Can Prophylaxis Prevent Epilepsy in Patients With Traumatic Brain Injury?

SAN DIEGO—Prophylactic treatment with established antiepileptic drugs (AEDs) has not prevented epilepsy in trials involving patients with traumatic brain injury (TBI), said investigators at the 66th Annual Meeting of the American Epilepsy Society. Newer AEDs have not been tested in randomized trials, however, and other prophylactic measures have shown promise in animal models, neurologists reported.

In its report titled "Epilepsy Across the Spectrum," the Institute of Medicine called for the development and evaluation of prevention efforts that focus on established risk factors for epilepsy, such as TBI. The prevalence of TBI among returning soldiers and among National Football League players has drawn attention to this risk factor. Preventing epilepsy after known risks, such as TBI is "one of the major issues in epilepsy at the present time," according to Marc A. Dichter, MD, PhD, Professor of Neurology at the University of Pennsylvania in Philadelphia.

Established AEDs Did Not Prevent Post-Traumatic Epilepsy
Almost all clinical trials of prophylactic AED treatment have defined post-traumatic epilepsy as unprovoked seizures that arise more than seven days after an acute brain trauma, said Patrick Kwan, MD, PhD, Professor of Neurology at the University of Melbourne. Seizures that occur within seven days of an acute brain trauma are classified as acute symptomatic or provoked seizures.

Observational studies conducted in the late 1970s and early 1980s suggested that treating patients prophylactically with the established AEDs (eg, phenytoin, phenobarbital, and valproate) would help prevent post-traumatic epilepsy. But a seminal double-blind, randomized trial performed by Nancy Temkin, PhD, Professor of Neurosurgery and Biostatistics at the University of Washington in Seattle, found no significant difference between patients who received phenytoin and controls in the development of late seizures. Patients who received phenytoin had a significantly reduced risk of developing early seizures, however.

In a second trial, Dr. Temkin randomized patients with severe TBI to receive phenytoin for one week or valproate for one month or six months. Neither drug prevented late seizures, and investigators observed a trend toward higher incidence of post-traumatic epilepsy in patients receiving valproate. Furthermore, patients who received valproate for six months had a trend toward high mortality, compared with untreated patients.

The results of the American Academy of Neurology's systematic review of prospective, controlled trials of AED prophylaxis for post-traumatic epilepsy were consistent with Dr. Temkin's findings. The pooled analysis of class 1 studies concluded that giving phenytoin prophylactically reduced early post-traumatic seizures. But a pooled analysis of class 1 and class 2 studies found that prophylactic phenytoin did not prevent late post-traumatic seizures.

Newer AEDs Have Not Been Tested in Randomized Trials
A recent nonrandomized phase II study compared levetiracetam prophylaxis with no treatment for the prevention of post-traumatic epilepsy. Levetiracetam was associated with a reduced risk of developing late seizures, compared with no treatment, but all patients were also given phenytoin for the first week of the trial to prevent early post-traumatic seizures, said Dr. Kwan. In addition, patients who presented within eight hours of a severe head injury received levetiracetam, but patients who presented between eight and 24 hours received no treatment.

Patients were followed for 24 months, and 12% of patients stopped taking levetiracetam. "Although it was not statistically significant, there was a numerically higher mortality rate in people who were treated, compared with the untreated group," observed Dr. Kwan. "Now, perhaps this was because those who were treated [had] presented early, and they tended to have a more severe head injury. These patients did have a lower Glasgow Coma Scale score, so it just shows that the study was not really looking at efficacy, but rather at feasibility and safety."

"We really need to examine the new AEDs to figure this out," said Dr. Dichter. "We need more basic research, including testing with the new AEDs," he added. "We need more clinical research to learn how best to perform clinical trials in this area, as well as to find effective therapies. AEDs may prove useful, but other strategies involving drugs that do not directly suppress seizures, or maybe devices, are likely to be useful as well. If we do not begin clinical trials now, once we do find effective antiepileptogenic therapies in animal models, the wait to bring them to the clinic will be much longer," he concluded.

Brain Cooling Prevented Post-Traumatic Epilepsy in Rats
Researchers have successfully prevented post-traumatic epilepsy in animals without using AEDs. Raimondo D'Ambrosio, PhD, Associate Professor of Neurosurgery at the University of Washington, administered frontal fluid percussion injuries to rats and subsequently observed, by invasive EEG, small, localized neocortical seizures that he called grade 1 seizures. The seizures eventually spread to the rest of the cortex, and Dr. D'Ambrosio called these spreading seizures grade 2 seizures. "If you record from the scalp during grade 1 events, you don't see anything at all," said Dr. Dichter, "but you will see the spreading grade 2 seizures."

When Dr. D'Ambrosio cooled the rats' brains by 2 °C, they did not develop post-traumatic epilepsy. Cooling eliminated short, medium-sized, and long seizures in treated animals. The amount of cooling performed in the study is "much less than we do in the ICU now for people who have had cardiac arrest," observed Dr. Dichter. So far, no studies have investigated whether cooling can prevent post-traumatic epilepsy in humans.

SAN DIEGO—Prophylactic treatment with established antiepileptic drugs (AEDs) has not prevented epilepsy in trials involving patients with traumatic brain injury (TBI), said investigators at the 66th Annual Meeting of the American Epilepsy Society. Newer AEDs have not been tested in randomized trials, however, and other prophylactic measures have shown promise in animal models, neurologists reported.

In its report titled "Epilepsy Across the Spectrum," the Institute of Medicine called for the development and evaluation of prevention efforts that focus on established risk factors for epilepsy, such as TBI. The prevalence of TBI among returning soldiers and among National Football League players has drawn attention to this risk factor. Preventing epilepsy after known risks, such as TBI is "one of the major issues in epilepsy at the present time," according to Marc A. Dichter, MD, PhD, Professor of Neurology at the University of Pennsylvania in Philadelphia.

Established AEDs Did Not Prevent Post-Traumatic Epilepsy
Almost all clinical trials of prophylactic AED treatment have defined post-traumatic epilepsy as unprovoked seizures that arise more than seven days after an acute brain trauma, said Patrick Kwan, MD, PhD, Professor of Neurology at the University of Melbourne. Seizures that occur within seven days of an acute brain trauma are classified as acute symptomatic or provoked seizures.

Observational studies conducted in the late 1970s and early 1980s suggested that treating patients prophylactically with the established AEDs (eg, phenytoin, phenobarbital, and valproate) would help prevent post-traumatic epilepsy. But a seminal double-blind, randomized trial performed by Nancy Temkin, PhD, Professor of Neurosurgery and Biostatistics at the University of Washington in Seattle, found no significant difference between patients who received phenytoin and controls in the development of late seizures. Patients who received phenytoin had a significantly reduced risk of developing early seizures, however.

In a second trial, Dr. Temkin randomized patients with severe TBI to receive phenytoin for one week or valproate for one month or six months. Neither drug prevented late seizures, and investigators observed a trend toward higher incidence of post-traumatic epilepsy in patients receiving valproate. Furthermore, patients who received valproate for six months had a trend toward high mortality, compared with untreated patients.

The results of the American Academy of Neurology's systematic review of prospective, controlled trials of AED prophylaxis for post-traumatic epilepsy were consistent with Dr. Temkin's findings. The pooled analysis of class 1 studies concluded that giving phenytoin prophylactically reduced early post-traumatic seizures. But a pooled analysis of class 1 and class 2 studies found that prophylactic phenytoin did not prevent late post-traumatic seizures.

Newer AEDs Have Not Been Tested in Randomized Trials
A recent nonrandomized phase II study compared levetiracetam prophylaxis with no treatment for the prevention of post-traumatic epilepsy. Levetiracetam was associated with a reduced risk of developing late seizures, compared with no treatment, but all patients were also given phenytoin for the first week of the trial to prevent early post-traumatic seizures, said Dr. Kwan. In addition, patients who presented within eight hours of a severe head injury received levetiracetam, but patients who presented between eight and 24 hours received no treatment.

Patients were followed for 24 months, and 12% of patients stopped taking levetiracetam. "Although it was not statistically significant, there was a numerically higher mortality rate in people who were treated, compared with the untreated group," observed Dr. Kwan. "Now, perhaps this was because those who were treated [had] presented early, and they tended to have a more severe head injury. These patients did have a lower Glasgow Coma Scale score, so it just shows that the study was not really looking at efficacy, but rather at feasibility and safety."

"We really need to examine the new AEDs to figure this out," said Dr. Dichter. "We need more basic research, including testing with the new AEDs," he added. "We need more clinical research to learn how best to perform clinical trials in this area, as well as to find effective therapies. AEDs may prove useful, but other strategies involving drugs that do not directly suppress seizures, or maybe devices, are likely to be useful as well. If we do not begin clinical trials now, once we do find effective antiepileptogenic therapies in animal models, the wait to bring them to the clinic will be much longer," he concluded.

Brain Cooling Prevented Post-Traumatic Epilepsy in Rats
Researchers have successfully prevented post-traumatic epilepsy in animals without using AEDs. Raimondo D'Ambrosio, PhD, Associate Professor of Neurosurgery at the University of Washington, administered frontal fluid percussion injuries to rats and subsequently observed, by invasive EEG, small, localized neocortical seizures that he called grade 1 seizures. The seizures eventually spread to the rest of the cortex, and Dr. D'Ambrosio called these spreading seizures grade 2 seizures. "If you record from the scalp during grade 1 events, you don't see anything at all," said Dr. Dichter, "but you will see the spreading grade 2 seizures."

When Dr. D'Ambrosio cooled the rats' brains by 2 °C, they did not develop post-traumatic epilepsy. Cooling eliminated short, medium-sized, and long seizures in treated animals. The amount of cooling performed in the study is "much less than we do in the ICU now for people who have had cardiac arrest," observed Dr. Dichter. So far, no studies have investigated whether cooling can prevent post-traumatic epilepsy in humans.

SAN DIEGO—Prophylactic treatment with established antiepileptic drugs (AEDs) has not prevented epilepsy in trials involving patients with traumatic brain injury (TBI), said investigators at the 66th Annual Meeting of the American Epilepsy Society. Newer AEDs have not been tested in randomized trials, however, and other prophylactic measures have shown promise in animal models, neurologists reported.

In its report titled "Epilepsy Across the Spectrum," the Institute of Medicine called for the development and evaluation of prevention efforts that focus on established risk factors for epilepsy, such as TBI. The prevalence of TBI among returning soldiers and among National Football League players has drawn attention to this risk factor. Preventing epilepsy after known risks, such as TBI is "one of the major issues in epilepsy at the present time," according to Marc A. Dichter, MD, PhD, Professor of Neurology at the University of Pennsylvania in Philadelphia.

Established AEDs Did Not Prevent Post-Traumatic Epilepsy
Almost all clinical trials of prophylactic AED treatment have defined post-traumatic epilepsy as unprovoked seizures that arise more than seven days after an acute brain trauma, said Patrick Kwan, MD, PhD, Professor of Neurology at the University of Melbourne. Seizures that occur within seven days of an acute brain trauma are classified as acute symptomatic or provoked seizures.

Observational studies conducted in the late 1970s and early 1980s suggested that treating patients prophylactically with the established AEDs (eg, phenytoin, phenobarbital, and valproate) would help prevent post-traumatic epilepsy. But a seminal double-blind, randomized trial performed by Nancy Temkin, PhD, Professor of Neurosurgery and Biostatistics at the University of Washington in Seattle, found no significant difference between patients who received phenytoin and controls in the development of late seizures. Patients who received phenytoin had a significantly reduced risk of developing early seizures, however.

In a second trial, Dr. Temkin randomized patients with severe TBI to receive phenytoin for one week or valproate for one month or six months. Neither drug prevented late seizures, and investigators observed a trend toward higher incidence of post-traumatic epilepsy in patients receiving valproate. Furthermore, patients who received valproate for six months had a trend toward high mortality, compared with untreated patients.

The results of the American Academy of Neurology's systematic review of prospective, controlled trials of AED prophylaxis for post-traumatic epilepsy were consistent with Dr. Temkin's findings. The pooled analysis of class 1 studies concluded that giving phenytoin prophylactically reduced early post-traumatic seizures. But a pooled analysis of class 1 and class 2 studies found that prophylactic phenytoin did not prevent late post-traumatic seizures.

Newer AEDs Have Not Been Tested in Randomized Trials
A recent nonrandomized phase II study compared levetiracetam prophylaxis with no treatment for the prevention of post-traumatic epilepsy. Levetiracetam was associated with a reduced risk of developing late seizures, compared with no treatment, but all patients were also given phenytoin for the first week of the trial to prevent early post-traumatic seizures, said Dr. Kwan. In addition, patients who presented within eight hours of a severe head injury received levetiracetam, but patients who presented between eight and 24 hours received no treatment.

Patients were followed for 24 months, and 12% of patients stopped taking levetiracetam. "Although it was not statistically significant, there was a numerically higher mortality rate in people who were treated, compared with the untreated group," observed Dr. Kwan. "Now, perhaps this was because those who were treated [had] presented early, and they tended to have a more severe head injury. These patients did have a lower Glasgow Coma Scale score, so it just shows that the study was not really looking at efficacy, but rather at feasibility and safety."

"We really need to examine the new AEDs to figure this out," said Dr. Dichter. "We need more basic research, including testing with the new AEDs," he added. "We need more clinical research to learn how best to perform clinical trials in this area, as well as to find effective therapies. AEDs may prove useful, but other strategies involving drugs that do not directly suppress seizures, or maybe devices, are likely to be useful as well. If we do not begin clinical trials now, once we do find effective antiepileptogenic therapies in animal models, the wait to bring them to the clinic will be much longer," he concluded.

Brain Cooling Prevented Post-Traumatic Epilepsy in Rats
Researchers have successfully prevented post-traumatic epilepsy in animals without using AEDs. Raimondo D'Ambrosio, PhD, Associate Professor of Neurosurgery at the University of Washington, administered frontal fluid percussion injuries to rats and subsequently observed, by invasive EEG, small, localized neocortical seizures that he called grade 1 seizures. The seizures eventually spread to the rest of the cortex, and Dr. D'Ambrosio called these spreading seizures grade 2 seizures. "If you record from the scalp during grade 1 events, you don't see anything at all," said Dr. Dichter, "but you will see the spreading grade 2 seizures."

When Dr. D'Ambrosio cooled the rats' brains by 2 °C, they did not develop post-traumatic epilepsy. Cooling eliminated short, medium-sized, and long seizures in treated animals. The amount of cooling performed in the study is "much less than we do in the ICU now for people who have had cardiac arrest," observed Dr. Dichter. So far, no studies have investigated whether cooling can prevent post-traumatic epilepsy in humans.