within the hippocampus was "fleeting," he emphasized, peaking at 6-24 hours and no longer present after a week following status epilepticus (J. Neurosci. 2010;30:6188-96).

The identification of a "critical period" for molecular events setting the stage for future seizures raises the enticing possibility of designing a brief intervention to halt the process, Dr. McNamara said.

Dr. McNamara and his team put this theory to the test by introducing a TrkB inhibitor to genetically engineered mice soon after they had experienced an episode of status epilepticus. This prevented subsequent seizures or sharply reduced their frequency.

"Can we identify a drug – a.k.a. ‘magic bullet’ – to inhibit TrkB or causal downstream signaling pathway [in humans]? I think that globally in this field there is progress that invites optimism," Dr. McNamara said.

Such an intervention could potentially prevent development of a life-altering form of epilepsy using a short-term strategy.

"Limiting drug treatment to a week or two following status epilepticus minimizes unwanted effects inherent in lifelong drug exposure," he noted.

How early would one need to intervene following status epilepticus?

"That is an incredibly important question," he said in response to an audience query about timing. "We hope that [the National Institute for Neurological Disorders and Stroke] will continue its support so we can answer that."

Dr. Berkovic reported receiving honoraria from UCB Pharma and Wolters Kluwer. Dr. McNamara disclosed that he is a consultant for Pappas Ventures and founder and member of the board of directors of NeurOp.

Courtesy Dr. Samuel F. Berkovic

SAN DIEGO – Like pivotal puzzle pieces, new genetic and molecular clues to the etiology of epilepsy are bringing into focus processes that have long perplexed clinicians and researchers.

New genetic findings and the unmasking of epileptogenic molecular seizure responses were among the advances outlined by speakers at the meeting’s presidential symposium.

Photo credit: Dr. Samuel F. Berkovic

Dr. Samuel F. Berkovic, codiscoverer of the first epilepsy gene in 1995, announced that "the impact of the new genetics is here now for clinical neurologists," bringing abundant opportunities for translational research and the possibility of unraveling causation within families burdened by epilepsy.

Population studies, twin studies, and multiplex family studies now point to a far greater impact of genetics on the development of epilepsy than ever suspected, said Dr. Berkovic, director of the Epilepsy Research Centre and laureate professor of medicine at the University of Melbourne.

"Most patients who walk into my clinic or yours don’t [speak of] a family history," he said.

Instead, "fairy stories" such as minor birth injuries or "a fall from a swing" are often cited as explanations for a family member’s seizures.

Incomplete family histories, de novo mutagenesis, and complex genetic inherence patterns all contribute to an underappreciation of the genetic underpinnings of many forms of epilepsy, not only among family members, but by clinicians as well, Dr. Berkovic explained.

His center’s study of more than 300 twins with epilepsy has now detected a concordance rate of 0.73 for generalized epilepsy among monozygous twins.

"That’s about as high as it gets in any complex disease," he said.

Monozygous concordance rates for focal epilepsy (0.34) and febrile epilepsy (0.60) were also much higher than anticipated, he said.

Epilepsy due to a single genetic mutation has proved to be rare, but "the smart money is going to be downstream, ... [with] a whole array of variants acting on common pathways."

Several unexpected findings have already surfaced in the search for genetic clues to epilepsy, including a link between mutations in the GLUT-1 gene (a glucose transporter to the brain) and paroxysmal exercise-induced dystonia and a wide spectrum of idiopathic generalized epilepsies, particularly those with absence seizures.

Unexpected deletions or duplications of gene copies have also been a fruitful avenue of study in epilepsy that includes intellectual disability or autism, Dr. Berkovic said.

Genetic investigations have become essential in such cases, producing a "hit rate on the order of 10%, somewhat of a big surprise," he said.

Studies from Dr. Berkovic’s group also revealed that the de novo mutation in the SCN1A gene found in 80% of individuals with Dravet syndrome likely occurs as early as the two-cell stage of embryonic development, since the mutation was present in a variety of tissue samples – lymphocytes, hair, buccal cells, and neuronal cells of one twin and not the other in studied pairs.

Deletion of chromosome 15q has been found to knock out seven genes and has been linked to autism, intellectual disability, and schizophrenia. Ironically, it is linked to merely a mild form of genetic generalized epilepsy.

At the opposite end of the spectrum are de novo mutations that cause profoundly severe epileptic encephalopathies in early childhood. These have now been identified as the cause of "at least a third if not half of these previously unsolved cases," he said.

"Diagnosis can be made rapidly in the clinic and one can get on with the business of counseling the families and doing the best one can with a terrible genetic burden," he said.

New technology that permits the sequencing of 20,000 genes for less than $1,000 is leading to the rapid discovery of genes underlying rare forms of epilepsy, such as the identification of the GOSR2 gene responsible for progressive myoclonic epilepsy (Am. J. Hum. Genet. 2011;88:657-63).

Genetic advances with massive parallel sequencing are "just astonishing," he said, pointing to the discovery of 50 new recessive genes for myogenic disorders.

Dr. James O. McNamara, chairman of neurobiology at Duke University Medical Center in Durham, N.C., shared Dr. Berkovic’s enthusiasm.

"This is an incredibly exciting time for the epilepsies," he marveled, embarking on a talk about a promising suspect in the search for the molecular link between complicated febrile seizures and subsequent development of mesial temporal lobe epilepsy.

Dr. McNamara reviewed a series of animal studies showing that activation of the tyrosine receptor kinase TrkB immediately following status epilepticus is both necessary and sufficient to produce temporal lobe epilepsy later in life.

Increased activity of TrkB in synapses ipsilateral to the amygdala within the hippocampus was "fleeting," he emphasized, peaking at 6-24 hours and no longer present after a week following status epilepticus (J. Neurosci. 2010;30:6188-96).

The identification of a "critical period" for molecular events setting the stage for future seizures raises the enticing possibility of designing a brief intervention to halt the process, Dr. McNamara said.

Dr. McNamara and his team put this theory to the test by introducing a TrkB inhibitor to genetically engineered mice soon after they had experienced an episode of status epilepticus. This prevented subsequent seizures or sharply reduced their frequency.

"Can we identify a drug – a.k.a. ‘magic bullet’ – to inhibit TrkB or causal downstream signaling pathway [in humans]? I think that globally in this field there is progress that invites optimism," Dr. McNamara said.

Such an intervention could potentially prevent development of a life-altering form of epilepsy using a short-term strategy.

"Limiting drug treatment to a week or two following status epilepticus minimizes unwanted effects inherent in lifelong drug exposure," he noted.

How early would one need to intervene following status epilepticus?

"That is an incredibly important question," he said in response to an audience query about timing. "We hope that [the National Institute for Neurological Disorders and Stroke] will continue its support so we can answer that."

Dr. Berkovic reported receiving honoraria from UCB Pharma and Wolters Kluwer. Dr. McNamara disclosed that he is a consultant for Pappas Ventures and founder and member of the board of directors of NeurOp.

Courtesy Dr. Samuel F. Berkovic

SAN DIEGO – Tick, tick, tick.

It’s a familiar sound to neurologists, who have grown accustomed to watching the clock as they hurry to get tissue plasminogen activator on board in ischemic stroke patients.

If Dr. Steven Cramer proves correct, a second timer may soon be ticking, this one measuring in days or weeks a limited "golden" period in which combined restorative therapies and rehabilitation efforts should be initiated to achieve maximum effect.

"Therapeutic windows open and close," stressed the University of California, Irvine (UCI), professor of neurology during a presentation at the annual meeting of the American Neurological Association.

Comparing brain plasticity after stroke to that seen in early development, Dr. Cramer emphasized the need for pairing restorative therapeutic targets with behavioral conditioning, and doing it all at the optimal time.

"It takes a lot of practice to make the brain better."

Nature provides its own best rationale, propelling "most of the action" in spontaneous recovery within a month post-stroke, he said.

In animal models, brain response to a unilateral lesion is rapid and intense, Dr. Cramer explained.

"We see inflammation and a wealth of growth events that look very much like a developing brain. It’s an excitable brain," ushering in building blocks for repair and regrowth of cells, dendrites, and synapses.

"Some people look at this and say these are molecular underpinnings of spontaneous recovery. Some people look at this and say, these are therapeutic targets, because if these are the components that are the backbone of spontaneous repair, amplifying these sorts of processes could lead to enhanced outcomes compared to the natural processes."

Quickly administered stand-alone treatments have indeed been shown to mimic and expand on this natural boost to early recovery, but Dr. Cramer predicted far more will happen if active rehabilitation is added to the mix.

"When the brain is fertile to undergo repair, whatever substance you give has maximum effect if it is paired with the right kind of experience," Dr. Cramer said.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

"Pixie dust" may soon come in the guise of growth factors; monoclonal antibodies; existing drugs such as amphetamines, levodopa, or SSRIs; or cell-based therapies, he said.

Similarly, on the rehabilitation side, labs around the world – including Dr. Cramer’s at UCI – are experimenting with robot-assisted movement devices that show moderate but nonetheless impressive results when used long after a stroke.

UCI’s Hand-Wrist Assisting Robotic Device (HWARD), like the MIT-Manus, Stanford University’s MIME, the United Kingdom’s GENTLE/S, and other, unnamed devices, have mostly been put to use providing intensive movement assistance to chronic stroke patients, sometimes years after a stroke.

For example, the HWARD device at UCI currently helps chronic stroke patients do such engaging activities as playing blackjack, and soon will move into their homes for round-the-clock skill-building athletics and games, Dr. Cramer said.

A pilot study of the HWARD robot found significant arm and hand functional improvement in 13 patients who had a hemiparetic stroke a mean of 2.9 years prior to the study. The improvement was noted on changes in their performance on the Action Research Arm Test and the arm motor score of the Fugl-Meyer Assessment (Brain. 2008;131:425-37).

In a recent study of another device, researchers at the VA Medical Center and Brown University in Providence, R.I., randomized 127 chronic stroke patients to usual care, intensive traditional physical therapy, or robot-assisted physical therapy that involved more than 1,000 upper limb movements per session.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

The robot-assisted group trended toward a significant improvement in Fugl-Meyer Assessment scores, while function declined in the usual care group over the 12-week trial.

Notably, the trial’s participants were enrolled an average of 5 years following their strokes, with a range of 6 months to 24 years.

Dr. Cramer’s suggestion is that it might make more sense to strike while the iron is hot. And he warns, it may not be hot very long after a stroke.

"Repair is an organizational problem, and it’s time sensitive," he said.

In fact, some candidates for repair boosting – gamma-aminobutyric acid (GABA) agonists, for example – are "excellent targets in the first few hours, but wait a few days and these become toxic."

Just as injured brains may be receptive early on to neurochemical or cellular assistance, they also may need early reinforcement of experiences at risk of being lost forever.

This is the time when robotic assistance of movements, applied multiple times, may be especially useful in properly selected patients, especially those with evidence of abundant preserved regions of the corticospinal tract.

"It takes a lot of practice to make the brain better," he said.

Perhaps, he said, that practice should begin during the "black box" period, during the 90 days following hospital discharge. In fact, Dr. Cramer and his colleagues are now enrolling up to 72 patients who had a hemiparetic stroke within the past 11-26 weeks in a phase II trial of 3 weeks of therapy with the HWARD robot.

Dr. Cramer disclosed that he has received grant support and has served as a paid consultant for GlaxoSmithKline, and has also consulted for PhotoThera, Allergan, Pfizer/CogState, and Johnson & Johnson.

SAN DIEGO – Tick, tick, tick.

It’s a familiar sound to neurologists, who have grown accustomed to watching the clock as they hurry to get tissue plasminogen activator on board in ischemic stroke patients.

If Dr. Steven Cramer proves correct, a second timer may soon be ticking, this one measuring in days or weeks a limited "golden" period in which combined restorative therapies and rehabilitation efforts should be initiated to achieve maximum effect.

"Therapeutic windows open and close," stressed the University of California, Irvine (UCI), professor of neurology during a presentation at the annual meeting of the American Neurological Association.

Comparing brain plasticity after stroke to that seen in early development, Dr. Cramer emphasized the need for pairing restorative therapeutic targets with behavioral conditioning, and doing it all at the optimal time.

"It takes a lot of practice to make the brain better."

Nature provides its own best rationale, propelling "most of the action" in spontaneous recovery within a month post-stroke, he said.

In animal models, brain response to a unilateral lesion is rapid and intense, Dr. Cramer explained.

"We see inflammation and a wealth of growth events that look very much like a developing brain. It’s an excitable brain," ushering in building blocks for repair and regrowth of cells, dendrites, and synapses.

"Some people look at this and say these are molecular underpinnings of spontaneous recovery. Some people look at this and say, these are therapeutic targets, because if these are the components that are the backbone of spontaneous repair, amplifying these sorts of processes could lead to enhanced outcomes compared to the natural processes."

Quickly administered stand-alone treatments have indeed been shown to mimic and expand on this natural boost to early recovery, but Dr. Cramer predicted far more will happen if active rehabilitation is added to the mix.

"When the brain is fertile to undergo repair, whatever substance you give has maximum effect if it is paired with the right kind of experience," Dr. Cramer said.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

"Pixie dust" may soon come in the guise of growth factors; monoclonal antibodies; existing drugs such as amphetamines, levodopa, or SSRIs; or cell-based therapies, he said.

Similarly, on the rehabilitation side, labs around the world – including Dr. Cramer’s at UCI – are experimenting with robot-assisted movement devices that show moderate but nonetheless impressive results when used long after a stroke.

UCI’s Hand-Wrist Assisting Robotic Device (HWARD), like the MIT-Manus, Stanford University’s MIME, the United Kingdom’s GENTLE/S, and other, unnamed devices, have mostly been put to use providing intensive movement assistance to chronic stroke patients, sometimes years after a stroke.

For example, the HWARD device at UCI currently helps chronic stroke patients do such engaging activities as playing blackjack, and soon will move into their homes for round-the-clock skill-building athletics and games, Dr. Cramer said.

A pilot study of the HWARD robot found significant arm and hand functional improvement in 13 patients who had a hemiparetic stroke a mean of 2.9 years prior to the study. The improvement was noted on changes in their performance on the Action Research Arm Test and the arm motor score of the Fugl-Meyer Assessment (Brain. 2008;131:425-37).

In a recent study of another device, researchers at the VA Medical Center and Brown University in Providence, R.I., randomized 127 chronic stroke patients to usual care, intensive traditional physical therapy, or robot-assisted physical therapy that involved more than 1,000 upper limb movements per session.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

The robot-assisted group trended toward a significant improvement in Fugl-Meyer Assessment scores, while function declined in the usual care group over the 12-week trial.

Notably, the trial’s participants were enrolled an average of 5 years following their strokes, with a range of 6 months to 24 years.

Dr. Cramer’s suggestion is that it might make more sense to strike while the iron is hot. And he warns, it may not be hot very long after a stroke.

"Repair is an organizational problem, and it’s time sensitive," he said.

In fact, some candidates for repair boosting – gamma-aminobutyric acid (GABA) agonists, for example – are "excellent targets in the first few hours, but wait a few days and these become toxic."

Just as injured brains may be receptive early on to neurochemical or cellular assistance, they also may need early reinforcement of experiences at risk of being lost forever.

This is the time when robotic assistance of movements, applied multiple times, may be especially useful in properly selected patients, especially those with evidence of abundant preserved regions of the corticospinal tract.

"It takes a lot of practice to make the brain better," he said.

Perhaps, he said, that practice should begin during the "black box" period, during the 90 days following hospital discharge. In fact, Dr. Cramer and his colleagues are now enrolling up to 72 patients who had a hemiparetic stroke within the past 11-26 weeks in a phase II trial of 3 weeks of therapy with the HWARD robot.

Dr. Cramer disclosed that he has received grant support and has served as a paid consultant for GlaxoSmithKline, and has also consulted for PhotoThera, Allergan, Pfizer/CogState, and Johnson & Johnson.

SAN DIEGO – Tick, tick, tick.

It’s a familiar sound to neurologists, who have grown accustomed to watching the clock as they hurry to get tissue plasminogen activator on board in ischemic stroke patients.

If Dr. Steven Cramer proves correct, a second timer may soon be ticking, this one measuring in days or weeks a limited "golden" period in which combined restorative therapies and rehabilitation efforts should be initiated to achieve maximum effect.

"Therapeutic windows open and close," stressed the University of California, Irvine (UCI), professor of neurology during a presentation at the annual meeting of the American Neurological Association.

Comparing brain plasticity after stroke to that seen in early development, Dr. Cramer emphasized the need for pairing restorative therapeutic targets with behavioral conditioning, and doing it all at the optimal time.

"It takes a lot of practice to make the brain better."

Nature provides its own best rationale, propelling "most of the action" in spontaneous recovery within a month post-stroke, he said.

In animal models, brain response to a unilateral lesion is rapid and intense, Dr. Cramer explained.

"We see inflammation and a wealth of growth events that look very much like a developing brain. It’s an excitable brain," ushering in building blocks for repair and regrowth of cells, dendrites, and synapses.

"Some people look at this and say these are molecular underpinnings of spontaneous recovery. Some people look at this and say, these are therapeutic targets, because if these are the components that are the backbone of spontaneous repair, amplifying these sorts of processes could lead to enhanced outcomes compared to the natural processes."

Quickly administered stand-alone treatments have indeed been shown to mimic and expand on this natural boost to early recovery, but Dr. Cramer predicted far more will happen if active rehabilitation is added to the mix.

"When the brain is fertile to undergo repair, whatever substance you give has maximum effect if it is paired with the right kind of experience," Dr. Cramer said.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

"Pixie dust" may soon come in the guise of growth factors; monoclonal antibodies; existing drugs such as amphetamines, levodopa, or SSRIs; or cell-based therapies, he said.

Similarly, on the rehabilitation side, labs around the world – including Dr. Cramer’s at UCI – are experimenting with robot-assisted movement devices that show moderate but nonetheless impressive results when used long after a stroke.

UCI’s Hand-Wrist Assisting Robotic Device (HWARD), like the MIT-Manus, Stanford University’s MIME, the United Kingdom’s GENTLE/S, and other, unnamed devices, have mostly been put to use providing intensive movement assistance to chronic stroke patients, sometimes years after a stroke.

For example, the HWARD device at UCI currently helps chronic stroke patients do such engaging activities as playing blackjack, and soon will move into their homes for round-the-clock skill-building athletics and games, Dr. Cramer said.

A pilot study of the HWARD robot found significant arm and hand functional improvement in 13 patients who had a hemiparetic stroke a mean of 2.9 years prior to the study. The improvement was noted on changes in their performance on the Action Research Arm Test and the arm motor score of the Fugl-Meyer Assessment (Brain. 2008;131:425-37).

In a recent study of another device, researchers at the VA Medical Center and Brown University in Providence, R.I., randomized 127 chronic stroke patients to usual care, intensive traditional physical therapy, or robot-assisted physical therapy that involved more than 1,000 upper limb movements per session.

"If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping."

The robot-assisted group trended toward a significant improvement in Fugl-Meyer Assessment scores, while function declined in the usual care group over the 12-week trial.

Notably, the trial’s participants were enrolled an average of 5 years following their strokes, with a range of 6 months to 24 years.

Dr. Cramer’s suggestion is that it might make more sense to strike while the iron is hot. And he warns, it may not be hot very long after a stroke.

"Repair is an organizational problem, and it’s time sensitive," he said.

In fact, some candidates for repair boosting – gamma-aminobutyric acid (GABA) agonists, for example – are "excellent targets in the first few hours, but wait a few days and these become toxic."

Just as injured brains may be receptive early on to neurochemical or cellular assistance, they also may need early reinforcement of experiences at risk of being lost forever.

This is the time when robotic assistance of movements, applied multiple times, may be especially useful in properly selected patients, especially those with evidence of abundant preserved regions of the corticospinal tract.

"It takes a lot of practice to make the brain better," he said.

Perhaps, he said, that practice should begin during the "black box" period, during the 90 days following hospital discharge. In fact, Dr. Cramer and his colleagues are now enrolling up to 72 patients who had a hemiparetic stroke within the past 11-26 weeks in a phase II trial of 3 weeks of therapy with the HWARD robot.

Dr. Cramer disclosed that he has received grant support and has served as a paid consultant for GlaxoSmithKline, and has also consulted for PhotoThera, Allergan, Pfizer/CogState, and Johnson & Johnson.

SAN DIEGO – A series of "on-off" switches regulates sleep, clarifying many of the mechanisms underlying narcolepsy, cataplexy, and REM sleep behavior disorder, according to Dr. Clifford B. Saper.

The states of sleep, wakefulness, rapid eye movement and non-REM sleep can best be understood as "flip-flop" mechanisms of brain circuitry, akin to light switches, said Dr. Saper, professor of neurology and neuroscience at Harvard Medical School and head of the department of neurology at Beth Israel Deaconess Medical Center in Boston.

"Each side inhibits the other" in an ascending arousal pathway to the cortex, facilitating rapid transitions from one state to the other.

Normally, human beings spend 99% of the 24-hour day fully awake or fully asleep, and just 1% of the time transitioning. This is due to an on-off switch that regulates arousal and sleep, Dr. Saper said at the annual meeting of the American Neurological Association.

"One of the problems with a flip-flop switch is that it has a tendency, sometimes, to fall into the wrong position too easily. One can imagine driving down a boring road and flipping into the wrong state and suddenly being asleep behind the wheel of a car," he said.

To prevent such an occurrence, the brain stabilizes wakefulness by the use of orexins, or hypocretins, which are neuropeptides produced by excitatory neurons in the lateral region of the hypothalamus.

Narcolepsy, in which patients do fall asleep essentially at the "flip of a switch," is the result of a single neurotransmitter deficit in sleep’s "master switch," the ventrolateral preoptic nucleus, Dr. Saper explained.

A similar "flip-flop" switch regulates the normally rapid transition between REM and non-REM (slow-wave) sleep, he said.

The development of REM sleep behavior disorder (in which patients make jerky motor maneuvers as they act out dreams during sleep) and cataplexy – atonic lapses in muscle control from a waking state – are opposites on a spectrum, both indicative of triggering of the on-off mechanism at an inappropriate point in the cycle.

Of great interest to Dr. Saper is an evolving apparent link between the development of REM sleep behavior disorder in young adulthood and later development of Parkinson’s disease, a phenomenon that occurs in about half of REM behavior disorder patients within 12 years.

He noted that Dr. Ronald B. Postuma and his associates at Montreal General Hospital have identified early markers of Parkinson’s disease in idiopathic REM sleep behavior disorder patients, including difficulties with visual and olfactory discrimination tasks and subthreshold but low scores on the Unified Parkinson's Disease Rating Scale.

The connection has led some researchers to suspect that synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies may begin at the brainstem level of the locus coeruleus or the subcoeruleus complex and slowly progress in an ascending pathway to the basal ganglia over years or decades, offering the possibility of introducing neuroprotective therapy to stop that progression.

Dr. Saper reported having no relevant financial disclosures.

SAN DIEGO – A series of "on-off" switches regulates sleep, clarifying many of the mechanisms underlying narcolepsy, cataplexy, and REM sleep behavior disorder, according to Dr. Clifford B. Saper.

The states of sleep, wakefulness, rapid eye movement and non-REM sleep can best be understood as "flip-flop" mechanisms of brain circuitry, akin to light switches, said Dr. Saper, professor of neurology and neuroscience at Harvard Medical School and head of the department of neurology at Beth Israel Deaconess Medical Center in Boston.

"Each side inhibits the other" in an ascending arousal pathway to the cortex, facilitating rapid transitions from one state to the other.

Normally, human beings spend 99% of the 24-hour day fully awake or fully asleep, and just 1% of the time transitioning. This is due to an on-off switch that regulates arousal and sleep, Dr. Saper said at the annual meeting of the American Neurological Association.

"One of the problems with a flip-flop switch is that it has a tendency, sometimes, to fall into the wrong position too easily. One can imagine driving down a boring road and flipping into the wrong state and suddenly being asleep behind the wheel of a car," he said.

To prevent such an occurrence, the brain stabilizes wakefulness by the use of orexins, or hypocretins, which are neuropeptides produced by excitatory neurons in the lateral region of the hypothalamus.

Narcolepsy, in which patients do fall asleep essentially at the "flip of a switch," is the result of a single neurotransmitter deficit in sleep’s "master switch," the ventrolateral preoptic nucleus, Dr. Saper explained.

A similar "flip-flop" switch regulates the normally rapid transition between REM and non-REM (slow-wave) sleep, he said.

The development of REM sleep behavior disorder (in which patients make jerky motor maneuvers as they act out dreams during sleep) and cataplexy – atonic lapses in muscle control from a waking state – are opposites on a spectrum, both indicative of triggering of the on-off mechanism at an inappropriate point in the cycle.

Of great interest to Dr. Saper is an evolving apparent link between the development of REM sleep behavior disorder in young adulthood and later development of Parkinson’s disease, a phenomenon that occurs in about half of REM behavior disorder patients within 12 years.

He noted that Dr. Ronald B. Postuma and his associates at Montreal General Hospital have identified early markers of Parkinson’s disease in idiopathic REM sleep behavior disorder patients, including difficulties with visual and olfactory discrimination tasks and subthreshold but low scores on the Unified Parkinson's Disease Rating Scale.

The connection has led some researchers to suspect that synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies may begin at the brainstem level of the locus coeruleus or the subcoeruleus complex and slowly progress in an ascending pathway to the basal ganglia over years or decades, offering the possibility of introducing neuroprotective therapy to stop that progression.

Dr. Saper reported having no relevant financial disclosures.

SAN DIEGO – A series of "on-off" switches regulates sleep, clarifying many of the mechanisms underlying narcolepsy, cataplexy, and REM sleep behavior disorder, according to Dr. Clifford B. Saper.

The states of sleep, wakefulness, rapid eye movement and non-REM sleep can best be understood as "flip-flop" mechanisms of brain circuitry, akin to light switches, said Dr. Saper, professor of neurology and neuroscience at Harvard Medical School and head of the department of neurology at Beth Israel Deaconess Medical Center in Boston.

"Each side inhibits the other" in an ascending arousal pathway to the cortex, facilitating rapid transitions from one state to the other.

Normally, human beings spend 99% of the 24-hour day fully awake or fully asleep, and just 1% of the time transitioning. This is due to an on-off switch that regulates arousal and sleep, Dr. Saper said at the annual meeting of the American Neurological Association.

"One of the problems with a flip-flop switch is that it has a tendency, sometimes, to fall into the wrong position too easily. One can imagine driving down a boring road and flipping into the wrong state and suddenly being asleep behind the wheel of a car," he said.

To prevent such an occurrence, the brain stabilizes wakefulness by the use of orexins, or hypocretins, which are neuropeptides produced by excitatory neurons in the lateral region of the hypothalamus.

Narcolepsy, in which patients do fall asleep essentially at the "flip of a switch," is the result of a single neurotransmitter deficit in sleep’s "master switch," the ventrolateral preoptic nucleus, Dr. Saper explained.

A similar "flip-flop" switch regulates the normally rapid transition between REM and non-REM (slow-wave) sleep, he said.

The development of REM sleep behavior disorder (in which patients make jerky motor maneuvers as they act out dreams during sleep) and cataplexy – atonic lapses in muscle control from a waking state – are opposites on a spectrum, both indicative of triggering of the on-off mechanism at an inappropriate point in the cycle.

Of great interest to Dr. Saper is an evolving apparent link between the development of REM sleep behavior disorder in young adulthood and later development of Parkinson’s disease, a phenomenon that occurs in about half of REM behavior disorder patients within 12 years.

He noted that Dr. Ronald B. Postuma and his associates at Montreal General Hospital have identified early markers of Parkinson’s disease in idiopathic REM sleep behavior disorder patients, including difficulties with visual and olfactory discrimination tasks and subthreshold but low scores on the Unified Parkinson's Disease Rating Scale.

The connection has led some researchers to suspect that synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies may begin at the brainstem level of the locus coeruleus or the subcoeruleus complex and slowly progress in an ascending pathway to the basal ganglia over years or decades, offering the possibility of introducing neuroprotective therapy to stop that progression.

Dr. Saper reported having no relevant financial disclosures.

SAN DIEGO – Citing vastly improved management of carotid stenosis, the principal investigator of the Carotid Revascularization Endarterectomy vs. Stenting Trial has called for yet another trial, this one to clarify risks and benefits of surgery vs. aggressive medical management to prevent stroke in asymptomatic patients.

Every contemporary intervention to prevent strokes – endarterectomy, carotid stenting, and aggressive medical management of risk factors – is becoming safer and more efficacious, said Dr. Thomas G. Brott of the Mayo Clinic, Jacksonville, Fla., at the opening symposium of the annual meeting of the American Neurological Association.

The dilemma, according to Dr. Brott: "We don’t know how they stack up."

"Unfortunately, the new opinions outweigh the new data."

Current clinical practice was shaped by results of the ACAS (Asymptomatic Carotid Atherosclerosis Study) and the ACST (Asymptomatic Carotid Surgery Trial), in which carotid endarterectomy (CEA) trumped medical management for prevention of stroke, Dr. Brott explained.

CREST (Carotid Revascularization Endarterectomy vs. Stenting Trial), which began enrolling only symptomatic patients, added asymptomatic subjects after publication of ACST results in 2004. In the end, it concluded that perioperative stroke and death rates were "low and similar" for stenting (2.5%) and endarterectomy (1.4%).

Revascularization with carotid artery stenting has remained somewhat controversial, with the current body of evidence suggesting the need for better control of rare, but real, complications and mortality, particularly in certain populations, including Medicare patients.

Meanwhile, recent epidemiologic studies demonstrate profoundly lowered stroke rates without surgery or stenting, via intensive medical therapy to control risk factors such as hypertension, hyperlipidemia, and insulin resistance. For example, a population-based study in the United Kingdom found that the rate of ipsilateral stroke in medically treated patients who had carotid stenosis of 50% or greater was 0.3%.

Two new, randomized trials suggest that intensive medical therapy can indeed produce far more impressive results than anticipated in a prospective study of patients with asymptomatic carotid stenosis (Arch. Neurol. 2010;67:180-6), and even in patients with severe intracranial artery stenosis in the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial (N. Engl. J. Med. 2011;365:993-1003), Dr. Brott noted.

Various groups, including the Centers for Medicare and Medicaid Services, the American Heart Association, and the American Stroke Association, have weighed in with opinions on the management of asymptomatic patients in the hopes of preventing an estimated 5%-10% of all strokes.

The problem, Dr. Brott said, is not a lack of guidance for current treatment decisions, but the lack of a direct comparison of carotid revascularization vs. contemporary medical therapy.

"We have evolving opinion without evolving data," he asserted.

Much is at stake, with carotid revascularization selected for 80,000-90,000 asymptomatic patients each year in the United States, and carotid artery stenting for another 40,000 patients.

Dr. Brott proposed a trial to enroll 950 patients at 70 centers, with the CREST team providing the interventional arm and the SAMMPRIS team providing the medical management arm in asymptomatic patients exhibiting at least 70% carotid stenosis by angiography or ultrasound.

The effect size proposed by Dr. Brott of 1.2% would be equal to the absolute difference in the primary end point (periprocedural stroke and death or subsequent ipsilateral stroke) in the ACAS trial, a difference substantial enough to alter clinical practice.

"We think such a trial can be done in a reasonable amount of time and provide us with ... contemporary data," he said.

Dr. Walter J. Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke, said by e-mail that a grant proposal for such a study has been received by the institute, but he would not elaborate on its feasibility or methodology, noting that the institute’s "leadership depends heavily on ... peer review study sections to provide advice."

Dr. Brott said that he had no relevant financial disclosures.

SAN DIEGO – Citing vastly improved management of carotid stenosis, the principal investigator of the Carotid Revascularization Endarterectomy vs. Stenting Trial has called for yet another trial, this one to clarify risks and benefits of surgery vs. aggressive medical management to prevent stroke in asymptomatic patients.

Every contemporary intervention to prevent strokes – endarterectomy, carotid stenting, and aggressive medical management of risk factors – is becoming safer and more efficacious, said Dr. Thomas G. Brott of the Mayo Clinic, Jacksonville, Fla., at the opening symposium of the annual meeting of the American Neurological Association.

The dilemma, according to Dr. Brott: "We don’t know how they stack up."

"Unfortunately, the new opinions outweigh the new data."

Current clinical practice was shaped by results of the ACAS (Asymptomatic Carotid Atherosclerosis Study) and the ACST (Asymptomatic Carotid Surgery Trial), in which carotid endarterectomy (CEA) trumped medical management for prevention of stroke, Dr. Brott explained.

CREST (Carotid Revascularization Endarterectomy vs. Stenting Trial), which began enrolling only symptomatic patients, added asymptomatic subjects after publication of ACST results in 2004. In the end, it concluded that perioperative stroke and death rates were "low and similar" for stenting (2.5%) and endarterectomy (1.4%).

Revascularization with carotid artery stenting has remained somewhat controversial, with the current body of evidence suggesting the need for better control of rare, but real, complications and mortality, particularly in certain populations, including Medicare patients.

Meanwhile, recent epidemiologic studies demonstrate profoundly lowered stroke rates without surgery or stenting, via intensive medical therapy to control risk factors such as hypertension, hyperlipidemia, and insulin resistance. For example, a population-based study in the United Kingdom found that the rate of ipsilateral stroke in medically treated patients who had carotid stenosis of 50% or greater was 0.3%.

Two new, randomized trials suggest that intensive medical therapy can indeed produce far more impressive results than anticipated in a prospective study of patients with asymptomatic carotid stenosis (Arch. Neurol. 2010;67:180-6), and even in patients with severe intracranial artery stenosis in the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial (N. Engl. J. Med. 2011;365:993-1003), Dr. Brott noted.

Various groups, including the Centers for Medicare and Medicaid Services, the American Heart Association, and the American Stroke Association, have weighed in with opinions on the management of asymptomatic patients in the hopes of preventing an estimated 5%-10% of all strokes.

The problem, Dr. Brott said, is not a lack of guidance for current treatment decisions, but the lack of a direct comparison of carotid revascularization vs. contemporary medical therapy.

"We have evolving opinion without evolving data," he asserted.

Much is at stake, with carotid revascularization selected for 80,000-90,000 asymptomatic patients each year in the United States, and carotid artery stenting for another 40,000 patients.

Dr. Brott proposed a trial to enroll 950 patients at 70 centers, with the CREST team providing the interventional arm and the SAMMPRIS team providing the medical management arm in asymptomatic patients exhibiting at least 70% carotid stenosis by angiography or ultrasound.

The effect size proposed by Dr. Brott of 1.2% would be equal to the absolute difference in the primary end point (periprocedural stroke and death or subsequent ipsilateral stroke) in the ACAS trial, a difference substantial enough to alter clinical practice.

"We think such a trial can be done in a reasonable amount of time and provide us with ... contemporary data," he said.

Dr. Walter J. Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke, said by e-mail that a grant proposal for such a study has been received by the institute, but he would not elaborate on its feasibility or methodology, noting that the institute’s "leadership depends heavily on ... peer review study sections to provide advice."

Dr. Brott said that he had no relevant financial disclosures.

SAN DIEGO – Citing vastly improved management of carotid stenosis, the principal investigator of the Carotid Revascularization Endarterectomy vs. Stenting Trial has called for yet another trial, this one to clarify risks and benefits of surgery vs. aggressive medical management to prevent stroke in asymptomatic patients.

Every contemporary intervention to prevent strokes – endarterectomy, carotid stenting, and aggressive medical management of risk factors – is becoming safer and more efficacious, said Dr. Thomas G. Brott of the Mayo Clinic, Jacksonville, Fla., at the opening symposium of the annual meeting of the American Neurological Association.

The dilemma, according to Dr. Brott: "We don’t know how they stack up."

"Unfortunately, the new opinions outweigh the new data."

Current clinical practice was shaped by results of the ACAS (Asymptomatic Carotid Atherosclerosis Study) and the ACST (Asymptomatic Carotid Surgery Trial), in which carotid endarterectomy (CEA) trumped medical management for prevention of stroke, Dr. Brott explained.

CREST (Carotid Revascularization Endarterectomy vs. Stenting Trial), which began enrolling only symptomatic patients, added asymptomatic subjects after publication of ACST results in 2004. In the end, it concluded that perioperative stroke and death rates were "low and similar" for stenting (2.5%) and endarterectomy (1.4%).

Revascularization with carotid artery stenting has remained somewhat controversial, with the current body of evidence suggesting the need for better control of rare, but real, complications and mortality, particularly in certain populations, including Medicare patients.

Meanwhile, recent epidemiologic studies demonstrate profoundly lowered stroke rates without surgery or stenting, via intensive medical therapy to control risk factors such as hypertension, hyperlipidemia, and insulin resistance. For example, a population-based study in the United Kingdom found that the rate of ipsilateral stroke in medically treated patients who had carotid stenosis of 50% or greater was 0.3%.

Two new, randomized trials suggest that intensive medical therapy can indeed produce far more impressive results than anticipated in a prospective study of patients with asymptomatic carotid stenosis (Arch. Neurol. 2010;67:180-6), and even in patients with severe intracranial artery stenosis in the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial (N. Engl. J. Med. 2011;365:993-1003), Dr. Brott noted.

Various groups, including the Centers for Medicare and Medicaid Services, the American Heart Association, and the American Stroke Association, have weighed in with opinions on the management of asymptomatic patients in the hopes of preventing an estimated 5%-10% of all strokes.

The problem, Dr. Brott said, is not a lack of guidance for current treatment decisions, but the lack of a direct comparison of carotid revascularization vs. contemporary medical therapy.

"We have evolving opinion without evolving data," he asserted.

Much is at stake, with carotid revascularization selected for 80,000-90,000 asymptomatic patients each year in the United States, and carotid artery stenting for another 40,000 patients.

Dr. Brott proposed a trial to enroll 950 patients at 70 centers, with the CREST team providing the interventional arm and the SAMMPRIS team providing the medical management arm in asymptomatic patients exhibiting at least 70% carotid stenosis by angiography or ultrasound.

The effect size proposed by Dr. Brott of 1.2% would be equal to the absolute difference in the primary end point (periprocedural stroke and death or subsequent ipsilateral stroke) in the ACAS trial, a difference substantial enough to alter clinical practice.

"We think such a trial can be done in a reasonable amount of time and provide us with ... contemporary data," he said.

Dr. Walter J. Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke, said by e-mail that a grant proposal for such a study has been received by the institute, but he would not elaborate on its feasibility or methodology, noting that the institute’s "leadership depends heavily on ... peer review study sections to provide advice."

Dr. Brott said that he had no relevant financial disclosures.

SAN DIEGO – What if 3-6 million Americans had an asymptomatic condition that was easily, but coincidentally, detected on CT and MRI scans?

What if a number of excellent, but expensive, options existed to treat this condition, potentially preventing a catastrophic event in 0%-53% of cases, depending on the size, location, and duration of the problematic entity?

Obviously, you would look to well-designed, prospective, randomized, controlled trials intended to determine which patients should be referred for treatment, which patients should be watched, and which should be reassured.

But such trials don’t exist.

This real-life scenario describes asymptomatic, saccular, unruptured intracranial aneurysms (UIAs), which pose a management conundrum for virtually every neurologist in practice today.

"These are extremely common. About 2% of the population has a UIA," including perhaps 14 of the 700 attendees of the annual meeting of the American Neurological Association, noted Dr. Robert D. Brown during a symposium at the meeting.

"Not to fret," Dr. Brown assured the audience after personalizing his statistics. "That doesn’t necessary mean [14 attendees possess] a ticking time bomb."

Aneurysmal subarachnoid hemorrhages affect 6-10 per 100,000 U.S. population annually, with a case fatality rate of 30%-40%.

Still, "most aneurysms do not rupture," said Dr. Brown, chair of neurology at the Mayo Clinic in Rochester, Minn.

The predominance of natural history studies point to size as being of critical importance in the assessment of rupture risk, "no matter where the location or what the age of the patient," he said.

Secondarily, location and age matter, with posterior aneurysms and those in older patients being at seemingly greater risk of rupture.

But with smaller and smaller aneurysms becoming increasingly easy to see on scans, "we’re in the situation right now where the question is not ‘Can we do anything [with incidentally discovered aneurysms in younger patients],’ but should we?" he remarked.

Beyond patient age and aneurysm size and position, the hypothesized risk factors for rupture include smoking, hypertension, alcohol consumption (with risk associated with no alcohol or high alcohol use), and perhaps family history, as well as morphological characteristics and growth of the aneurysm itself over time.

Epidemiologic cohort studies can help to direct management in the absence of a well-designed, randomized trial, Dr. Brown said.

For example, data on unoperated patients who were enrolled in the 5,500-patient ISUIA (International Study of Unruptured Intracranial Aneurysms) suggest that smaller aneurysms located in the anterior circulation of the circle of Willis and the cavernous segment of the internal carotid artery are quite unlikely to hemorrhage when they are followed conservatively for 5 years.

Available data from the trial also suggest that even very small (less than 7 mm) aneurysms have a potential for hemorrhage that is "noteworthy and certainly far from zero" if they are located in the posterior communicating artery or posterior circulation.

Current and future research is exploring whether more precise analysis of the features of such aneurysms – including their undulation and elliptical indices and nonspherical shape – may be more predictive of rupture risk.

Computational fluid dynamics, drawn from engineering principles, may also provide better guidance, Dr. Brown said.

In the meantime, he cited a "huge variation" in clinical practice when it comes to management of smaller, unruptured aneurysms, with some centers opting to treat 90% with coils or clips and others treating fewer than 10% of such cases.

His own practice, guided by the literature, is to advise treatment in the following situations:

• In younger patients in otherwise good health whose aneurysms measure 7 mm or greater.

• In younger patients in otherwise good health whose aneurysms measure less than 7 mm but are in the posterior circulation.

• Possibly, in older patients with aneurysms measuring 7-12 mm in the posterior circulation.

• In older patients with aneurysms greater than 12 mm in which a reasonable treatment option exists.

Dr. Brown advised aggressive treatment of hypertension and smoking-cessation management in all patients with unruptured aneurysms, as well as careful, imaging-based follow-up of conservatively managed patients based on limited data showing growth in moderate and large lesions over time.

Even 1 in 12 small (measuring less than 8 mm) aneurysms demonstrated "clear, definitive growth" over 4 years in a study of 165 patients (Stroke 2009;40:406-11), he noted.

Aspirin therapy may be beneficial, based on soon-to-be-released data from the ISUIA study showing a "strong and significant" trend toward lower rupture risk in patients taking the highest aspirin doses, he said.

Dr. Brown disclosed no conflicts of interest relative to his talk.

SAN DIEGO – What if 3-6 million Americans had an asymptomatic condition that was easily, but coincidentally, detected on CT and MRI scans?

What if a number of excellent, but expensive, options existed to treat this condition, potentially preventing a catastrophic event in 0%-53% of cases, depending on the size, location, and duration of the problematic entity?

Obviously, you would look to well-designed, prospective, randomized, controlled trials intended to determine which patients should be referred for treatment, which patients should be watched, and which should be reassured.

But such trials don’t exist.

This real-life scenario describes asymptomatic, saccular, unruptured intracranial aneurysms (UIAs), which pose a management conundrum for virtually every neurologist in practice today.

"These are extremely common. About 2% of the population has a UIA," including perhaps 14 of the 700 attendees of the annual meeting of the American Neurological Association, noted Dr. Robert D. Brown during a symposium at the meeting.

"Not to fret," Dr. Brown assured the audience after personalizing his statistics. "That doesn’t necessary mean [14 attendees possess] a ticking time bomb."

Aneurysmal subarachnoid hemorrhages affect 6-10 per 100,000 U.S. population annually, with a case fatality rate of 30%-40%.

Still, "most aneurysms do not rupture," said Dr. Brown, chair of neurology at the Mayo Clinic in Rochester, Minn.

The predominance of natural history studies point to size as being of critical importance in the assessment of rupture risk, "no matter where the location or what the age of the patient," he said.

Secondarily, location and age matter, with posterior aneurysms and those in older patients being at seemingly greater risk of rupture.

But with smaller and smaller aneurysms becoming increasingly easy to see on scans, "we’re in the situation right now where the question is not ‘Can we do anything [with incidentally discovered aneurysms in younger patients],’ but should we?" he remarked.

Beyond patient age and aneurysm size and position, the hypothesized risk factors for rupture include smoking, hypertension, alcohol consumption (with risk associated with no alcohol or high alcohol use), and perhaps family history, as well as morphological characteristics and growth of the aneurysm itself over time.

Epidemiologic cohort studies can help to direct management in the absence of a well-designed, randomized trial, Dr. Brown said.

For example, data on unoperated patients who were enrolled in the 5,500-patient ISUIA (International Study of Unruptured Intracranial Aneurysms) suggest that smaller aneurysms located in the anterior circulation of the circle of Willis and the cavernous segment of the internal carotid artery are quite unlikely to hemorrhage when they are followed conservatively for 5 years.

Available data from the trial also suggest that even very small (less than 7 mm) aneurysms have a potential for hemorrhage that is "noteworthy and certainly far from zero" if they are located in the posterior communicating artery or posterior circulation.

Current and future research is exploring whether more precise analysis of the features of such aneurysms – including their undulation and elliptical indices and nonspherical shape – may be more predictive of rupture risk.

Computational fluid dynamics, drawn from engineering principles, may also provide better guidance, Dr. Brown said.

In the meantime, he cited a "huge variation" in clinical practice when it comes to management of smaller, unruptured aneurysms, with some centers opting to treat 90% with coils or clips and others treating fewer than 10% of such cases.

His own practice, guided by the literature, is to advise treatment in the following situations:

• In younger patients in otherwise good health whose aneurysms measure 7 mm or greater.

• In younger patients in otherwise good health whose aneurysms measure less than 7 mm but are in the posterior circulation.

• Possibly, in older patients with aneurysms measuring 7-12 mm in the posterior circulation.

• In older patients with aneurysms greater than 12 mm in which a reasonable treatment option exists.

Dr. Brown advised aggressive treatment of hypertension and smoking-cessation management in all patients with unruptured aneurysms, as well as careful, imaging-based follow-up of conservatively managed patients based on limited data showing growth in moderate and large lesions over time.

Even 1 in 12 small (measuring less than 8 mm) aneurysms demonstrated "clear, definitive growth" over 4 years in a study of 165 patients (Stroke 2009;40:406-11), he noted.

Aspirin therapy may be beneficial, based on soon-to-be-released data from the ISUIA study showing a "strong and significant" trend toward lower rupture risk in patients taking the highest aspirin doses, he said.

Dr. Brown disclosed no conflicts of interest relative to his talk.

SAN DIEGO – What if 3-6 million Americans had an asymptomatic condition that was easily, but coincidentally, detected on CT and MRI scans?

What if a number of excellent, but expensive, options existed to treat this condition, potentially preventing a catastrophic event in 0%-53% of cases, depending on the size, location, and duration of the problematic entity?

Obviously, you would look to well-designed, prospective, randomized, controlled trials intended to determine which patients should be referred for treatment, which patients should be watched, and which should be reassured.

But such trials don’t exist.

This real-life scenario describes asymptomatic, saccular, unruptured intracranial aneurysms (UIAs), which pose a management conundrum for virtually every neurologist in practice today.

"These are extremely common. About 2% of the population has a UIA," including perhaps 14 of the 700 attendees of the annual meeting of the American Neurological Association, noted Dr. Robert D. Brown during a symposium at the meeting.

"Not to fret," Dr. Brown assured the audience after personalizing his statistics. "That doesn’t necessary mean [14 attendees possess] a ticking time bomb."

Aneurysmal subarachnoid hemorrhages affect 6-10 per 100,000 U.S. population annually, with a case fatality rate of 30%-40%.

Still, "most aneurysms do not rupture," said Dr. Brown, chair of neurology at the Mayo Clinic in Rochester, Minn.

The predominance of natural history studies point to size as being of critical importance in the assessment of rupture risk, "no matter where the location or what the age of the patient," he said.

Secondarily, location and age matter, with posterior aneurysms and those in older patients being at seemingly greater risk of rupture.

But with smaller and smaller aneurysms becoming increasingly easy to see on scans, "we’re in the situation right now where the question is not ‘Can we do anything [with incidentally discovered aneurysms in younger patients],’ but should we?" he remarked.

Beyond patient age and aneurysm size and position, the hypothesized risk factors for rupture include smoking, hypertension, alcohol consumption (with risk associated with no alcohol or high alcohol use), and perhaps family history, as well as morphological characteristics and growth of the aneurysm itself over time.

Epidemiologic cohort studies can help to direct management in the absence of a well-designed, randomized trial, Dr. Brown said.

For example, data on unoperated patients who were enrolled in the 5,500-patient ISUIA (International Study of Unruptured Intracranial Aneurysms) suggest that smaller aneurysms located in the anterior circulation of the circle of Willis and the cavernous segment of the internal carotid artery are quite unlikely to hemorrhage when they are followed conservatively for 5 years.

Available data from the trial also suggest that even very small (less than 7 mm) aneurysms have a potential for hemorrhage that is "noteworthy and certainly far from zero" if they are located in the posterior communicating artery or posterior circulation.

Current and future research is exploring whether more precise analysis of the features of such aneurysms – including their undulation and elliptical indices and nonspherical shape – may be more predictive of rupture risk.

Computational fluid dynamics, drawn from engineering principles, may also provide better guidance, Dr. Brown said.

In the meantime, he cited a "huge variation" in clinical practice when it comes to management of smaller, unruptured aneurysms, with some centers opting to treat 90% with coils or clips and others treating fewer than 10% of such cases.

His own practice, guided by the literature, is to advise treatment in the following situations:

• In younger patients in otherwise good health whose aneurysms measure 7 mm or greater.

• In younger patients in otherwise good health whose aneurysms measure less than 7 mm but are in the posterior circulation.

• Possibly, in older patients with aneurysms measuring 7-12 mm in the posterior circulation.

• In older patients with aneurysms greater than 12 mm in which a reasonable treatment option exists.

Dr. Brown advised aggressive treatment of hypertension and smoking-cessation management in all patients with unruptured aneurysms, as well as careful, imaging-based follow-up of conservatively managed patients based on limited data showing growth in moderate and large lesions over time.

Even 1 in 12 small (measuring less than 8 mm) aneurysms demonstrated "clear, definitive growth" over 4 years in a study of 165 patients (Stroke 2009;40:406-11), he noted.

Aspirin therapy may be beneficial, based on soon-to-be-released data from the ISUIA study showing a "strong and significant" trend toward lower rupture risk in patients taking the highest aspirin doses, he said.

Dr. Brown disclosed no conflicts of interest relative to his talk.