Traumatic Brain Injury

SAN DIEGO—The American Academy of Neurology (AAN) has released an evidence-based guideline for the assessment and management of athletes with concussion. This new guideline replaces the 1997 AAN guideline on the same topic. The new guideline was announced at a press conference at the 65th Annual Meeting of the AAN and was published in the March 18, 2013, online issue of Neurology.

"With over a million athletes experiencing sports-related concussion per year in the United States, the AAN is pleased to release this evidence-based guideline," said lead author Christopher C. Giza, MD, from the David Geffen School of Medicine and Mattel Children's Hospital at UCLA.

The guideline was developed using an evidence-based process and was multidisciplinary in nature, including neurologists and a panel of professionals from other specialties who are involved in the care and assessment of athletes with sports concussions. "These recommendations are the best summation of available science regarding the assessment and management of sports concussion," Dr. Giza said.

"One of the most important recommendations from this guideline is that an athlete who sustained or is suspected of sustaining a concussion should be removed from play that day and then be assessed by a licensed health care provider with expertise in management of concussion," Dr. Giza said.

Another important component that came out of the evidence was the effect of concussion on youth. "Evidence suggests that high school-age individuals with concussion take longer to recover than their older professional counterparts, and so they should be managed more conservatively." The guideline committee also found a dearth of evidence on concussion under the age of high school and this, they said, was an area for future investigation.

"Individuals with suspected injury should be removed from contact risk activity after concussion," Dr. Giza said. "The evidence is really sparse for complete cognitive restriction after concussion—complete cognitive rest. The guideline recommends that athletes be removed from sports activity that would put them back at contact risk. An important distinction of this guideline from the 1997 guideline is that it moves away from the grading system of concussion. We don't find that the evidence supports trying to rate the concussion at the moment of impact and determine how severe it was or how long a return to play would be. In this case the assessment of concussion would be done individually with multiple diagnostic tools, and the management plans are individualized because there are different factors that contribute to how long an athlete might recover from concussion."

Among the sports in the studies evaluated, risk of concussion is greatest in football and rugby, followed by hockey and soccer. The risk of concussion for young women and girls is greatest in soccer and basketball.

According to the guideline:

• An athlete who has a history of one or more concussions is at greater risk of being diagnosed with another concussion.

• The first 10 days after a concussion appear to be the period of greatest risk of being diagnosed with another concussion.

• There is no clear evidence that one type of football helmet can better protect against concussion compared with another kind of helmet. Helmets should fit properly and be well maintained.

• Licensed health care professionals trained in treating concussion should look for ongoing symptoms (especially headache and fogginess), history of concussions, and younger age in the athlete. Each of these factors has been linked to a longer recovery after a concussion.

• Risk factors linked to chronic neurobehavioral impairment in professional athletes include prior concussion, longer exposure to the sport, and having the APOE ε4 gene.

• Concussion is a clinical diagnosis. Symptom checklists, the Standardized Assessment of Concussion (SAC), neuropsychologic testing (paper-and-pencil and computerized), and the Balance Error Scoring System may be helpful tools in diagnosing and managing concussions but should not be used alone for making a diagnosis.

• Signs and symptoms of a concussion include headache and sensitivity to light and sound; changes to reaction time, balance, and coordination; changes in memory, judgment, speech, and sleep; loss of consciousness or a "blackout" (occurring in less than 10% of cases).

"If in doubt, sit it out," said Jeffrey S. Kutcher, MD, from the University of Michigan Medical School in Ann Arbor and a coauthor of the guideline. "Being seen by a trained professional is extremely important after a concussion. If headaches or other symptoms return with the start of exercise, stop the activity and consult a doctor."

The new AAN guideline has been endorsed by the National Football League Players Association, the Child Neurology Society, the National Association of Emergency Medical Service Physicians, the National Association of School Psychologists, the National Athletic Trainers Association, the American Football Coaches Association, the National Academy of Neuropsychology, and the Neurocritical Care Society.

SAN DIEGO—The American Academy of Neurology (AAN) has released an evidence-based guideline for the assessment and management of athletes with concussion. This new guideline replaces the 1997 AAN guideline on the same topic. The new guideline was announced at a press conference at the 65th Annual Meeting of the AAN and was published in the March 18, 2013, online issue of Neurology.

"With over a million athletes experiencing sports-related concussion per year in the United States, the AAN is pleased to release this evidence-based guideline," said lead author Christopher C. Giza, MD, from the David Geffen School of Medicine and Mattel Children's Hospital at UCLA.

The guideline was developed using an evidence-based process and was multidisciplinary in nature, including neurologists and a panel of professionals from other specialties who are involved in the care and assessment of athletes with sports concussions. "These recommendations are the best summation of available science regarding the assessment and management of sports concussion," Dr. Giza said.

"One of the most important recommendations from this guideline is that an athlete who sustained or is suspected of sustaining a concussion should be removed from play that day and then be assessed by a licensed health care provider with expertise in management of concussion," Dr. Giza said.

Another important component that came out of the evidence was the effect of concussion on youth. "Evidence suggests that high school-age individuals with concussion take longer to recover than their older professional counterparts, and so they should be managed more conservatively." The guideline committee also found a dearth of evidence on concussion under the age of high school and this, they said, was an area for future investigation.

"Individuals with suspected injury should be removed from contact risk activity after concussion," Dr. Giza said. "The evidence is really sparse for complete cognitive restriction after concussion—complete cognitive rest. The guideline recommends that athletes be removed from sports activity that would put them back at contact risk. An important distinction of this guideline from the 1997 guideline is that it moves away from the grading system of concussion. We don't find that the evidence supports trying to rate the concussion at the moment of impact and determine how severe it was or how long a return to play would be. In this case the assessment of concussion would be done individually with multiple diagnostic tools, and the management plans are individualized because there are different factors that contribute to how long an athlete might recover from concussion."

Among the sports in the studies evaluated, risk of concussion is greatest in football and rugby, followed by hockey and soccer. The risk of concussion for young women and girls is greatest in soccer and basketball.

According to the guideline:

• An athlete who has a history of one or more concussions is at greater risk of being diagnosed with another concussion.

• The first 10 days after a concussion appear to be the period of greatest risk of being diagnosed with another concussion.

• There is no clear evidence that one type of football helmet can better protect against concussion compared with another kind of helmet. Helmets should fit properly and be well maintained.

• Licensed health care professionals trained in treating concussion should look for ongoing symptoms (especially headache and fogginess), history of concussions, and younger age in the athlete. Each of these factors has been linked to a longer recovery after a concussion.

• Risk factors linked to chronic neurobehavioral impairment in professional athletes include prior concussion, longer exposure to the sport, and having the APOE ε4 gene.

• Concussion is a clinical diagnosis. Symptom checklists, the Standardized Assessment of Concussion (SAC), neuropsychologic testing (paper-and-pencil and computerized), and the Balance Error Scoring System may be helpful tools in diagnosing and managing concussions but should not be used alone for making a diagnosis.

• Signs and symptoms of a concussion include headache and sensitivity to light and sound; changes to reaction time, balance, and coordination; changes in memory, judgment, speech, and sleep; loss of consciousness or a "blackout" (occurring in less than 10% of cases).

"If in doubt, sit it out," said Jeffrey S. Kutcher, MD, from the University of Michigan Medical School in Ann Arbor and a coauthor of the guideline. "Being seen by a trained professional is extremely important after a concussion. If headaches or other symptoms return with the start of exercise, stop the activity and consult a doctor."

The new AAN guideline has been endorsed by the National Football League Players Association, the Child Neurology Society, the National Association of Emergency Medical Service Physicians, the National Association of School Psychologists, the National Athletic Trainers Association, the American Football Coaches Association, the National Academy of Neuropsychology, and the Neurocritical Care Society.

SAN DIEGO—The American Academy of Neurology (AAN) has released an evidence-based guideline for the assessment and management of athletes with concussion. This new guideline replaces the 1997 AAN guideline on the same topic. The new guideline was announced at a press conference at the 65th Annual Meeting of the AAN and was published in the March 18, 2013, online issue of Neurology.

"With over a million athletes experiencing sports-related concussion per year in the United States, the AAN is pleased to release this evidence-based guideline," said lead author Christopher C. Giza, MD, from the David Geffen School of Medicine and Mattel Children's Hospital at UCLA.

The guideline was developed using an evidence-based process and was multidisciplinary in nature, including neurologists and a panel of professionals from other specialties who are involved in the care and assessment of athletes with sports concussions. "These recommendations are the best summation of available science regarding the assessment and management of sports concussion," Dr. Giza said.

"One of the most important recommendations from this guideline is that an athlete who sustained or is suspected of sustaining a concussion should be removed from play that day and then be assessed by a licensed health care provider with expertise in management of concussion," Dr. Giza said.

Another important component that came out of the evidence was the effect of concussion on youth. "Evidence suggests that high school-age individuals with concussion take longer to recover than their older professional counterparts, and so they should be managed more conservatively." The guideline committee also found a dearth of evidence on concussion under the age of high school and this, they said, was an area for future investigation.

"Individuals with suspected injury should be removed from contact risk activity after concussion," Dr. Giza said. "The evidence is really sparse for complete cognitive restriction after concussion—complete cognitive rest. The guideline recommends that athletes be removed from sports activity that would put them back at contact risk. An important distinction of this guideline from the 1997 guideline is that it moves away from the grading system of concussion. We don't find that the evidence supports trying to rate the concussion at the moment of impact and determine how severe it was or how long a return to play would be. In this case the assessment of concussion would be done individually with multiple diagnostic tools, and the management plans are individualized because there are different factors that contribute to how long an athlete might recover from concussion."

Among the sports in the studies evaluated, risk of concussion is greatest in football and rugby, followed by hockey and soccer. The risk of concussion for young women and girls is greatest in soccer and basketball.

According to the guideline:

• An athlete who has a history of one or more concussions is at greater risk of being diagnosed with another concussion.

• The first 10 days after a concussion appear to be the period of greatest risk of being diagnosed with another concussion.

• There is no clear evidence that one type of football helmet can better protect against concussion compared with another kind of helmet. Helmets should fit properly and be well maintained.

• Licensed health care professionals trained in treating concussion should look for ongoing symptoms (especially headache and fogginess), history of concussions, and younger age in the athlete. Each of these factors has been linked to a longer recovery after a concussion.

• Risk factors linked to chronic neurobehavioral impairment in professional athletes include prior concussion, longer exposure to the sport, and having the APOE ε4 gene.

• Concussion is a clinical diagnosis. Symptom checklists, the Standardized Assessment of Concussion (SAC), neuropsychologic testing (paper-and-pencil and computerized), and the Balance Error Scoring System may be helpful tools in diagnosing and managing concussions but should not be used alone for making a diagnosis.

• Signs and symptoms of a concussion include headache and sensitivity to light and sound; changes to reaction time, balance, and coordination; changes in memory, judgment, speech, and sleep; loss of consciousness or a "blackout" (occurring in less than 10% of cases).

"If in doubt, sit it out," said Jeffrey S. Kutcher, MD, from the University of Michigan Medical School in Ann Arbor and a coauthor of the guideline. "Being seen by a trained professional is extremely important after a concussion. If headaches or other symptoms return with the start of exercise, stop the activity and consult a doctor."

The new AAN guideline has been endorsed by the National Football League Players Association, the Child Neurology Society, the National Association of Emergency Medical Service Physicians, the National Association of School Psychologists, the National Athletic Trainers Association, the American Football Coaches Association, the National Academy of Neuropsychology, and the Neurocritical Care Society.

HONOLULU—Cerebral vasospasm and intracranial hypertension may be frequent secondary insults following wartime traumatic brain injury (TBI), according to research presented at the 2013 International Stroke Conference.

In a retrospective study of 122 consecutive veterans, transcranial Doppler (TCD) ultrasonography signs of mild, moderate, and severe vasospasm involving anterior circulation vessels were observed in 71%, 42%, and 16% of the veterans with TBI, respectively. TCD signs involving posterior circulation vessels were observed in 57%, 32%, and 14%, respectively.

Intracranial hypertension was recorded in 43% of patients, lead author Alexander Razumovsky, PhD, reported. “Cerebral blood flow velocity measurements permit detection of early signs of cerebral vasospasm and allow physicians to better define management strategies,” he said.

TCD Commonly Used by US Army
TCD monitoring is routinely used by the US Army, but it has not been fully embraced elsewhere because many physicians are unaware of how it can be used within the continuum of TBI care to help reverse outcomes, said study coauthor Col. Rocco Armonda, MC, USA.

“There’s this lack of drive to change outcomes, because people haven’t seen how you can take someone who is in a comatose state and eventually gain functional independence,” said Dr. Armonda, who is the Director of Cerebrovascular Surgery and Interventional Neuroradiology at the National Naval Medical Center in Bethesda, Maryland.

A recent study from the Walter Reed National Military Medical Center, however, reported that 63% of veterans with a penetrating TBI and a mean discharge Glasgow Coma Scale (GCS) score of 6 to 8 progressed to functional independence, a number twice as high as would be expected, Dr. Armonda commented.

Dr. Razumovsky said that simple, noninvasive TCD monitoring should be performed in the daily management of hospitalized TBI patients to complement other monitoring strategies, and it can be used alone in emergency situations when intracranial pressure monitoring is contraindicated or not readily available.

TCD monitoring is not necessary during outpatient follow-up of patients with TBI, with the exception of the subset who have undergone hemicraniectomy, Dr. Armonda said.

“In those patients who’ve had hemicraniectomy, some of them suffer prolonged duration from atmospheric pressure of the cranial defect, and TCD has actually been helpful to look at the cerebral blood flow dynamics,” he said at a press briefing on the study.

The results confirm earlier data that TBI is associated with a high incidence of cerebral vasospasm, particularly in patients with severe TBI, and are applicable to civilian TBI patients, because a significant number will experience post-traumatic bleeding that will lead to vasospasm and intracranial hypertension, said Dr. Razumovsky, Director of Sentient NeuroCare Services in Hunt Valley, Maryland, which provides services to the National Naval Medical Hospital.

Detecting Vasospasm in TBI Patients
In the current study, patients were admitted to Walter Reed a mean of 6.7 days after injury from October 1, 2008, to November 30, 2012. Mean cerebral blood flow velocity (CBFV) of 100 to 139 cm/s was used to define mild vasospasm, 140 to 199 cm/s for moderate vasospasm, and more than 200 cm/s severe for vasospasm.

In all, 88 patients had penetrating head injury, of whom 45 (51%) had a secondary diagnosis of blast injury; and 34 patients had a closed head injury, of whom 15 (44%) had a secondary diagnosis of blast injury. Their mean age was 26 years.

In the mild vasospasm group, the mean anterior circulation CBFV was 122.5 cm/s and mean posterior CBFV was 61 cm/s. Their average GCS score changed from 8 at baseline to 6.1 at discharge, Dr. Razumovsky said.

In the moderate vasospasm group, the mean anterior circulation CBFV was 156.6 cm/s and mean posterior CBFV was 77.5 cm/s. Their average GCS score changed from 5.9 at baseline to 5.3 at discharge.

Patients with severe vasospasm had an average anterior circulation CBFV of 241.9 cm/s and a mean posterior CBFV of 101.8 cm/s. Their average GCS score was 4.8 at both time periods. Eight patients (7%) underwent transluminal angioplasty for post-traumatic symptomatic vasospasm, he said.

Larry Goldstein, MD, Director of the Duke Stroke Center in Durham, North Carolina, said in an interview that the detection of vasospasm by TCD was potentially important, because there is an increased risk of vasospasm after subarachnoid hemorrhage that can lead to delayed ischemic neurologic deficits. Although it was unclear from the data how many patients had traumatic subarachnoid hemorrhage associated with their brain injury, he noted that the risk of vasospasm seems to be similar for traumatic and nontraumatic subarachnoid hemorrhage.

“In many centers, both groups of patients are routinely monitored with transcranial Dopplers over the first couple of weeks or so, which is when the peak period of vasospasm develops,” Dr. Goldstein said. “Showing that monitoring leads to interventions that then change outcome, that’s not so straightforward.”

HONOLULU—Cerebral vasospasm and intracranial hypertension may be frequent secondary insults following wartime traumatic brain injury (TBI), according to research presented at the 2013 International Stroke Conference.

In a retrospective study of 122 consecutive veterans, transcranial Doppler (TCD) ultrasonography signs of mild, moderate, and severe vasospasm involving anterior circulation vessels were observed in 71%, 42%, and 16% of the veterans with TBI, respectively. TCD signs involving posterior circulation vessels were observed in 57%, 32%, and 14%, respectively.

Intracranial hypertension was recorded in 43% of patients, lead author Alexander Razumovsky, PhD, reported. “Cerebral blood flow velocity measurements permit detection of early signs of cerebral vasospasm and allow physicians to better define management strategies,” he said.

TCD Commonly Used by US Army
TCD monitoring is routinely used by the US Army, but it has not been fully embraced elsewhere because many physicians are unaware of how it can be used within the continuum of TBI care to help reverse outcomes, said study coauthor Col. Rocco Armonda, MC, USA.

“There’s this lack of drive to change outcomes, because people haven’t seen how you can take someone who is in a comatose state and eventually gain functional independence,” said Dr. Armonda, who is the Director of Cerebrovascular Surgery and Interventional Neuroradiology at the National Naval Medical Center in Bethesda, Maryland.

A recent study from the Walter Reed National Military Medical Center, however, reported that 63% of veterans with a penetrating TBI and a mean discharge Glasgow Coma Scale (GCS) score of 6 to 8 progressed to functional independence, a number twice as high as would be expected, Dr. Armonda commented.

Dr. Razumovsky said that simple, noninvasive TCD monitoring should be performed in the daily management of hospitalized TBI patients to complement other monitoring strategies, and it can be used alone in emergency situations when intracranial pressure monitoring is contraindicated or not readily available.

TCD monitoring is not necessary during outpatient follow-up of patients with TBI, with the exception of the subset who have undergone hemicraniectomy, Dr. Armonda said.

“In those patients who’ve had hemicraniectomy, some of them suffer prolonged duration from atmospheric pressure of the cranial defect, and TCD has actually been helpful to look at the cerebral blood flow dynamics,” he said at a press briefing on the study.

The results confirm earlier data that TBI is associated with a high incidence of cerebral vasospasm, particularly in patients with severe TBI, and are applicable to civilian TBI patients, because a significant number will experience post-traumatic bleeding that will lead to vasospasm and intracranial hypertension, said Dr. Razumovsky, Director of Sentient NeuroCare Services in Hunt Valley, Maryland, which provides services to the National Naval Medical Hospital.

Detecting Vasospasm in TBI Patients
In the current study, patients were admitted to Walter Reed a mean of 6.7 days after injury from October 1, 2008, to November 30, 2012. Mean cerebral blood flow velocity (CBFV) of 100 to 139 cm/s was used to define mild vasospasm, 140 to 199 cm/s for moderate vasospasm, and more than 200 cm/s severe for vasospasm.

In all, 88 patients had penetrating head injury, of whom 45 (51%) had a secondary diagnosis of blast injury; and 34 patients had a closed head injury, of whom 15 (44%) had a secondary diagnosis of blast injury. Their mean age was 26 years.

In the mild vasospasm group, the mean anterior circulation CBFV was 122.5 cm/s and mean posterior CBFV was 61 cm/s. Their average GCS score changed from 8 at baseline to 6.1 at discharge, Dr. Razumovsky said.

In the moderate vasospasm group, the mean anterior circulation CBFV was 156.6 cm/s and mean posterior CBFV was 77.5 cm/s. Their average GCS score changed from 5.9 at baseline to 5.3 at discharge.

Patients with severe vasospasm had an average anterior circulation CBFV of 241.9 cm/s and a mean posterior CBFV of 101.8 cm/s. Their average GCS score was 4.8 at both time periods. Eight patients (7%) underwent transluminal angioplasty for post-traumatic symptomatic vasospasm, he said.

Larry Goldstein, MD, Director of the Duke Stroke Center in Durham, North Carolina, said in an interview that the detection of vasospasm by TCD was potentially important, because there is an increased risk of vasospasm after subarachnoid hemorrhage that can lead to delayed ischemic neurologic deficits. Although it was unclear from the data how many patients had traumatic subarachnoid hemorrhage associated with their brain injury, he noted that the risk of vasospasm seems to be similar for traumatic and nontraumatic subarachnoid hemorrhage.

“In many centers, both groups of patients are routinely monitored with transcranial Dopplers over the first couple of weeks or so, which is when the peak period of vasospasm develops,” Dr. Goldstein said. “Showing that monitoring leads to interventions that then change outcome, that’s not so straightforward.”

HONOLULU—Cerebral vasospasm and intracranial hypertension may be frequent secondary insults following wartime traumatic brain injury (TBI), according to research presented at the 2013 International Stroke Conference.

In a retrospective study of 122 consecutive veterans, transcranial Doppler (TCD) ultrasonography signs of mild, moderate, and severe vasospasm involving anterior circulation vessels were observed in 71%, 42%, and 16% of the veterans with TBI, respectively. TCD signs involving posterior circulation vessels were observed in 57%, 32%, and 14%, respectively.

Intracranial hypertension was recorded in 43% of patients, lead author Alexander Razumovsky, PhD, reported. “Cerebral blood flow velocity measurements permit detection of early signs of cerebral vasospasm and allow physicians to better define management strategies,” he said.

TCD Commonly Used by US Army
TCD monitoring is routinely used by the US Army, but it has not been fully embraced elsewhere because many physicians are unaware of how it can be used within the continuum of TBI care to help reverse outcomes, said study coauthor Col. Rocco Armonda, MC, USA.

“There’s this lack of drive to change outcomes, because people haven’t seen how you can take someone who is in a comatose state and eventually gain functional independence,” said Dr. Armonda, who is the Director of Cerebrovascular Surgery and Interventional Neuroradiology at the National Naval Medical Center in Bethesda, Maryland.

A recent study from the Walter Reed National Military Medical Center, however, reported that 63% of veterans with a penetrating TBI and a mean discharge Glasgow Coma Scale (GCS) score of 6 to 8 progressed to functional independence, a number twice as high as would be expected, Dr. Armonda commented.

Dr. Razumovsky said that simple, noninvasive TCD monitoring should be performed in the daily management of hospitalized TBI patients to complement other monitoring strategies, and it can be used alone in emergency situations when intracranial pressure monitoring is contraindicated or not readily available.

TCD monitoring is not necessary during outpatient follow-up of patients with TBI, with the exception of the subset who have undergone hemicraniectomy, Dr. Armonda said.

“In those patients who’ve had hemicraniectomy, some of them suffer prolonged duration from atmospheric pressure of the cranial defect, and TCD has actually been helpful to look at the cerebral blood flow dynamics,” he said at a press briefing on the study.

The results confirm earlier data that TBI is associated with a high incidence of cerebral vasospasm, particularly in patients with severe TBI, and are applicable to civilian TBI patients, because a significant number will experience post-traumatic bleeding that will lead to vasospasm and intracranial hypertension, said Dr. Razumovsky, Director of Sentient NeuroCare Services in Hunt Valley, Maryland, which provides services to the National Naval Medical Hospital.

Detecting Vasospasm in TBI Patients
In the current study, patients were admitted to Walter Reed a mean of 6.7 days after injury from October 1, 2008, to November 30, 2012. Mean cerebral blood flow velocity (CBFV) of 100 to 139 cm/s was used to define mild vasospasm, 140 to 199 cm/s for moderate vasospasm, and more than 200 cm/s severe for vasospasm.

In all, 88 patients had penetrating head injury, of whom 45 (51%) had a secondary diagnosis of blast injury; and 34 patients had a closed head injury, of whom 15 (44%) had a secondary diagnosis of blast injury. Their mean age was 26 years.

In the mild vasospasm group, the mean anterior circulation CBFV was 122.5 cm/s and mean posterior CBFV was 61 cm/s. Their average GCS score changed from 8 at baseline to 6.1 at discharge, Dr. Razumovsky said.

In the moderate vasospasm group, the mean anterior circulation CBFV was 156.6 cm/s and mean posterior CBFV was 77.5 cm/s. Their average GCS score changed from 5.9 at baseline to 5.3 at discharge.

Patients with severe vasospasm had an average anterior circulation CBFV of 241.9 cm/s and a mean posterior CBFV of 101.8 cm/s. Their average GCS score was 4.8 at both time periods. Eight patients (7%) underwent transluminal angioplasty for post-traumatic symptomatic vasospasm, he said.

Larry Goldstein, MD, Director of the Duke Stroke Center in Durham, North Carolina, said in an interview that the detection of vasospasm by TCD was potentially important, because there is an increased risk of vasospasm after subarachnoid hemorrhage that can lead to delayed ischemic neurologic deficits. Although it was unclear from the data how many patients had traumatic subarachnoid hemorrhage associated with their brain injury, he noted that the risk of vasospasm seems to be similar for traumatic and nontraumatic subarachnoid hemorrhage.

“In many centers, both groups of patients are routinely monitored with transcranial Dopplers over the first couple of weeks or so, which is when the peak period of vasospasm develops,” Dr. Goldstein said. “Showing that monitoring leads to interventions that then change outcome, that’s not so straightforward.”

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.

Care based on intracranial pressure monitoring may not be superior to care based on imaging and clinical examination for patients with traumatic brain injury (TBI), according to research published in the December 27, 2012, New England Journal of Medicine. There was no significant difference in survival time, impaired consciousness, functional status, or neuropsychologic status among patients with TBI randomized to one of the two types of care.

Randall M. Chesnut, MD, Professor of Neurologic Surgery at the University of Washington in Seattle, and colleagues conducted a multicenter, controlled trial in which 324 patients with severe TBI were randomly assigned to guidelines-based management (ie, intracranial pressure monitoring) or imaging and clinical examination. Trained examiners who were unaware of treatment assignments assessed patients’ outcomes at three and six months after study onset. Tests included measures of mental status, working memory, information processing speed, episodic memory and learning, verbal fluency, executive function, and motor dexterity.

Eligible patients were 13 or older and had a Glasgow Coma Scale (GCS) score of 3 to 8. Patients with a GCS score of 3 and bilateral fixed and dilated pupils and those with an injury deemed unsurvivable were excluded. Patients’ median age was 29, and nearly 88% of patients were male.

Survival rates were similar for the two patient groups. For patients in the imaging and clinical examination group, 14-day mortality was 30%, compared with 21% for the pressure-monitoring group. Six-month mortality was 41% in the imaging and clinical examination group and 39% in the pressure-monitoring group. The median length of stay in the ICU was 12 days for patients in the pressure-monitoring group, compared with nine days for the imaging and clinical examination group.

“The value of knowing the precise intracranial pressure is not being challenged here, nor is the value of aggressively treating severe TBI being questioned,” said Dr. Chesnut. “Rather, our data suggest that a reassessment of the role of manipulating monitored intracranial pressure as part of multimodality monitoring and targeted treatment of severe TBI is in order,” he concluded.

Care based on intracranial pressure monitoring may not be superior to care based on imaging and clinical examination for patients with traumatic brain injury (TBI), according to research published in the December 27, 2012, New England Journal of Medicine. There was no significant difference in survival time, impaired consciousness, functional status, or neuropsychologic status among patients with TBI randomized to one of the two types of care.

Randall M. Chesnut, MD, Professor of Neurologic Surgery at the University of Washington in Seattle, and colleagues conducted a multicenter, controlled trial in which 324 patients with severe TBI were randomly assigned to guidelines-based management (ie, intracranial pressure monitoring) or imaging and clinical examination. Trained examiners who were unaware of treatment assignments assessed patients’ outcomes at three and six months after study onset. Tests included measures of mental status, working memory, information processing speed, episodic memory and learning, verbal fluency, executive function, and motor dexterity.

Eligible patients were 13 or older and had a Glasgow Coma Scale (GCS) score of 3 to 8. Patients with a GCS score of 3 and bilateral fixed and dilated pupils and those with an injury deemed unsurvivable were excluded. Patients’ median age was 29, and nearly 88% of patients were male.

Survival rates were similar for the two patient groups. For patients in the imaging and clinical examination group, 14-day mortality was 30%, compared with 21% for the pressure-monitoring group. Six-month mortality was 41% in the imaging and clinical examination group and 39% in the pressure-monitoring group. The median length of stay in the ICU was 12 days for patients in the pressure-monitoring group, compared with nine days for the imaging and clinical examination group.

“The value of knowing the precise intracranial pressure is not being challenged here, nor is the value of aggressively treating severe TBI being questioned,” said Dr. Chesnut. “Rather, our data suggest that a reassessment of the role of manipulating monitored intracranial pressure as part of multimodality monitoring and targeted treatment of severe TBI is in order,” he concluded.

Care based on intracranial pressure monitoring may not be superior to care based on imaging and clinical examination for patients with traumatic brain injury (TBI), according to research published in the December 27, 2012, New England Journal of Medicine. There was no significant difference in survival time, impaired consciousness, functional status, or neuropsychologic status among patients with TBI randomized to one of the two types of care.

Randall M. Chesnut, MD, Professor of Neurologic Surgery at the University of Washington in Seattle, and colleagues conducted a multicenter, controlled trial in which 324 patients with severe TBI were randomly assigned to guidelines-based management (ie, intracranial pressure monitoring) or imaging and clinical examination. Trained examiners who were unaware of treatment assignments assessed patients’ outcomes at three and six months after study onset. Tests included measures of mental status, working memory, information processing speed, episodic memory and learning, verbal fluency, executive function, and motor dexterity.

Eligible patients were 13 or older and had a Glasgow Coma Scale (GCS) score of 3 to 8. Patients with a GCS score of 3 and bilateral fixed and dilated pupils and those with an injury deemed unsurvivable were excluded. Patients’ median age was 29, and nearly 88% of patients were male.

Survival rates were similar for the two patient groups. For patients in the imaging and clinical examination group, 14-day mortality was 30%, compared with 21% for the pressure-monitoring group. Six-month mortality was 41% in the imaging and clinical examination group and 39% in the pressure-monitoring group. The median length of stay in the ICU was 12 days for patients in the pressure-monitoring group, compared with nine days for the imaging and clinical examination group.

“The value of knowing the precise intracranial pressure is not being challenged here, nor is the value of aggressively treating severe TBI being questioned,” said Dr. Chesnut. “Rather, our data suggest that a reassessment of the role of manipulating monitored intracranial pressure as part of multimodality monitoring and targeted treatment of severe TBI is in order,” he concluded.

Patients with traumatic brain injury (TBI) who were treated with citicoline failed to show improvements in functional and cognitive status, according to results of a multicenter phase III trial reported in the November 21, 2012, issue of JAMA. Citicoline proved to be no better than placebo at improving function or cognition after TBI in the first large randomized clinical trial to test it in this patient population.

Citicoline, an endogenous compound that is an intermediate in the biosynthesis of phosphatidylcholine from choline, is thought to have a range of neuroprotective properties and has been approved as a treatment for TBI in 59 countries other than the United States. But it is widely available in the US as a nutraceutical used for various neurologic disorders, said lead author Ross D. Zafonte, DO, of the Department of Physical Medicine and Rehabilitation at Harvard Medical School in Boston, and his associates.

Given these new findings, “the worldwide use of citicoline for TBI should now be questioned,” the investigators wrote.

It’s likely that no single therapeutic agent will ever be sufficient to improve functional outcomes in TBI, because so many pathologic mechanisms are at work, including hematoma, edema, infarction, contusions, and inflammation, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, of the Neurology and Polytrauma Services and the Department of Neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an accompanying editorial. “The diverse and complex nature of the pathologic mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery.”

Dr. Zafonte and his colleagues conducted the Citicoline Brain Injury Treatment Trial (COBRIT), the first large, phase III, double-blind study to compare citicoline with placebo in the acute and postacute phases after TBI. They enrolled patients with a broad range of severity of injury who had presented to eight level I trauma centers across the country.

The 1,213 study subjects ranged in age from 18 to 70, and the study population was ethnically and demographically diverse. As is typical for TBI patients, three-quarters of the study subjects were male, and more than half were younger than 45.

These patients were randomly assigned to receive 90 days of either citicoline (607 patients) or identical-looking placebo (606) through an enteral route; those who could not swallow the regular oral tablets received the compound as crushed tablets mixed with water or saline and administered through a nasogastric or percutaneous endoscopic gastrostomy tube. The dosage was 2,000 mg per day. Treatment commenced within 24 hours of sustaining the injury.

The primary outcome of the study was functional status and cognitive performance at 90 days, as measured by all nine components of the TBI Clinical Trials Network Core Battery. These components included the Glasgow Outcome Scale-Extended (GOS-E) instrument.

COBRIT was halted early when an interim analysis indicated that further accrual would not change the main outcome: Patients given citicoline did not differ from those given placebo when tested using the combined battery (odds ratio, 0.98) or when tested on any of the individual elements of the battery.

In particular, rates of improvement on the GOS-E were almost exactly the same: 35.4% among subjects given citicoline and 35.6% among those given placebo, the researchers reported. These findings did not change when the data were adjusted to account for patients’ results on the Abbreviated Injury Score at baseline or when the subjects were categorized by the severity of their TBI. The results also did not change when the analysis was restricted to only subjects who took at least 75% of their assigned study medication. There also were no significant differences between the groups in any measure at 180 days postinjury.

A total of 73 subjects died during the study, with no significant difference in survival between the groups.

Similarly, there were no differences between the groups in the overall rates of adverse events or in the rates of serious adverse events.

Patients with traumatic brain injury (TBI) who were treated with citicoline failed to show improvements in functional and cognitive status, according to results of a multicenter phase III trial reported in the November 21, 2012, issue of JAMA. Citicoline proved to be no better than placebo at improving function or cognition after TBI in the first large randomized clinical trial to test it in this patient population.

Citicoline, an endogenous compound that is an intermediate in the biosynthesis of phosphatidylcholine from choline, is thought to have a range of neuroprotective properties and has been approved as a treatment for TBI in 59 countries other than the United States. But it is widely available in the US as a nutraceutical used for various neurologic disorders, said lead author Ross D. Zafonte, DO, of the Department of Physical Medicine and Rehabilitation at Harvard Medical School in Boston, and his associates.

Given these new findings, “the worldwide use of citicoline for TBI should now be questioned,” the investigators wrote.

It’s likely that no single therapeutic agent will ever be sufficient to improve functional outcomes in TBI, because so many pathologic mechanisms are at work, including hematoma, edema, infarction, contusions, and inflammation, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, of the Neurology and Polytrauma Services and the Department of Neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an accompanying editorial. “The diverse and complex nature of the pathologic mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery.”

Dr. Zafonte and his colleagues conducted the Citicoline Brain Injury Treatment Trial (COBRIT), the first large, phase III, double-blind study to compare citicoline with placebo in the acute and postacute phases after TBI. They enrolled patients with a broad range of severity of injury who had presented to eight level I trauma centers across the country.

The 1,213 study subjects ranged in age from 18 to 70, and the study population was ethnically and demographically diverse. As is typical for TBI patients, three-quarters of the study subjects were male, and more than half were younger than 45.

These patients were randomly assigned to receive 90 days of either citicoline (607 patients) or identical-looking placebo (606) through an enteral route; those who could not swallow the regular oral tablets received the compound as crushed tablets mixed with water or saline and administered through a nasogastric or percutaneous endoscopic gastrostomy tube. The dosage was 2,000 mg per day. Treatment commenced within 24 hours of sustaining the injury.

The primary outcome of the study was functional status and cognitive performance at 90 days, as measured by all nine components of the TBI Clinical Trials Network Core Battery. These components included the Glasgow Outcome Scale-Extended (GOS-E) instrument.

COBRIT was halted early when an interim analysis indicated that further accrual would not change the main outcome: Patients given citicoline did not differ from those given placebo when tested using the combined battery (odds ratio, 0.98) or when tested on any of the individual elements of the battery.

In particular, rates of improvement on the GOS-E were almost exactly the same: 35.4% among subjects given citicoline and 35.6% among those given placebo, the researchers reported. These findings did not change when the data were adjusted to account for patients’ results on the Abbreviated Injury Score at baseline or when the subjects were categorized by the severity of their TBI. The results also did not change when the analysis was restricted to only subjects who took at least 75% of their assigned study medication. There also were no significant differences between the groups in any measure at 180 days postinjury.

A total of 73 subjects died during the study, with no significant difference in survival between the groups.

Similarly, there were no differences between the groups in the overall rates of adverse events or in the rates of serious adverse events.

Patients with traumatic brain injury (TBI) who were treated with citicoline failed to show improvements in functional and cognitive status, according to results of a multicenter phase III trial reported in the November 21, 2012, issue of JAMA. Citicoline proved to be no better than placebo at improving function or cognition after TBI in the first large randomized clinical trial to test it in this patient population.

Citicoline, an endogenous compound that is an intermediate in the biosynthesis of phosphatidylcholine from choline, is thought to have a range of neuroprotective properties and has been approved as a treatment for TBI in 59 countries other than the United States. But it is widely available in the US as a nutraceutical used for various neurologic disorders, said lead author Ross D. Zafonte, DO, of the Department of Physical Medicine and Rehabilitation at Harvard Medical School in Boston, and his associates.

Given these new findings, “the worldwide use of citicoline for TBI should now be questioned,” the investigators wrote.

It’s likely that no single therapeutic agent will ever be sufficient to improve functional outcomes in TBI, because so many pathologic mechanisms are at work, including hematoma, edema, infarction, contusions, and inflammation, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, of the Neurology and Polytrauma Services and the Department of Neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an accompanying editorial. “The diverse and complex nature of the pathologic mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery.”

Dr. Zafonte and his colleagues conducted the Citicoline Brain Injury Treatment Trial (COBRIT), the first large, phase III, double-blind study to compare citicoline with placebo in the acute and postacute phases after TBI. They enrolled patients with a broad range of severity of injury who had presented to eight level I trauma centers across the country.

The 1,213 study subjects ranged in age from 18 to 70, and the study population was ethnically and demographically diverse. As is typical for TBI patients, three-quarters of the study subjects were male, and more than half were younger than 45.

These patients were randomly assigned to receive 90 days of either citicoline (607 patients) or identical-looking placebo (606) through an enteral route; those who could not swallow the regular oral tablets received the compound as crushed tablets mixed with water or saline and administered through a nasogastric or percutaneous endoscopic gastrostomy tube. The dosage was 2,000 mg per day. Treatment commenced within 24 hours of sustaining the injury.

The primary outcome of the study was functional status and cognitive performance at 90 days, as measured by all nine components of the TBI Clinical Trials Network Core Battery. These components included the Glasgow Outcome Scale-Extended (GOS-E) instrument.

COBRIT was halted early when an interim analysis indicated that further accrual would not change the main outcome: Patients given citicoline did not differ from those given placebo when tested using the combined battery (odds ratio, 0.98) or when tested on any of the individual elements of the battery.

In particular, rates of improvement on the GOS-E were almost exactly the same: 35.4% among subjects given citicoline and 35.6% among those given placebo, the researchers reported. These findings did not change when the data were adjusted to account for patients’ results on the Abbreviated Injury Score at baseline or when the subjects were categorized by the severity of their TBI. The results also did not change when the analysis was restricted to only subjects who took at least 75% of their assigned study medication. There also were no significant differences between the groups in any measure at 180 days postinjury.

A total of 73 subjects died during the study, with no significant difference in survival between the groups.

Similarly, there were no differences between the groups in the overall rates of adverse events or in the rates of serious adverse events.

MRI may be better than CT scans at predicting whether patients with mild traumatic brain injuries (mTBI) are likely to have persistent neurologic problems, according to the results of a clinical trial published in the December 2012 Annals of Neurology.

Approximately 15% of patients with mTBI have measurable neurologic deficits at one year after injury, but clinicians have no definitive method of predicting patient outcomes.

To address this clinical need, Esther Yuh, MD, PhD, Assistant Professor in Residence at the University of California, San Francisco, School of Medicine, and her colleagues examined the potential of MRI to predict patient outcome three months after mTBI. The researchers prospectively followed 135 patients who were evaluated for acute head injury in the emergency departments of three level I trauma centers—San Francisco General Hospital and Trauma Center, the University of Pittsburgh Medical Center, and the University Medical Center Brackenridge in Austin, Texas. These centers were part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study (TRACK-TBI).

Patient Characteristics
Patients came from highly diverse socioeconomic backgrounds, had few exclusion factors, and ranged from age 15 to 86, with a mean age of 40. All patients underwent CT scans when they were admitted, and early brain MRI was performed approximately a week later.

The investigators used univariate and multivariate logistic regression to determine demographic, clinical, socioeconomic, CT, and MRI features that predicted outcomes at three months following the brain injury. Outcomes were assessed with the eight-point Extended Glasgow Outcome scale, a well-validated summary assessment suitable for clinical trials.

Multivariate models of the three-month outcome scale were analyzed based on three sets of predictive variables. The first set examined only clinical, demographic, and socioeconomic variables, the second set incorporated head CT features, and the third set used all the preceding variables, as well as brain MRI features.

Evidence of subarachnoid hemorrhage on CT was associated with a multivariate odds ratio of 3.5 for poorer three-month outcome, after accounting for demographic, clinical, and socioeconomic factors, said the researchers.

Normal CT Is Not Enough
However, 27% of patients who were admitted with normal head CT had an abnormal early brain MRI. After adjusting for head CT findings and demographic, clinical, and socioeconomic factors, the investigators found that one or more brain contusions and four or more foci of hemorrhagic axonal injury on MRI were each independently associated with poorer three-month outcome. Multivariate odds ratios were 4.5 and 3.2, respectively.

This work raises questions of how we’re currently managing patients via CT scan,” said senior author Geoff Manley, MD, PhD, Chief of Neurosurgery at San Francisco General Hospital. “Having a normal CT scan doesn’t, in fact, say you’re normal,” he added.

A Step Forward
Each year, at least 1.7 million Americans seek medical attention for acute head injuries, and 75% of those injuries are mTBIs, most with mild symptoms such as temporary loss of consciousness, vomiting, or amnesia.

The majority of patients with mTBI recover fully, but approximately one in six eventually develop persistent and sometimes permanent disability from the injury. In the past, some socioeconomic factors have helped to predict disability, but Dr. Yuh’s study shows that an imaging feature can help to predict the rate or extent of a patient’s recovery.

According to Dr. Manley, this study represents an important step toward developing a more quantitative, precise method of evaluating, monitoring, and treating patients with mTBI. At present, performing routine brain MRI on mTBI patients may not be cost-effective, but smaller and less-costly MRI scanners that examine only the patient’s head are in development. Furthermore, continuing advances in the MRI field may eventually reduce expenses to a manageable level.

The study’s strengths are its greater specification of types of lesions that may predict outcome, control for other predictors, multicenter patient sample, and use of TBI Common Data Elements to categorize the imaging results, the investigators said.

They believe the findings will benefit clinicians and researchers conducting clinical trials. “Progress beyond mere definition of mTBI toward evidence-based diagnosis is essential for clinical trials that evaluate treatments and, ultimately, more effective triage to follow-up care,” stated the authors.

MRI may be better than CT scans at predicting whether patients with mild traumatic brain injuries (mTBI) are likely to have persistent neurologic problems, according to the results of a clinical trial published in the December 2012 Annals of Neurology.

Approximately 15% of patients with mTBI have measurable neurologic deficits at one year after injury, but clinicians have no definitive method of predicting patient outcomes.

To address this clinical need, Esther Yuh, MD, PhD, Assistant Professor in Residence at the University of California, San Francisco, School of Medicine, and her colleagues examined the potential of MRI to predict patient outcome three months after mTBI. The researchers prospectively followed 135 patients who were evaluated for acute head injury in the emergency departments of three level I trauma centers—San Francisco General Hospital and Trauma Center, the University of Pittsburgh Medical Center, and the University Medical Center Brackenridge in Austin, Texas. These centers were part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study (TRACK-TBI).

Patient Characteristics
Patients came from highly diverse socioeconomic backgrounds, had few exclusion factors, and ranged from age 15 to 86, with a mean age of 40. All patients underwent CT scans when they were admitted, and early brain MRI was performed approximately a week later.

The investigators used univariate and multivariate logistic regression to determine demographic, clinical, socioeconomic, CT, and MRI features that predicted outcomes at three months following the brain injury. Outcomes were assessed with the eight-point Extended Glasgow Outcome scale, a well-validated summary assessment suitable for clinical trials.

Multivariate models of the three-month outcome scale were analyzed based on three sets of predictive variables. The first set examined only clinical, demographic, and socioeconomic variables, the second set incorporated head CT features, and the third set used all the preceding variables, as well as brain MRI features.

Evidence of subarachnoid hemorrhage on CT was associated with a multivariate odds ratio of 3.5 for poorer three-month outcome, after accounting for demographic, clinical, and socioeconomic factors, said the researchers.

Normal CT Is Not Enough
However, 27% of patients who were admitted with normal head CT had an abnormal early brain MRI. After adjusting for head CT findings and demographic, clinical, and socioeconomic factors, the investigators found that one or more brain contusions and four or more foci of hemorrhagic axonal injury on MRI were each independently associated with poorer three-month outcome. Multivariate odds ratios were 4.5 and 3.2, respectively.

This work raises questions of how we’re currently managing patients via CT scan,” said senior author Geoff Manley, MD, PhD, Chief of Neurosurgery at San Francisco General Hospital. “Having a normal CT scan doesn’t, in fact, say you’re normal,” he added.

A Step Forward
Each year, at least 1.7 million Americans seek medical attention for acute head injuries, and 75% of those injuries are mTBIs, most with mild symptoms such as temporary loss of consciousness, vomiting, or amnesia.

The majority of patients with mTBI recover fully, but approximately one in six eventually develop persistent and sometimes permanent disability from the injury. In the past, some socioeconomic factors have helped to predict disability, but Dr. Yuh’s study shows that an imaging feature can help to predict the rate or extent of a patient’s recovery.

According to Dr. Manley, this study represents an important step toward developing a more quantitative, precise method of evaluating, monitoring, and treating patients with mTBI. At present, performing routine brain MRI on mTBI patients may not be cost-effective, but smaller and less-costly MRI scanners that examine only the patient’s head are in development. Furthermore, continuing advances in the MRI field may eventually reduce expenses to a manageable level.

The study’s strengths are its greater specification of types of lesions that may predict outcome, control for other predictors, multicenter patient sample, and use of TBI Common Data Elements to categorize the imaging results, the investigators said.

They believe the findings will benefit clinicians and researchers conducting clinical trials. “Progress beyond mere definition of mTBI toward evidence-based diagnosis is essential for clinical trials that evaluate treatments and, ultimately, more effective triage to follow-up care,” stated the authors.

MRI may be better than CT scans at predicting whether patients with mild traumatic brain injuries (mTBI) are likely to have persistent neurologic problems, according to the results of a clinical trial published in the December 2012 Annals of Neurology.

Approximately 15% of patients with mTBI have measurable neurologic deficits at one year after injury, but clinicians have no definitive method of predicting patient outcomes.

To address this clinical need, Esther Yuh, MD, PhD, Assistant Professor in Residence at the University of California, San Francisco, School of Medicine, and her colleagues examined the potential of MRI to predict patient outcome three months after mTBI. The researchers prospectively followed 135 patients who were evaluated for acute head injury in the emergency departments of three level I trauma centers—San Francisco General Hospital and Trauma Center, the University of Pittsburgh Medical Center, and the University Medical Center Brackenridge in Austin, Texas. These centers were part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study (TRACK-TBI).

Patient Characteristics
Patients came from highly diverse socioeconomic backgrounds, had few exclusion factors, and ranged from age 15 to 86, with a mean age of 40. All patients underwent CT scans when they were admitted, and early brain MRI was performed approximately a week later.

The investigators used univariate and multivariate logistic regression to determine demographic, clinical, socioeconomic, CT, and MRI features that predicted outcomes at three months following the brain injury. Outcomes were assessed with the eight-point Extended Glasgow Outcome scale, a well-validated summary assessment suitable for clinical trials.

Multivariate models of the three-month outcome scale were analyzed based on three sets of predictive variables. The first set examined only clinical, demographic, and socioeconomic variables, the second set incorporated head CT features, and the third set used all the preceding variables, as well as brain MRI features.

Evidence of subarachnoid hemorrhage on CT was associated with a multivariate odds ratio of 3.5 for poorer three-month outcome, after accounting for demographic, clinical, and socioeconomic factors, said the researchers.

Normal CT Is Not Enough
However, 27% of patients who were admitted with normal head CT had an abnormal early brain MRI. After adjusting for head CT findings and demographic, clinical, and socioeconomic factors, the investigators found that one or more brain contusions and four or more foci of hemorrhagic axonal injury on MRI were each independently associated with poorer three-month outcome. Multivariate odds ratios were 4.5 and 3.2, respectively.

This work raises questions of how we’re currently managing patients via CT scan,” said senior author Geoff Manley, MD, PhD, Chief of Neurosurgery at San Francisco General Hospital. “Having a normal CT scan doesn’t, in fact, say you’re normal,” he added.

A Step Forward
Each year, at least 1.7 million Americans seek medical attention for acute head injuries, and 75% of those injuries are mTBIs, most with mild symptoms such as temporary loss of consciousness, vomiting, or amnesia.

The majority of patients with mTBI recover fully, but approximately one in six eventually develop persistent and sometimes permanent disability from the injury. In the past, some socioeconomic factors have helped to predict disability, but Dr. Yuh’s study shows that an imaging feature can help to predict the rate or extent of a patient’s recovery.

According to Dr. Manley, this study represents an important step toward developing a more quantitative, precise method of evaluating, monitoring, and treating patients with mTBI. At present, performing routine brain MRI on mTBI patients may not be cost-effective, but smaller and less-costly MRI scanners that examine only the patient’s head are in development. Furthermore, continuing advances in the MRI field may eventually reduce expenses to a manageable level.

The study’s strengths are its greater specification of types of lesions that may predict outcome, control for other predictors, multicenter patient sample, and use of TBI Common Data Elements to categorize the imaging results, the investigators said.

They believe the findings will benefit clinicians and researchers conducting clinical trials. “Progress beyond mere definition of mTBI toward evidence-based diagnosis is essential for clinical trials that evaluate treatments and, ultimately, more effective triage to follow-up care,” stated the authors.