Traumatic Brain Injury

SEATTLE—Insomnia is significantly more prevalent among patients with mild traumatic brain injury (TBI) than in the general population, according to research presented at the 23rd Annual Meeting of the Associated Professional Sleep Societies. Other nighttime sleep problems and excessive daytime sleepiness are also strongly associated with mild TBI, reported Michael B. Russo, MD, and colleagues.

Because TBI may disrupt various components of the sleep/wake regulatory network, the investigators had hypothesized that patients with TBI would have a high incidence of insomnia and other sleep-related problems. Dr. Russo’s group reviewed medical records of 35 patients (30 males; mean age, 30) with mild TBI; 20 subjects were military service members. All patients had attended a military neurology clinic for sleep-related complaints, and no patients had had insomnia before incurring a head injury.

The researchers found that 31 patients (89%) had insomnia, compared with an estimated rate of 10% in the general adult population. In addition, 27 patients had sleep-onset insomnia, 30 had difficulty staying asleep, 15 awakened throughout the night, and 11 awakened in the early morning. Furthermore, 23 patients had more than one type of insomnia, according to Dr. Russo, Colonel, Medical Corps, US Army, Tripler Army Medical Center in Honolulu.

The investigators also found that 34 patients had a sleep/wake-related problem and that 31 had excessive daytime sleepiness. Sleep/wake-related problems were defined as having daytime dysfunction associated with not being able to fall asleep, feeling restless at night, having nightmares, awakening at night, awakening in the early morning, and having excessive daytime sleepiness. Excessive daytime sleepiness was defined as having direct complaints, naps, and decreased social and work performance due to sleepiness.

“We suggest that screening for insomnia and sleep/wake-related problems be considered in all patients suspected of having mild TBI,” said Dr. Russo.

NR

—Colby Stong

SEATTLE—Insomnia is significantly more prevalent among patients with mild traumatic brain injury (TBI) than in the general population, according to research presented at the 23rd Annual Meeting of the Associated Professional Sleep Societies. Other nighttime sleep problems and excessive daytime sleepiness are also strongly associated with mild TBI, reported Michael B. Russo, MD, and colleagues.

Because TBI may disrupt various components of the sleep/wake regulatory network, the investigators had hypothesized that patients with TBI would have a high incidence of insomnia and other sleep-related problems. Dr. Russo’s group reviewed medical records of 35 patients (30 males; mean age, 30) with mild TBI; 20 subjects were military service members. All patients had attended a military neurology clinic for sleep-related complaints, and no patients had had insomnia before incurring a head injury.

The researchers found that 31 patients (89%) had insomnia, compared with an estimated rate of 10% in the general adult population. In addition, 27 patients had sleep-onset insomnia, 30 had difficulty staying asleep, 15 awakened throughout the night, and 11 awakened in the early morning. Furthermore, 23 patients had more than one type of insomnia, according to Dr. Russo, Colonel, Medical Corps, US Army, Tripler Army Medical Center in Honolulu.

The investigators also found that 34 patients had a sleep/wake-related problem and that 31 had excessive daytime sleepiness. Sleep/wake-related problems were defined as having daytime dysfunction associated with not being able to fall asleep, feeling restless at night, having nightmares, awakening at night, awakening in the early morning, and having excessive daytime sleepiness. Excessive daytime sleepiness was defined as having direct complaints, naps, and decreased social and work performance due to sleepiness.

“We suggest that screening for insomnia and sleep/wake-related problems be considered in all patients suspected of having mild TBI,” said Dr. Russo.

NR

—Colby Stong

SEATTLE—Insomnia is significantly more prevalent among patients with mild traumatic brain injury (TBI) than in the general population, according to research presented at the 23rd Annual Meeting of the Associated Professional Sleep Societies. Other nighttime sleep problems and excessive daytime sleepiness are also strongly associated with mild TBI, reported Michael B. Russo, MD, and colleagues.

Because TBI may disrupt various components of the sleep/wake regulatory network, the investigators had hypothesized that patients with TBI would have a high incidence of insomnia and other sleep-related problems. Dr. Russo’s group reviewed medical records of 35 patients (30 males; mean age, 30) with mild TBI; 20 subjects were military service members. All patients had attended a military neurology clinic for sleep-related complaints, and no patients had had insomnia before incurring a head injury.

The researchers found that 31 patients (89%) had insomnia, compared with an estimated rate of 10% in the general adult population. In addition, 27 patients had sleep-onset insomnia, 30 had difficulty staying asleep, 15 awakened throughout the night, and 11 awakened in the early morning. Furthermore, 23 patients had more than one type of insomnia, according to Dr. Russo, Colonel, Medical Corps, US Army, Tripler Army Medical Center in Honolulu.

The investigators also found that 34 patients had a sleep/wake-related problem and that 31 had excessive daytime sleepiness. Sleep/wake-related problems were defined as having daytime dysfunction associated with not being able to fall asleep, feeling restless at night, having nightmares, awakening at night, awakening in the early morning, and having excessive daytime sleepiness. Excessive daytime sleepiness was defined as having direct complaints, naps, and decreased social and work performance due to sleepiness.

“We suggest that screening for insomnia and sleep/wake-related problems be considered in all patients suspected of having mild TBI,” said Dr. Russo.

NR

—Colby Stong

SEATTLE—A new, more reliable, efficient, and valid classification system for traumatic brain injury (TBI) is under development, with the goal of driving more focused research and individualized therapy for patients with head injury, reported Geoffrey Manley, MD, PhD, at the 61st Annual Meeting of the American Academy of Neurology.

Problems With the Current Classification System
TBI classification is “still a symptoms-based classification system,” said Dr. Manley, Professor of Neurosurgery at the University of California, San Francisco, and Chief of Neurosurgery at San Francisco General Hospital.

In fact, Dr. Manley argued, “we probably had a better classification system for head injury 200 years ago than we have today.” In the beginning of the 18th century, autopsies became more routine and many disease conditions, including head injuries, started to be classified based on pathoanatomic features. At that time, TBI was classified as follows: commotio (ie, concussion), contusio (ie, bruising of the brain, contusions), and compresio (ie, compressive injuries such as subdural and epidural hematomas). Today, “we classify TBI as mild, moderate, and severe, and that’s based upon the Glasgow Coma Score (GCS),” said Dr. Manley. “I think that, pathoanatomically, we’re looking at a much more heterogeneous disease process than just mild, moderate, and severe.”

As an example of the insufficiency of classifying TBI based solely on GCS score, Dr. Manley described the case of a 56-year-old executive. The patient fell and was found to have a GCS of 15. “The residents thought he was doing fine, because the day after the injury he’s showing two fingers, he seems to be conversing just fine,” stated Dr. Manley. However, the patient had an orbitofrontal lesion, and at 12-month follow-up he was found to be impulsive, unemployed, and divorced. “So I don’t think this was a mild head injury for this guy,” said Dr. Manley. “We don’t consider this lesion mild just because this patient had a GCS of 14 or 15. We look at this kind of injury, and we say, ‘This is someone who’s going to have social dysregulation in the future.’”

Dr. Manley suggested that because the GCS does not provide information about the pathophysiologic mechanisms behind neurologic deficits, a more multidimensional classification system is needed to develop more targeted treatment and improve outcomes. Cancer, for example, is classified using a multidimensional system. “It’s really the pinnacle of disease classification. It’s a mixture of anatomy, physiology, metabolomics, immunology, and genetically defined diseases,” said Dr. Manley. “We didn’t get as far as we did with cancer by saying ‘You’ve got mild cancer,’ ‘You’ve got moderate cancer,’ and ‘You’re on death’s door.’”

Workshop Recommendations
In October 2007, the NINDS, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to discuss the limitations of using the GCS for classification of TBI and the need to develop a more pathoanatomic-based classification system. The organizing committee was cochaired by Dr. Manley, and their recommendations were published in the July 2008 Journal of Neurotrauma.

In order to begin to reclassify TBI, “we really have to restructure the field from the ground up,” said Dr. Manley. “We need to define a common set of demographic data elements so that we’re all collecting the same kind of information across studies, whether they’re funded by the NIH, whether they’re funded by the Department of Defense, whether this is just a study that you’re going to get funded out of your individual funds at your own department. We should all be collecting the same demographic data.”

Dr. Manley emphasized the need for agreement on outcome measures. “We have to do more in terms of getting better outcome measures that define the disabilities that these patients have.” He also suggested that imaging requirements should be better defined. When doing CT and MRI scans, he said, the same kind of sequences should be used so that films can be compared from site to site and across different studies.

Lastly, Dr. Manley recommended defining requirements for genomics and proteomics. Setting standards for collecting, processing, and sorting is essential for investigating biomarkers, he said.

New Horizons in TBI Research
Dr. Manley noted that in the upcoming months, “diffusion tensor imaging … is going to be very important. We’ve been doing a lot of work with magnetoencephalography and looking at things like functional connectivity…. It’s not where the lesion is, but how it affects the connectivity in the brain.”

Higher resolution imaging will also be studied. “We’ve been doing a lot of scanning of our [TBI] patients on our new 7-Tesla magnet … and it’s just absolutely amazing, the structural images,” Dr. Manley commented.

“The other thing that I think we really need to improve upon is medical informatics,” said Dr. Manley, noting that better clinical decision-making tools are needed to assist clinicians who do not focus solely on TBI. “Most importantly, I think we need a prospective, multivariate TBI database. I’m not sure we even know what TBI is in 2009. Almost everything we do as clinicians is based on what we learned from the Traumatic Coma Data Bank, which contains patient data collected over 25 years ago,” said Dr. Manley. Prospective observational studies across the entire TBI injury spectrum will require 1,000 to 2,000 patients, rather than 20 to 30, to develop a clearer picture of TBI and help to focus future research and clinical efforts.

In March 2009, a total of 49 institutions and government agencies, including the NIH, National Institute on Disability and Rehabilitation Reasearch, Defense Centers of Excellence, Defense and Veterans Brain Injury Center, Veterans Affairs, and other stakeholders, organized a consensus conference in Washington, DC to discuss these issues. “What I hope you’ll see by the end of the year is a series of white papers that essentially outline what these common data elements are for TBI demographics, neuroimaging, biomarkers, outcome, and assessment of psychological health. The vision is to provide the tools to standardize data collection to improve TBI research and clinical care.”

SEATTLE—A new, more reliable, efficient, and valid classification system for traumatic brain injury (TBI) is under development, with the goal of driving more focused research and individualized therapy for patients with head injury, reported Geoffrey Manley, MD, PhD, at the 61st Annual Meeting of the American Academy of Neurology.

Problems With the Current Classification System
TBI classification is “still a symptoms-based classification system,” said Dr. Manley, Professor of Neurosurgery at the University of California, San Francisco, and Chief of Neurosurgery at San Francisco General Hospital.

In fact, Dr. Manley argued, “we probably had a better classification system for head injury 200 years ago than we have today.” In the beginning of the 18th century, autopsies became more routine and many disease conditions, including head injuries, started to be classified based on pathoanatomic features. At that time, TBI was classified as follows: commotio (ie, concussion), contusio (ie, bruising of the brain, contusions), and compresio (ie, compressive injuries such as subdural and epidural hematomas). Today, “we classify TBI as mild, moderate, and severe, and that’s based upon the Glasgow Coma Score (GCS),” said Dr. Manley. “I think that, pathoanatomically, we’re looking at a much more heterogeneous disease process than just mild, moderate, and severe.”

As an example of the insufficiency of classifying TBI based solely on GCS score, Dr. Manley described the case of a 56-year-old executive. The patient fell and was found to have a GCS of 15. “The residents thought he was doing fine, because the day after the injury he’s showing two fingers, he seems to be conversing just fine,” stated Dr. Manley. However, the patient had an orbitofrontal lesion, and at 12-month follow-up he was found to be impulsive, unemployed, and divorced. “So I don’t think this was a mild head injury for this guy,” said Dr. Manley. “We don’t consider this lesion mild just because this patient had a GCS of 14 or 15. We look at this kind of injury, and we say, ‘This is someone who’s going to have social dysregulation in the future.’”

Dr. Manley suggested that because the GCS does not provide information about the pathophysiologic mechanisms behind neurologic deficits, a more multidimensional classification system is needed to develop more targeted treatment and improve outcomes. Cancer, for example, is classified using a multidimensional system. “It’s really the pinnacle of disease classification. It’s a mixture of anatomy, physiology, metabolomics, immunology, and genetically defined diseases,” said Dr. Manley. “We didn’t get as far as we did with cancer by saying ‘You’ve got mild cancer,’ ‘You’ve got moderate cancer,’ and ‘You’re on death’s door.’”

Workshop Recommendations
In October 2007, the NINDS, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to discuss the limitations of using the GCS for classification of TBI and the need to develop a more pathoanatomic-based classification system. The organizing committee was cochaired by Dr. Manley, and their recommendations were published in the July 2008 Journal of Neurotrauma.

In order to begin to reclassify TBI, “we really have to restructure the field from the ground up,” said Dr. Manley. “We need to define a common set of demographic data elements so that we’re all collecting the same kind of information across studies, whether they’re funded by the NIH, whether they’re funded by the Department of Defense, whether this is just a study that you’re going to get funded out of your individual funds at your own department. We should all be collecting the same demographic data.”

Dr. Manley emphasized the need for agreement on outcome measures. “We have to do more in terms of getting better outcome measures that define the disabilities that these patients have.” He also suggested that imaging requirements should be better defined. When doing CT and MRI scans, he said, the same kind of sequences should be used so that films can be compared from site to site and across different studies.

Lastly, Dr. Manley recommended defining requirements for genomics and proteomics. Setting standards for collecting, processing, and sorting is essential for investigating biomarkers, he said.

New Horizons in TBI Research
Dr. Manley noted that in the upcoming months, “diffusion tensor imaging … is going to be very important. We’ve been doing a lot of work with magnetoencephalography and looking at things like functional connectivity…. It’s not where the lesion is, but how it affects the connectivity in the brain.”

Higher resolution imaging will also be studied. “We’ve been doing a lot of scanning of our [TBI] patients on our new 7-Tesla magnet … and it’s just absolutely amazing, the structural images,” Dr. Manley commented.

“The other thing that I think we really need to improve upon is medical informatics,” said Dr. Manley, noting that better clinical decision-making tools are needed to assist clinicians who do not focus solely on TBI. “Most importantly, I think we need a prospective, multivariate TBI database. I’m not sure we even know what TBI is in 2009. Almost everything we do as clinicians is based on what we learned from the Traumatic Coma Data Bank, which contains patient data collected over 25 years ago,” said Dr. Manley. Prospective observational studies across the entire TBI injury spectrum will require 1,000 to 2,000 patients, rather than 20 to 30, to develop a clearer picture of TBI and help to focus future research and clinical efforts.

In March 2009, a total of 49 institutions and government agencies, including the NIH, National Institute on Disability and Rehabilitation Reasearch, Defense Centers of Excellence, Defense and Veterans Brain Injury Center, Veterans Affairs, and other stakeholders, organized a consensus conference in Washington, DC to discuss these issues. “What I hope you’ll see by the end of the year is a series of white papers that essentially outline what these common data elements are for TBI demographics, neuroimaging, biomarkers, outcome, and assessment of psychological health. The vision is to provide the tools to standardize data collection to improve TBI research and clinical care.”

SEATTLE—A new, more reliable, efficient, and valid classification system for traumatic brain injury (TBI) is under development, with the goal of driving more focused research and individualized therapy for patients with head injury, reported Geoffrey Manley, MD, PhD, at the 61st Annual Meeting of the American Academy of Neurology.

Problems With the Current Classification System
TBI classification is “still a symptoms-based classification system,” said Dr. Manley, Professor of Neurosurgery at the University of California, San Francisco, and Chief of Neurosurgery at San Francisco General Hospital.

In fact, Dr. Manley argued, “we probably had a better classification system for head injury 200 years ago than we have today.” In the beginning of the 18th century, autopsies became more routine and many disease conditions, including head injuries, started to be classified based on pathoanatomic features. At that time, TBI was classified as follows: commotio (ie, concussion), contusio (ie, bruising of the brain, contusions), and compresio (ie, compressive injuries such as subdural and epidural hematomas). Today, “we classify TBI as mild, moderate, and severe, and that’s based upon the Glasgow Coma Score (GCS),” said Dr. Manley. “I think that, pathoanatomically, we’re looking at a much more heterogeneous disease process than just mild, moderate, and severe.”

As an example of the insufficiency of classifying TBI based solely on GCS score, Dr. Manley described the case of a 56-year-old executive. The patient fell and was found to have a GCS of 15. “The residents thought he was doing fine, because the day after the injury he’s showing two fingers, he seems to be conversing just fine,” stated Dr. Manley. However, the patient had an orbitofrontal lesion, and at 12-month follow-up he was found to be impulsive, unemployed, and divorced. “So I don’t think this was a mild head injury for this guy,” said Dr. Manley. “We don’t consider this lesion mild just because this patient had a GCS of 14 or 15. We look at this kind of injury, and we say, ‘This is someone who’s going to have social dysregulation in the future.’”

Dr. Manley suggested that because the GCS does not provide information about the pathophysiologic mechanisms behind neurologic deficits, a more multidimensional classification system is needed to develop more targeted treatment and improve outcomes. Cancer, for example, is classified using a multidimensional system. “It’s really the pinnacle of disease classification. It’s a mixture of anatomy, physiology, metabolomics, immunology, and genetically defined diseases,” said Dr. Manley. “We didn’t get as far as we did with cancer by saying ‘You’ve got mild cancer,’ ‘You’ve got moderate cancer,’ and ‘You’re on death’s door.’”

Workshop Recommendations
In October 2007, the NINDS, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to discuss the limitations of using the GCS for classification of TBI and the need to develop a more pathoanatomic-based classification system. The organizing committee was cochaired by Dr. Manley, and their recommendations were published in the July 2008 Journal of Neurotrauma.

In order to begin to reclassify TBI, “we really have to restructure the field from the ground up,” said Dr. Manley. “We need to define a common set of demographic data elements so that we’re all collecting the same kind of information across studies, whether they’re funded by the NIH, whether they’re funded by the Department of Defense, whether this is just a study that you’re going to get funded out of your individual funds at your own department. We should all be collecting the same demographic data.”

Dr. Manley emphasized the need for agreement on outcome measures. “We have to do more in terms of getting better outcome measures that define the disabilities that these patients have.” He also suggested that imaging requirements should be better defined. When doing CT and MRI scans, he said, the same kind of sequences should be used so that films can be compared from site to site and across different studies.

Lastly, Dr. Manley recommended defining requirements for genomics and proteomics. Setting standards for collecting, processing, and sorting is essential for investigating biomarkers, he said.

New Horizons in TBI Research
Dr. Manley noted that in the upcoming months, “diffusion tensor imaging … is going to be very important. We’ve been doing a lot of work with magnetoencephalography and looking at things like functional connectivity…. It’s not where the lesion is, but how it affects the connectivity in the brain.”

Higher resolution imaging will also be studied. “We’ve been doing a lot of scanning of our [TBI] patients on our new 7-Tesla magnet … and it’s just absolutely amazing, the structural images,” Dr. Manley commented.

“The other thing that I think we really need to improve upon is medical informatics,” said Dr. Manley, noting that better clinical decision-making tools are needed to assist clinicians who do not focus solely on TBI. “Most importantly, I think we need a prospective, multivariate TBI database. I’m not sure we even know what TBI is in 2009. Almost everything we do as clinicians is based on what we learned from the Traumatic Coma Data Bank, which contains patient data collected over 25 years ago,” said Dr. Manley. Prospective observational studies across the entire TBI injury spectrum will require 1,000 to 2,000 patients, rather than 20 to 30, to develop a clearer picture of TBI and help to focus future research and clinical efforts.

In March 2009, a total of 49 institutions and government agencies, including the NIH, National Institute on Disability and Rehabilitation Reasearch, Defense Centers of Excellence, Defense and Veterans Brain Injury Center, Veterans Affairs, and other stakeholders, organized a consensus conference in Washington, DC to discuss these issues. “What I hope you’ll see by the end of the year is a series of white papers that essentially outline what these common data elements are for TBI demographics, neuroimaging, biomarkers, outcome, and assessment of psychological health. The vision is to provide the tools to standardize data collection to improve TBI research and clinical care.”

NASHVILLE—Therapeutic hypothermia is being used with increasing frequency to treat patients with neurologic injury from conditions such as stroke, cardiac arrest, and traumatic brain injury (TBI). “Induced hypothermia can sometimes be risky, but it’s potentially highly rewarding,” said Kees H. Polderman, MD, PhD, at the Society of Critical Care Medicine’s 38th Critical Care Congress. Effective use of hypothermia is strongly dependent on the quality of other aspects of ICU care; therefore, he recommended that clinicians give careful attention to all of these factors.

When interpreting findings from studies examining therapeutic hypothermia, “you should always look at where it’s being performed, the context in which this treatment is taking place, and what other aspects of care are similar to your own and which ones are different; then you can assess if you can reproduce those results in your own center, or if you need to adapt your policy a bit,” commented Dr. Polderman, Professor in Intensive Care Medicine at the Department of Critical Care, University of Pittsburgh Medical Center.

Goals of Therapeutic Hypothermia
Stroke, cardiac arrest, and, to a lesser extent, TBI are characterized by ischemia and reperfusion injury. After a period of ischemia, a series of destructive processes takes place in the injured cells of the brain. “The damage is ongoing while the patient is in your ICU or your emergency room,” said Dr. Polderman.

Therefore, the first goal of treatment with hypothermia is to try to limit this injury. “Hypothermia acts as a sort of blanket therapy,” he said. “It can interrupt every single one of these harmful processes, in contrast to many other therapies that we’ve tried in the past.”

Another goal is to treat brain edema, which may also play a role in some disease states—TBI being one example. For patients with brain edema, the approach to treatment is slightly different, requiring a longer period of cooling.

Controlling Brain Temperature
When using hypothermia for patients with neurologic injury, physicians should do their best to prevent fever, Dr. Polderman advised. “Most of our patients in the neurocritical care units develop fever at some point in their ICU stay. The more severe the injury, the more likely the chance that [the patient] will develop fever,” he said.

Fever is associated with longer length of stay, worse neurologic outcome, and higher mortality. In two studies involving patients with subarachnoid hemorrhage and intracerebral hemorrhage, researchers reported that even a minimal elevation in temperature to slightly greater than 37.5°C—not considered a real fever by some—had a significant adverse effect on outcome.

One explanation for this could be that brain temperature exceeds core temperature. “The destructive processes triggered by ischemia generate heat. Local brain edema makes it difficult to get rid of the excess heat, and this leads to overheating of the brain,” explained Dr. Polderman. “So fever after neurologic injury seems to be extremely harmful, and hypothermia seems to be really protective.”

Proven Efficacy
Three randomized controlled trials have assessed neurologic outcome in patients who underwent therapeutic hypothermia following witnessed cardiac arrest, with significant improvement seen in patients treated with hypothermia across all three studies, said Dr. Polderman. In addition, a number of nonrandomized studies have reported good outcomes following treatment with induced hypothermia.

Dr. Polderman and his colleagues conducted a prospective, multicenter study in which 64 patients with witnessed cardiac arrest underwent therapeutic hypothermia. The results have not yet been published as a full paper. In this study, 60% of patients with ventricular tachycardia/ventricular fibrillation (VT/VF) had a good neurologic outcome (defined as return to their home situation with no or only minimal neurologic impairment). In addition, 50% of patients with an initial rhythm of asystole who reached the hospital alive also had a good neurologic outcome.

“We should lose the pessimism surrounding patients with witnessed cardiac arrest, because the good outcome rates can be better than 50% in this category of patients when hypothermia has been used,” commented Dr. Polderman. “We need to get the cardiologist to do the appropriate intervention, even when the patient is comatose. We need to promote bystander CPR, because the chances of this therapy helping the patient are much better if basic CPR has been performed.”

Some studies have also reported good outcome following therapeutic cooling in patients with severe TBI. Meta-analyses have reported a 22% to 48% reduction in the risk for adverse neurologic outcome in patients with severe TBI treated with therapeutic hypothermia, although not all these differences were statistically significant.

However, the treatment looks highly promising, according to Dr. Polderman. He pointed out for comparison that data on the use of barbiturates and mannitol do not show any benefit on neurologic outcome in patients with TBI.

Cooling in the Right Context
Although hypothermia has beneficial effects on neurologic outcome, “a treatment can only be effective if the other aspects of intensive care are good,” cautioned Dr. Polderman. Therefore, “context matters. It’s not just about cooling.”

When using hypothermia, temperature should be lowered rapidly, but rewarming should be done very slowly, noted Dr. Polderman. “If you do it rapidly, you could lose some or all of the protective effects of hypothermia,” he warned.

In addition, physicians should consider other aspects of ICU treatment, such as prevention of hypo- and hypercapnia, electrolyte disorders, hyperglycemia, and hypoglycemia. “All these things matter, and they may make all the difference,” he said. “Without getting that right, hypothermia can be an ineffective or even dangerous therapy.”

“The idea of context applies even more strongly to areas like severe TBI,” he asserted. “Speed and duration of cooling are important.” For patients with TBI who receive hypothermia, longer duration of cooling (ie, greater than 48 hours) and slow rewarming protocols are associated with better outcome. He noted that one way to determine the optimal duration of cooling in individual patients is to measure intracranial pressure. Intracranial pressure is both a marker of ongoing brain injury and a potential cause of additional injury.

“The use of hypothermia is not risk-free. There are severe side effects, which we should take into account, but the good news is that these can be fairly easily managed,” concluded Dr. Polderman.   

NASHVILLE—Therapeutic hypothermia is being used with increasing frequency to treat patients with neurologic injury from conditions such as stroke, cardiac arrest, and traumatic brain injury (TBI). “Induced hypothermia can sometimes be risky, but it’s potentially highly rewarding,” said Kees H. Polderman, MD, PhD, at the Society of Critical Care Medicine’s 38th Critical Care Congress. Effective use of hypothermia is strongly dependent on the quality of other aspects of ICU care; therefore, he recommended that clinicians give careful attention to all of these factors.

When interpreting findings from studies examining therapeutic hypothermia, “you should always look at where it’s being performed, the context in which this treatment is taking place, and what other aspects of care are similar to your own and which ones are different; then you can assess if you can reproduce those results in your own center, or if you need to adapt your policy a bit,” commented Dr. Polderman, Professor in Intensive Care Medicine at the Department of Critical Care, University of Pittsburgh Medical Center.

Goals of Therapeutic Hypothermia
Stroke, cardiac arrest, and, to a lesser extent, TBI are characterized by ischemia and reperfusion injury. After a period of ischemia, a series of destructive processes takes place in the injured cells of the brain. “The damage is ongoing while the patient is in your ICU or your emergency room,” said Dr. Polderman.

Therefore, the first goal of treatment with hypothermia is to try to limit this injury. “Hypothermia acts as a sort of blanket therapy,” he said. “It can interrupt every single one of these harmful processes, in contrast to many other therapies that we’ve tried in the past.”

Another goal is to treat brain edema, which may also play a role in some disease states—TBI being one example. For patients with brain edema, the approach to treatment is slightly different, requiring a longer period of cooling.

Controlling Brain Temperature
When using hypothermia for patients with neurologic injury, physicians should do their best to prevent fever, Dr. Polderman advised. “Most of our patients in the neurocritical care units develop fever at some point in their ICU stay. The more severe the injury, the more likely the chance that [the patient] will develop fever,” he said.

Fever is associated with longer length of stay, worse neurologic outcome, and higher mortality. In two studies involving patients with subarachnoid hemorrhage and intracerebral hemorrhage, researchers reported that even a minimal elevation in temperature to slightly greater than 37.5°C—not considered a real fever by some—had a significant adverse effect on outcome.

One explanation for this could be that brain temperature exceeds core temperature. “The destructive processes triggered by ischemia generate heat. Local brain edema makes it difficult to get rid of the excess heat, and this leads to overheating of the brain,” explained Dr. Polderman. “So fever after neurologic injury seems to be extremely harmful, and hypothermia seems to be really protective.”

Proven Efficacy
Three randomized controlled trials have assessed neurologic outcome in patients who underwent therapeutic hypothermia following witnessed cardiac arrest, with significant improvement seen in patients treated with hypothermia across all three studies, said Dr. Polderman. In addition, a number of nonrandomized studies have reported good outcomes following treatment with induced hypothermia.

Dr. Polderman and his colleagues conducted a prospective, multicenter study in which 64 patients with witnessed cardiac arrest underwent therapeutic hypothermia. The results have not yet been published as a full paper. In this study, 60% of patients with ventricular tachycardia/ventricular fibrillation (VT/VF) had a good neurologic outcome (defined as return to their home situation with no or only minimal neurologic impairment). In addition, 50% of patients with an initial rhythm of asystole who reached the hospital alive also had a good neurologic outcome.

“We should lose the pessimism surrounding patients with witnessed cardiac arrest, because the good outcome rates can be better than 50% in this category of patients when hypothermia has been used,” commented Dr. Polderman. “We need to get the cardiologist to do the appropriate intervention, even when the patient is comatose. We need to promote bystander CPR, because the chances of this therapy helping the patient are much better if basic CPR has been performed.”

Some studies have also reported good outcome following therapeutic cooling in patients with severe TBI. Meta-analyses have reported a 22% to 48% reduction in the risk for adverse neurologic outcome in patients with severe TBI treated with therapeutic hypothermia, although not all these differences were statistically significant.

However, the treatment looks highly promising, according to Dr. Polderman. He pointed out for comparison that data on the use of barbiturates and mannitol do not show any benefit on neurologic outcome in patients with TBI.

Cooling in the Right Context
Although hypothermia has beneficial effects on neurologic outcome, “a treatment can only be effective if the other aspects of intensive care are good,” cautioned Dr. Polderman. Therefore, “context matters. It’s not just about cooling.”

When using hypothermia, temperature should be lowered rapidly, but rewarming should be done very slowly, noted Dr. Polderman. “If you do it rapidly, you could lose some or all of the protective effects of hypothermia,” he warned.

In addition, physicians should consider other aspects of ICU treatment, such as prevention of hypo- and hypercapnia, electrolyte disorders, hyperglycemia, and hypoglycemia. “All these things matter, and they may make all the difference,” he said. “Without getting that right, hypothermia can be an ineffective or even dangerous therapy.”

“The idea of context applies even more strongly to areas like severe TBI,” he asserted. “Speed and duration of cooling are important.” For patients with TBI who receive hypothermia, longer duration of cooling (ie, greater than 48 hours) and slow rewarming protocols are associated with better outcome. He noted that one way to determine the optimal duration of cooling in individual patients is to measure intracranial pressure. Intracranial pressure is both a marker of ongoing brain injury and a potential cause of additional injury.

“The use of hypothermia is not risk-free. There are severe side effects, which we should take into account, but the good news is that these can be fairly easily managed,” concluded Dr. Polderman.   

NASHVILLE—Therapeutic hypothermia is being used with increasing frequency to treat patients with neurologic injury from conditions such as stroke, cardiac arrest, and traumatic brain injury (TBI). “Induced hypothermia can sometimes be risky, but it’s potentially highly rewarding,” said Kees H. Polderman, MD, PhD, at the Society of Critical Care Medicine’s 38th Critical Care Congress. Effective use of hypothermia is strongly dependent on the quality of other aspects of ICU care; therefore, he recommended that clinicians give careful attention to all of these factors.

When interpreting findings from studies examining therapeutic hypothermia, “you should always look at where it’s being performed, the context in which this treatment is taking place, and what other aspects of care are similar to your own and which ones are different; then you can assess if you can reproduce those results in your own center, or if you need to adapt your policy a bit,” commented Dr. Polderman, Professor in Intensive Care Medicine at the Department of Critical Care, University of Pittsburgh Medical Center.

Goals of Therapeutic Hypothermia
Stroke, cardiac arrest, and, to a lesser extent, TBI are characterized by ischemia and reperfusion injury. After a period of ischemia, a series of destructive processes takes place in the injured cells of the brain. “The damage is ongoing while the patient is in your ICU or your emergency room,” said Dr. Polderman.

Therefore, the first goal of treatment with hypothermia is to try to limit this injury. “Hypothermia acts as a sort of blanket therapy,” he said. “It can interrupt every single one of these harmful processes, in contrast to many other therapies that we’ve tried in the past.”

Another goal is to treat brain edema, which may also play a role in some disease states—TBI being one example. For patients with brain edema, the approach to treatment is slightly different, requiring a longer period of cooling.

Controlling Brain Temperature
When using hypothermia for patients with neurologic injury, physicians should do their best to prevent fever, Dr. Polderman advised. “Most of our patients in the neurocritical care units develop fever at some point in their ICU stay. The more severe the injury, the more likely the chance that [the patient] will develop fever,” he said.

Fever is associated with longer length of stay, worse neurologic outcome, and higher mortality. In two studies involving patients with subarachnoid hemorrhage and intracerebral hemorrhage, researchers reported that even a minimal elevation in temperature to slightly greater than 37.5°C—not considered a real fever by some—had a significant adverse effect on outcome.

One explanation for this could be that brain temperature exceeds core temperature. “The destructive processes triggered by ischemia generate heat. Local brain edema makes it difficult to get rid of the excess heat, and this leads to overheating of the brain,” explained Dr. Polderman. “So fever after neurologic injury seems to be extremely harmful, and hypothermia seems to be really protective.”

Proven Efficacy
Three randomized controlled trials have assessed neurologic outcome in patients who underwent therapeutic hypothermia following witnessed cardiac arrest, with significant improvement seen in patients treated with hypothermia across all three studies, said Dr. Polderman. In addition, a number of nonrandomized studies have reported good outcomes following treatment with induced hypothermia.

Dr. Polderman and his colleagues conducted a prospective, multicenter study in which 64 patients with witnessed cardiac arrest underwent therapeutic hypothermia. The results have not yet been published as a full paper. In this study, 60% of patients with ventricular tachycardia/ventricular fibrillation (VT/VF) had a good neurologic outcome (defined as return to their home situation with no or only minimal neurologic impairment). In addition, 50% of patients with an initial rhythm of asystole who reached the hospital alive also had a good neurologic outcome.

“We should lose the pessimism surrounding patients with witnessed cardiac arrest, because the good outcome rates can be better than 50% in this category of patients when hypothermia has been used,” commented Dr. Polderman. “We need to get the cardiologist to do the appropriate intervention, even when the patient is comatose. We need to promote bystander CPR, because the chances of this therapy helping the patient are much better if basic CPR has been performed.”

Some studies have also reported good outcome following therapeutic cooling in patients with severe TBI. Meta-analyses have reported a 22% to 48% reduction in the risk for adverse neurologic outcome in patients with severe TBI treated with therapeutic hypothermia, although not all these differences were statistically significant.

However, the treatment looks highly promising, according to Dr. Polderman. He pointed out for comparison that data on the use of barbiturates and mannitol do not show any benefit on neurologic outcome in patients with TBI.

Cooling in the Right Context
Although hypothermia has beneficial effects on neurologic outcome, “a treatment can only be effective if the other aspects of intensive care are good,” cautioned Dr. Polderman. Therefore, “context matters. It’s not just about cooling.”

When using hypothermia, temperature should be lowered rapidly, but rewarming should be done very slowly, noted Dr. Polderman. “If you do it rapidly, you could lose some or all of the protective effects of hypothermia,” he warned.

In addition, physicians should consider other aspects of ICU treatment, such as prevention of hypo- and hypercapnia, electrolyte disorders, hyperglycemia, and hypoglycemia. “All these things matter, and they may make all the difference,” he said. “Without getting that right, hypothermia can be an ineffective or even dangerous therapy.”

“The idea of context applies even more strongly to areas like severe TBI,” he asserted. “Speed and duration of cooling are important.” For patients with TBI who receive hypothermia, longer duration of cooling (ie, greater than 48 hours) and slow rewarming protocols are associated with better outcome. He noted that one way to determine the optimal duration of cooling in individual patients is to measure intracranial pressure. Intracranial pressure is both a marker of ongoing brain injury and a potential cause of additional injury.

“The use of hypothermia is not risk-free. There are severe side effects, which we should take into account, but the good news is that these can be fairly easily managed,” concluded Dr. Polderman.   

STOWE, VT—US soldiers who have sustained a mild head injury have an increased risk for chronic posttraumatic headaches, which typically involve moderate to severe migraine-like pain and functional impairment, according to Jay Erickson, MD, PhD. Soldiers with posttraumatic headache are also likely to have a high burden of psychiatric comorbidity and sleep disturbance, he reported at the Headache Cooperative of New England’s 19th Annual Headache Symposium.

Among 5,000 soldiers who returned from deployment to Fort Lewis, Washington, in the summer of 2008, Dr. Erickson and colleagues found that 19% had had a concussion, and more than 90% of this group reported having headaches during the previous three months. About a third of the soldiers had headache onset within one week of head trauma, which meets the definition of a posttraumatic headache per the International Classification of Headache Disorders, Second Edition (ICHD-2).

“A mild head injury is a concussion,” noted Dr. Erickson, Lieutenant Colonel, US Army Medical Corps, and Director of the Neurology Residency Program at Madigan Army Medical Center (MAMC) in Tacoma, Washington. “To have a concussion, you don’t necessarily need to have a loss of consciousness.”

Evaluating and Treating Posttraumatic Headache
Dr. Erickson and colleagues conducted an observational, longitudinal study of 189 soldiers with chronic posttraumatic headaches secondary to mild head injury. The soldiers underwent a standardized clinical evaluation at baseline and were followed up three months later. The examination included a headache questionnaire and use of the Migraine Disability Assessment (MIDAS), Headache Impact Test (HIT)-6, Posttraumatic Syndrome Checklist, and Patient Health Questionnaire (PHQ)-9.

The patients (96% male; mean age, 27) had had a mild head injury while deployed—80% had a mild head injury related to a blast exposure, while others had blunt trauma, a motor vehicle accident, a fall, injury due to fighting, and other accidents. Two-thirds had a concussion with loss of consciousness. About 52% had multiple concussions, and the average number of concussions per soldier was 2.2. The average time from headache onset until the soldiers were evaluated by Dr. Erickson’s group was 16.9 months, and half had had headaches for more than a year. “For many of them, this has been a very chronic process,” said Dr. Erickson.

Two-thirds of participants had moderate pain accompanying their headache, and 24% had severe headaches. Per the ICHD-2 criteria, 96% of these headaches would be classified as migraine-type headaches. In contrast, Lew et al found that 28% of posttraumatic headaches in civilians were migraine-like.

On average, the soldiers had a mean of 16 headache days per month, and half had 15 or more headache days per month during the previous three months. About 72% of the soldiers had severe disability from their headache, per MIDAS scores. Participants had used their acute medications, on average, 12 days per month.

“One-third used acute analgesics for 15 or more days per month and therefore had possible medication-overuse headache,” said Dr. Erickson. Two-thirds of the soldiers had inadequate headache relief with their acute medication, defined as complete or nearly complete relief of head pain within two hours of taking the medication and enabling the individual to return to normal activities.

Psychiatric Comorbidity
According to the PTSD Symptom Checklist, 41% of soldiers screened positive for PTSD, and an additional 21% were in the indeterminate range for PTSD. One-third screened positive for depression on the PHQ-9 scale, and 82% reported moderate or severe difficulty sleeping. Most (71%) reported regular nightmares. “We definitely try to address and treat these comorbid sleep conditions as well as the comorbid psychiatric conditions,” said Dr. Erickson. A number also reported cognitive symptoms, such as decreased concentration, memory impairment, and slowed thinking. “In my experience, the cognitive symptoms are  mostly related to sleep deprivation, anxiety, depression, medications, and alcohol,” noted Dr. Erickson. “Little of this is actually due to the traumatic injury to their brain.”

Treatment Recommendations
Thus far, no randomized controlled trials have been conducted regarding treatment for posttraumatic headache. However, the Defense and Veterans Brain Injury Coalition has developed treatment guidelines, and the Department of Defense has mandated screening for traumatic brain injury in all soldiers returning from deployment. For prophylactic agents in individuals with posttraumatic headache, the coalition recommends amitriptyline, propranolol, topiramate, or gabapentin. For acute therapies, it recommends NSAIDs, triptans, and then cautious use of combination analgesics, as well as trying to avoid narcotics.

Dr. Erickson and colleagues have prescribed triptans to three-quarters of soldiers and NSAIDs to 18% as acute headache medication. As for prophylactic therapies, the researchers have prescribed a tricyclic antidepressant to about half of soldiers, followed by topiramate, propranolol, and valproate. Nonpharmacologic treatment approaches, such as behavioral health, headache education class, and biofeedback therapy, have also been recommended by Dr. Erickson’s group.

“In this population at baseline, 20% were using an acute medication that provided adequate relief,” said Dr. Erickson. “With our treatments, we got that up to 64%.” About 79% of soldiers who were given a triptan reported having adequate two-hour headache relief, compared with 29% who were taking a nontriptan. “This provides evidence that triptans are effective in this population,” he added. “It also helps support the idea that in many of these [cases], the headache itself is a migraine or something very similar to a migraine.”

The response to prophylactic therapies for posttraumatic headache has been “disappointing,” however, said Dr. Erickson. “We don’t seem to have a robust response in terms of headache frequency in the short term,” he commented. “In comparison, if you look at patients with nontraumatic migraine in our clinic, we get a pretty robust response with the initial prophylactic agent. Likewise, patients with nontraumatic migraine who have PTSD also seem to have a pretty good response to prophylactic therapy. So traumatic migraine doesn’t seem to respond the same as nontraumatic migraine. Disability scores do decrease between baseline and follow-up, and I think this is largely related to the effectiveness of acute medications. The triptan is effective, so [soldiers] are less disabled from their headache attacks. If we were able to reduce headache frequency, then I would expect their disability to drop even further.

“Trying to treat their headache in isolation is not going to be as successful as trying to identify all of the problems that are contributing to it,” he continued. “It is important to follow these patients maybe a little bit more closely than you would a typical migraine patient, knowing that the response to prophylactic therapies is not quite as robust. I believe that these patients are going to need more adjustments of their treatment. Finally, I think patient education and expectations for recovery are key in this population.”

STOWE, VT—US soldiers who have sustained a mild head injury have an increased risk for chronic posttraumatic headaches, which typically involve moderate to severe migraine-like pain and functional impairment, according to Jay Erickson, MD, PhD. Soldiers with posttraumatic headache are also likely to have a high burden of psychiatric comorbidity and sleep disturbance, he reported at the Headache Cooperative of New England’s 19th Annual Headache Symposium.

Among 5,000 soldiers who returned from deployment to Fort Lewis, Washington, in the summer of 2008, Dr. Erickson and colleagues found that 19% had had a concussion, and more than 90% of this group reported having headaches during the previous three months. About a third of the soldiers had headache onset within one week of head trauma, which meets the definition of a posttraumatic headache per the International Classification of Headache Disorders, Second Edition (ICHD-2).

“A mild head injury is a concussion,” noted Dr. Erickson, Lieutenant Colonel, US Army Medical Corps, and Director of the Neurology Residency Program at Madigan Army Medical Center (MAMC) in Tacoma, Washington. “To have a concussion, you don’t necessarily need to have a loss of consciousness.”

Evaluating and Treating Posttraumatic Headache
Dr. Erickson and colleagues conducted an observational, longitudinal study of 189 soldiers with chronic posttraumatic headaches secondary to mild head injury. The soldiers underwent a standardized clinical evaluation at baseline and were followed up three months later. The examination included a headache questionnaire and use of the Migraine Disability Assessment (MIDAS), Headache Impact Test (HIT)-6, Posttraumatic Syndrome Checklist, and Patient Health Questionnaire (PHQ)-9.

The patients (96% male; mean age, 27) had had a mild head injury while deployed—80% had a mild head injury related to a blast exposure, while others had blunt trauma, a motor vehicle accident, a fall, injury due to fighting, and other accidents. Two-thirds had a concussion with loss of consciousness. About 52% had multiple concussions, and the average number of concussions per soldier was 2.2. The average time from headache onset until the soldiers were evaluated by Dr. Erickson’s group was 16.9 months, and half had had headaches for more than a year. “For many of them, this has been a very chronic process,” said Dr. Erickson.

Two-thirds of participants had moderate pain accompanying their headache, and 24% had severe headaches. Per the ICHD-2 criteria, 96% of these headaches would be classified as migraine-type headaches. In contrast, Lew et al found that 28% of posttraumatic headaches in civilians were migraine-like.

On average, the soldiers had a mean of 16 headache days per month, and half had 15 or more headache days per month during the previous three months. About 72% of the soldiers had severe disability from their headache, per MIDAS scores. Participants had used their acute medications, on average, 12 days per month.

“One-third used acute analgesics for 15 or more days per month and therefore had possible medication-overuse headache,” said Dr. Erickson. Two-thirds of the soldiers had inadequate headache relief with their acute medication, defined as complete or nearly complete relief of head pain within two hours of taking the medication and enabling the individual to return to normal activities.

Psychiatric Comorbidity
According to the PTSD Symptom Checklist, 41% of soldiers screened positive for PTSD, and an additional 21% were in the indeterminate range for PTSD. One-third screened positive for depression on the PHQ-9 scale, and 82% reported moderate or severe difficulty sleeping. Most (71%) reported regular nightmares. “We definitely try to address and treat these comorbid sleep conditions as well as the comorbid psychiatric conditions,” said Dr. Erickson. A number also reported cognitive symptoms, such as decreased concentration, memory impairment, and slowed thinking. “In my experience, the cognitive symptoms are  mostly related to sleep deprivation, anxiety, depression, medications, and alcohol,” noted Dr. Erickson. “Little of this is actually due to the traumatic injury to their brain.”

Treatment Recommendations
Thus far, no randomized controlled trials have been conducted regarding treatment for posttraumatic headache. However, the Defense and Veterans Brain Injury Coalition has developed treatment guidelines, and the Department of Defense has mandated screening for traumatic brain injury in all soldiers returning from deployment. For prophylactic agents in individuals with posttraumatic headache, the coalition recommends amitriptyline, propranolol, topiramate, or gabapentin. For acute therapies, it recommends NSAIDs, triptans, and then cautious use of combination analgesics, as well as trying to avoid narcotics.

Dr. Erickson and colleagues have prescribed triptans to three-quarters of soldiers and NSAIDs to 18% as acute headache medication. As for prophylactic therapies, the researchers have prescribed a tricyclic antidepressant to about half of soldiers, followed by topiramate, propranolol, and valproate. Nonpharmacologic treatment approaches, such as behavioral health, headache education class, and biofeedback therapy, have also been recommended by Dr. Erickson’s group.

“In this population at baseline, 20% were using an acute medication that provided adequate relief,” said Dr. Erickson. “With our treatments, we got that up to 64%.” About 79% of soldiers who were given a triptan reported having adequate two-hour headache relief, compared with 29% who were taking a nontriptan. “This provides evidence that triptans are effective in this population,” he added. “It also helps support the idea that in many of these [cases], the headache itself is a migraine or something very similar to a migraine.”

The response to prophylactic therapies for posttraumatic headache has been “disappointing,” however, said Dr. Erickson. “We don’t seem to have a robust response in terms of headache frequency in the short term,” he commented. “In comparison, if you look at patients with nontraumatic migraine in our clinic, we get a pretty robust response with the initial prophylactic agent. Likewise, patients with nontraumatic migraine who have PTSD also seem to have a pretty good response to prophylactic therapy. So traumatic migraine doesn’t seem to respond the same as nontraumatic migraine. Disability scores do decrease between baseline and follow-up, and I think this is largely related to the effectiveness of acute medications. The triptan is effective, so [soldiers] are less disabled from their headache attacks. If we were able to reduce headache frequency, then I would expect their disability to drop even further.

“Trying to treat their headache in isolation is not going to be as successful as trying to identify all of the problems that are contributing to it,” he continued. “It is important to follow these patients maybe a little bit more closely than you would a typical migraine patient, knowing that the response to prophylactic therapies is not quite as robust. I believe that these patients are going to need more adjustments of their treatment. Finally, I think patient education and expectations for recovery are key in this population.”

STOWE, VT—US soldiers who have sustained a mild head injury have an increased risk for chronic posttraumatic headaches, which typically involve moderate to severe migraine-like pain and functional impairment, according to Jay Erickson, MD, PhD. Soldiers with posttraumatic headache are also likely to have a high burden of psychiatric comorbidity and sleep disturbance, he reported at the Headache Cooperative of New England’s 19th Annual Headache Symposium.

Among 5,000 soldiers who returned from deployment to Fort Lewis, Washington, in the summer of 2008, Dr. Erickson and colleagues found that 19% had had a concussion, and more than 90% of this group reported having headaches during the previous three months. About a third of the soldiers had headache onset within one week of head trauma, which meets the definition of a posttraumatic headache per the International Classification of Headache Disorders, Second Edition (ICHD-2).

“A mild head injury is a concussion,” noted Dr. Erickson, Lieutenant Colonel, US Army Medical Corps, and Director of the Neurology Residency Program at Madigan Army Medical Center (MAMC) in Tacoma, Washington. “To have a concussion, you don’t necessarily need to have a loss of consciousness.”

Evaluating and Treating Posttraumatic Headache
Dr. Erickson and colleagues conducted an observational, longitudinal study of 189 soldiers with chronic posttraumatic headaches secondary to mild head injury. The soldiers underwent a standardized clinical evaluation at baseline and were followed up three months later. The examination included a headache questionnaire and use of the Migraine Disability Assessment (MIDAS), Headache Impact Test (HIT)-6, Posttraumatic Syndrome Checklist, and Patient Health Questionnaire (PHQ)-9.

The patients (96% male; mean age, 27) had had a mild head injury while deployed—80% had a mild head injury related to a blast exposure, while others had blunt trauma, a motor vehicle accident, a fall, injury due to fighting, and other accidents. Two-thirds had a concussion with loss of consciousness. About 52% had multiple concussions, and the average number of concussions per soldier was 2.2. The average time from headache onset until the soldiers were evaluated by Dr. Erickson’s group was 16.9 months, and half had had headaches for more than a year. “For many of them, this has been a very chronic process,” said Dr. Erickson.

Two-thirds of participants had moderate pain accompanying their headache, and 24% had severe headaches. Per the ICHD-2 criteria, 96% of these headaches would be classified as migraine-type headaches. In contrast, Lew et al found that 28% of posttraumatic headaches in civilians were migraine-like.

On average, the soldiers had a mean of 16 headache days per month, and half had 15 or more headache days per month during the previous three months. About 72% of the soldiers had severe disability from their headache, per MIDAS scores. Participants had used their acute medications, on average, 12 days per month.

“One-third used acute analgesics for 15 or more days per month and therefore had possible medication-overuse headache,” said Dr. Erickson. Two-thirds of the soldiers had inadequate headache relief with their acute medication, defined as complete or nearly complete relief of head pain within two hours of taking the medication and enabling the individual to return to normal activities.

Psychiatric Comorbidity
According to the PTSD Symptom Checklist, 41% of soldiers screened positive for PTSD, and an additional 21% were in the indeterminate range for PTSD. One-third screened positive for depression on the PHQ-9 scale, and 82% reported moderate or severe difficulty sleeping. Most (71%) reported regular nightmares. “We definitely try to address and treat these comorbid sleep conditions as well as the comorbid psychiatric conditions,” said Dr. Erickson. A number also reported cognitive symptoms, such as decreased concentration, memory impairment, and slowed thinking. “In my experience, the cognitive symptoms are  mostly related to sleep deprivation, anxiety, depression, medications, and alcohol,” noted Dr. Erickson. “Little of this is actually due to the traumatic injury to their brain.”

Treatment Recommendations
Thus far, no randomized controlled trials have been conducted regarding treatment for posttraumatic headache. However, the Defense and Veterans Brain Injury Coalition has developed treatment guidelines, and the Department of Defense has mandated screening for traumatic brain injury in all soldiers returning from deployment. For prophylactic agents in individuals with posttraumatic headache, the coalition recommends amitriptyline, propranolol, topiramate, or gabapentin. For acute therapies, it recommends NSAIDs, triptans, and then cautious use of combination analgesics, as well as trying to avoid narcotics.

Dr. Erickson and colleagues have prescribed triptans to three-quarters of soldiers and NSAIDs to 18% as acute headache medication. As for prophylactic therapies, the researchers have prescribed a tricyclic antidepressant to about half of soldiers, followed by topiramate, propranolol, and valproate. Nonpharmacologic treatment approaches, such as behavioral health, headache education class, and biofeedback therapy, have also been recommended by Dr. Erickson’s group.

“In this population at baseline, 20% were using an acute medication that provided adequate relief,” said Dr. Erickson. “With our treatments, we got that up to 64%.” About 79% of soldiers who were given a triptan reported having adequate two-hour headache relief, compared with 29% who were taking a nontriptan. “This provides evidence that triptans are effective in this population,” he added. “It also helps support the idea that in many of these [cases], the headache itself is a migraine or something very similar to a migraine.”

The response to prophylactic therapies for posttraumatic headache has been “disappointing,” however, said Dr. Erickson. “We don’t seem to have a robust response in terms of headache frequency in the short term,” he commented. “In comparison, if you look at patients with nontraumatic migraine in our clinic, we get a pretty robust response with the initial prophylactic agent. Likewise, patients with nontraumatic migraine who have PTSD also seem to have a pretty good response to prophylactic therapy. So traumatic migraine doesn’t seem to respond the same as nontraumatic migraine. Disability scores do decrease between baseline and follow-up, and I think this is largely related to the effectiveness of acute medications. The triptan is effective, so [soldiers] are less disabled from their headache attacks. If we were able to reduce headache frequency, then I would expect their disability to drop even further.

“Trying to treat their headache in isolation is not going to be as successful as trying to identify all of the problems that are contributing to it,” he continued. “It is important to follow these patients maybe a little bit more closely than you would a typical migraine patient, knowing that the response to prophylactic therapies is not quite as robust. I believe that these patients are going to need more adjustments of their treatment. Finally, I think patient education and expectations for recovery are key in this population.”

SALT LAKE CITY—The estimated total cost of the Iraq War is currently $3 trillion, with long-term medical care and disability benefits to veterans projected to cost about $700 billion, according to Linda J. Bilmes. With the inclusion of medical expenses for veterans with neurologic and neuropsychiatric disorders, such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), the costs of long-term medical care are likely to surpass the operating costs of the war, Ms. Bilmes reported at the 133rd Annual Meeting of the American Neurological Association.

Iraq War More Costly Than Previous Wars
The Iraq War is the most expensive conflict since World War II, noted Ms. Bilmes, who calculated the $3 trillion war estimate by assessing the short- and long-term budgetary, social, and economic expenses. Budgetary expenses include money appropriated to date, as well as future running costs, veterans’ medical and disability costs, military replenishment, and interest on money borrowed to finance the war. Social and economic costs, such as loss of life or loss due to serious injury and oil price increases, are war-related costs not paid for by the government.

Congress has thus far appropriated close to $900 billion for military operations in Iraq and Afghanistan, enhanced security at US bases, reconstruction, and foreign aid programs; 75% of this cost pays for military operations in Iraq. Per month, the cost of the war has increased from $4.4 billion to $15 billion since 2003. One of the major factors contributing to the rising monthly expense has been the increase in fuel costs. Another factor is the use of contractors—195,000 contractors are currently operating in Iraq, compared with 170,000 contractors in 2007. Many contracts were originally set up without the expectation of a long war; yet, the conflict in Iraq and Afghanistan has surpassed the length of World War I, World War II, and the Korean War. “Part of the scale of these costs and the injuries is simply the sheer length of time that we have been involved in this war,” said Ms. Bilmes, who is a Professor of Public Finance at the Harvard Kennedy School in Cambridge, Massachussetts.

Projected Disability and Health Care Benefits for Veterans
Veterans’ medical and disability costs, among the budgetary costs contributing to the $3 trillion estimate, may eventually total $700 billion, Ms. Bilmes noted. Stabilization, transport, and emergency care for a small number of patients have accounted for a significant portion of the medical expenses thus far. However, the financial burden is expected to be most significant in the future. “The long-term costs of treating veterans over the course of their lives and paying disability compensation are where the major costs come in,” Ms. Bilmes said. She pointed out that, compared with previous wars, there is currently better medical treatment in the field, a higher survival rate for soldiers with traumatic injuries, and more comprehensive medical treatment, diagnostic treatment, and rehabilitation, which has markedly increased costs.

In the Iraq War, 1.72 million troops have been deployed. Among 868,717 soldiers discharged, 288,000 have filed disability claims, and 347,000 were treated in Veterans Affairs (VA) medical facilities, of which 147,744 were treated for mental health disorders. Among Iraq and Afghanistan veterans, 33% have already filed disability claims, and more than 90% have been granted. A projected 45% of veterans will eventually file disability claims, of which about 89% are likely to be granted. Relating to medical costs, Ms. Bilmes’ Operation Iraqi Freedom/Operation Enduring Freedom model projects that the 35% of Iraq and Afghanistan veterans who use VA medical care initially will increase to 50%, assuming that one third will continue to use the VA as their long-term health care provider.

Veterans With TBI and PTSD
Although Ms. Bilmes’ initial model did not account for mild TBI, it did project 15% of disability benefits for the PTSD cohort. After the model was revised for the inclusion of patients with mild TBI, it was estimated that approximately 8% would seek treatment and file claims for mild TBI. The model also assumes that 85% of these patients would receive medical care for one year and 15% would receive care for five years. Thus, the financial burden of TBI and PTSD would add about $28 billion in long-term medical and disability costs and roughly $29 billion in social costs to the total estimate of the war.

A major expense that complicates treatment for TBI and PTSD is the disability process. “When troops are injured and [after] they come back, when they are … most vulnerable, they have to face both within the Department of Defense (DOD) and the VA a very complicated process of securing the paperwork that will enable them to get disability status and to get treatment in some cases,” Ms. Bilmes commented. The disability process involves a medical stabilization process, an acute care stage, and military evaluation to determine whether the soldier is fit for duty. The system is appropriate for soldiers with a physical disability, Ms. Bilmes noted, but not for those who have had a TBI or PTSD complications. Compounding this issue is the backlog of more than 400,000 pending disability claims at the VA. It takes 177 days to process an initial claim and 657 days to process an appeal; 14% of claims are appealed, a 5% increase since 2003.

Ms. Bilmes concluded that veterans returning from Iraq and Afghanistan with PTSD or TBI are likely to encounter long treatment delays and bureaucratic conflicts during the initial period after the trigger incident. Delayed treatment may lead to slower recovery and increased medical, disability, and social costs, which may eventually exceed the operating costs of the war. However, she believes that many problems can be corrected. She has proposed 17 specific reforms, including a more seamless transition between the DOD and VA, particularly for patients with TBI and PTSD. “A key recommendation I have made is to shift the ‘presumption,’ so that veterans with a TBI or concussive event are presumed to have been injured during active duty. This would mean they no longer had to prove that their injuries resulted from warfare—and it would change the basis of the entire veterans’ process.”

SALT LAKE CITY—The estimated total cost of the Iraq War is currently $3 trillion, with long-term medical care and disability benefits to veterans projected to cost about $700 billion, according to Linda J. Bilmes. With the inclusion of medical expenses for veterans with neurologic and neuropsychiatric disorders, such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), the costs of long-term medical care are likely to surpass the operating costs of the war, Ms. Bilmes reported at the 133rd Annual Meeting of the American Neurological Association.

Iraq War More Costly Than Previous Wars
The Iraq War is the most expensive conflict since World War II, noted Ms. Bilmes, who calculated the $3 trillion war estimate by assessing the short- and long-term budgetary, social, and economic expenses. Budgetary expenses include money appropriated to date, as well as future running costs, veterans’ medical and disability costs, military replenishment, and interest on money borrowed to finance the war. Social and economic costs, such as loss of life or loss due to serious injury and oil price increases, are war-related costs not paid for by the government.

Congress has thus far appropriated close to $900 billion for military operations in Iraq and Afghanistan, enhanced security at US bases, reconstruction, and foreign aid programs; 75% of this cost pays for military operations in Iraq. Per month, the cost of the war has increased from $4.4 billion to $15 billion since 2003. One of the major factors contributing to the rising monthly expense has been the increase in fuel costs. Another factor is the use of contractors—195,000 contractors are currently operating in Iraq, compared with 170,000 contractors in 2007. Many contracts were originally set up without the expectation of a long war; yet, the conflict in Iraq and Afghanistan has surpassed the length of World War I, World War II, and the Korean War. “Part of the scale of these costs and the injuries is simply the sheer length of time that we have been involved in this war,” said Ms. Bilmes, who is a Professor of Public Finance at the Harvard Kennedy School in Cambridge, Massachussetts.

Projected Disability and Health Care Benefits for Veterans
Veterans’ medical and disability costs, among the budgetary costs contributing to the $3 trillion estimate, may eventually total $700 billion, Ms. Bilmes noted. Stabilization, transport, and emergency care for a small number of patients have accounted for a significant portion of the medical expenses thus far. However, the financial burden is expected to be most significant in the future. “The long-term costs of treating veterans over the course of their lives and paying disability compensation are where the major costs come in,” Ms. Bilmes said. She pointed out that, compared with previous wars, there is currently better medical treatment in the field, a higher survival rate for soldiers with traumatic injuries, and more comprehensive medical treatment, diagnostic treatment, and rehabilitation, which has markedly increased costs.

In the Iraq War, 1.72 million troops have been deployed. Among 868,717 soldiers discharged, 288,000 have filed disability claims, and 347,000 were treated in Veterans Affairs (VA) medical facilities, of which 147,744 were treated for mental health disorders. Among Iraq and Afghanistan veterans, 33% have already filed disability claims, and more than 90% have been granted. A projected 45% of veterans will eventually file disability claims, of which about 89% are likely to be granted. Relating to medical costs, Ms. Bilmes’ Operation Iraqi Freedom/Operation Enduring Freedom model projects that the 35% of Iraq and Afghanistan veterans who use VA medical care initially will increase to 50%, assuming that one third will continue to use the VA as their long-term health care provider.

Veterans With TBI and PTSD
Although Ms. Bilmes’ initial model did not account for mild TBI, it did project 15% of disability benefits for the PTSD cohort. After the model was revised for the inclusion of patients with mild TBI, it was estimated that approximately 8% would seek treatment and file claims for mild TBI. The model also assumes that 85% of these patients would receive medical care for one year and 15% would receive care for five years. Thus, the financial burden of TBI and PTSD would add about $28 billion in long-term medical and disability costs and roughly $29 billion in social costs to the total estimate of the war.

A major expense that complicates treatment for TBI and PTSD is the disability process. “When troops are injured and [after] they come back, when they are … most vulnerable, they have to face both within the Department of Defense (DOD) and the VA a very complicated process of securing the paperwork that will enable them to get disability status and to get treatment in some cases,” Ms. Bilmes commented. The disability process involves a medical stabilization process, an acute care stage, and military evaluation to determine whether the soldier is fit for duty. The system is appropriate for soldiers with a physical disability, Ms. Bilmes noted, but not for those who have had a TBI or PTSD complications. Compounding this issue is the backlog of more than 400,000 pending disability claims at the VA. It takes 177 days to process an initial claim and 657 days to process an appeal; 14% of claims are appealed, a 5% increase since 2003.

Ms. Bilmes concluded that veterans returning from Iraq and Afghanistan with PTSD or TBI are likely to encounter long treatment delays and bureaucratic conflicts during the initial period after the trigger incident. Delayed treatment may lead to slower recovery and increased medical, disability, and social costs, which may eventually exceed the operating costs of the war. However, she believes that many problems can be corrected. She has proposed 17 specific reforms, including a more seamless transition between the DOD and VA, particularly for patients with TBI and PTSD. “A key recommendation I have made is to shift the ‘presumption,’ so that veterans with a TBI or concussive event are presumed to have been injured during active duty. This would mean they no longer had to prove that their injuries resulted from warfare—and it would change the basis of the entire veterans’ process.”

SALT LAKE CITY—The estimated total cost of the Iraq War is currently $3 trillion, with long-term medical care and disability benefits to veterans projected to cost about $700 billion, according to Linda J. Bilmes. With the inclusion of medical expenses for veterans with neurologic and neuropsychiatric disorders, such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), the costs of long-term medical care are likely to surpass the operating costs of the war, Ms. Bilmes reported at the 133rd Annual Meeting of the American Neurological Association.

Iraq War More Costly Than Previous Wars
The Iraq War is the most expensive conflict since World War II, noted Ms. Bilmes, who calculated the $3 trillion war estimate by assessing the short- and long-term budgetary, social, and economic expenses. Budgetary expenses include money appropriated to date, as well as future running costs, veterans’ medical and disability costs, military replenishment, and interest on money borrowed to finance the war. Social and economic costs, such as loss of life or loss due to serious injury and oil price increases, are war-related costs not paid for by the government.

Congress has thus far appropriated close to $900 billion for military operations in Iraq and Afghanistan, enhanced security at US bases, reconstruction, and foreign aid programs; 75% of this cost pays for military operations in Iraq. Per month, the cost of the war has increased from $4.4 billion to $15 billion since 2003. One of the major factors contributing to the rising monthly expense has been the increase in fuel costs. Another factor is the use of contractors—195,000 contractors are currently operating in Iraq, compared with 170,000 contractors in 2007. Many contracts were originally set up without the expectation of a long war; yet, the conflict in Iraq and Afghanistan has surpassed the length of World War I, World War II, and the Korean War. “Part of the scale of these costs and the injuries is simply the sheer length of time that we have been involved in this war,” said Ms. Bilmes, who is a Professor of Public Finance at the Harvard Kennedy School in Cambridge, Massachussetts.

Projected Disability and Health Care Benefits for Veterans
Veterans’ medical and disability costs, among the budgetary costs contributing to the $3 trillion estimate, may eventually total $700 billion, Ms. Bilmes noted. Stabilization, transport, and emergency care for a small number of patients have accounted for a significant portion of the medical expenses thus far. However, the financial burden is expected to be most significant in the future. “The long-term costs of treating veterans over the course of their lives and paying disability compensation are where the major costs come in,” Ms. Bilmes said. She pointed out that, compared with previous wars, there is currently better medical treatment in the field, a higher survival rate for soldiers with traumatic injuries, and more comprehensive medical treatment, diagnostic treatment, and rehabilitation, which has markedly increased costs.

In the Iraq War, 1.72 million troops have been deployed. Among 868,717 soldiers discharged, 288,000 have filed disability claims, and 347,000 were treated in Veterans Affairs (VA) medical facilities, of which 147,744 were treated for mental health disorders. Among Iraq and Afghanistan veterans, 33% have already filed disability claims, and more than 90% have been granted. A projected 45% of veterans will eventually file disability claims, of which about 89% are likely to be granted. Relating to medical costs, Ms. Bilmes’ Operation Iraqi Freedom/Operation Enduring Freedom model projects that the 35% of Iraq and Afghanistan veterans who use VA medical care initially will increase to 50%, assuming that one third will continue to use the VA as their long-term health care provider.

Veterans With TBI and PTSD
Although Ms. Bilmes’ initial model did not account for mild TBI, it did project 15% of disability benefits for the PTSD cohort. After the model was revised for the inclusion of patients with mild TBI, it was estimated that approximately 8% would seek treatment and file claims for mild TBI. The model also assumes that 85% of these patients would receive medical care for one year and 15% would receive care for five years. Thus, the financial burden of TBI and PTSD would add about $28 billion in long-term medical and disability costs and roughly $29 billion in social costs to the total estimate of the war.

A major expense that complicates treatment for TBI and PTSD is the disability process. “When troops are injured and [after] they come back, when they are … most vulnerable, they have to face both within the Department of Defense (DOD) and the VA a very complicated process of securing the paperwork that will enable them to get disability status and to get treatment in some cases,” Ms. Bilmes commented. The disability process involves a medical stabilization process, an acute care stage, and military evaluation to determine whether the soldier is fit for duty. The system is appropriate for soldiers with a physical disability, Ms. Bilmes noted, but not for those who have had a TBI or PTSD complications. Compounding this issue is the backlog of more than 400,000 pending disability claims at the VA. It takes 177 days to process an initial claim and 657 days to process an appeal; 14% of claims are appealed, a 5% increase since 2003.

Ms. Bilmes concluded that veterans returning from Iraq and Afghanistan with PTSD or TBI are likely to encounter long treatment delays and bureaucratic conflicts during the initial period after the trigger incident. Delayed treatment may lead to slower recovery and increased medical, disability, and social costs, which may eventually exceed the operating costs of the war. However, she believes that many problems can be corrected. She has proposed 17 specific reforms, including a more seamless transition between the DOD and VA, particularly for patients with TBI and PTSD. “A key recommendation I have made is to shift the ‘presumption,’ so that veterans with a TBI or concussive event are presumed to have been injured during active duty. This would mean they no longer had to prove that their injuries resulted from warfare—and it would change the basis of the entire veterans’ process.”

SALT LAKE CITY—The incidence of epilepsy among soldiers who have experienced head trauma in the Iraq War is expected to increase, with no clearly effective strategy available to treat or prevent it, according to Daniel H. Lowenstein, MD. Although traumatic brain injury (TBI)-induced epilepsy has been a well-documented phenomenon after combat, the rate is expected to be particularly high in veterans of the Iraq conflict due to the nature of the weaponry, with explosive devices being a key source of injury.

“Brain trauma has been the signature injury of the Iraq War,” said Dr. Lowenstein, Professor and Vice Chairman of the Department of Neurology at the University of California, San Francisco (UCSF). Although the rate of thoracic injuries has been much lower among American soldiers in Iraq than that observed in previous conflicts, including Vietnam and World War II, concussive explosions are a common phenomenon, he reported at the 133rd Annual Meeting of the American Neurological Association.

No Clear Evidence for Preventive Measures
Seizures can usually be controlled in those who experience them immediately (within the first week) after TBI, noted Dr. Lowenstein, who is also Director of the UCSF Epilepsy Center and Director of Physician-Scientist and Education Training Programs for the UCSF School of Medicine. However, it is estimated that between 25% and 50% of individuals who have a severe brain injury will eventually develop epilepsy. Although more than half will develop seizures within the first year of the injury, a substantial number will not experience their first seizure for years or as much as a decade later. Various studies have looked at prophylaxis, usually with conventional antiepileptic drugs, but there is no clear evidence of protection.

Dr. Lowenstein characterized results of the four placebo-controlled trials that have been conducted thus far as “quite sobering.” Not only was there no clear-cut preventive effect with such drugs as phenytoin, but “the more troubling result was that in the two most carefully controlled studies, there was a suggestion that the intervention was actually increasing the relative risk of epilepsy after TBI.” Although some noncontrolled studies have associated antiepileptic agents with potential protection from trauma-induced seizures, a meta-analysis of the placebo-controlled trials also indicated an absence of preventive effect.

When stratifying head injuries by mild (loss of consciousness for less than 30 minutes and no fracture), moderate (loss of consciousness from 30 minutes to 24 hours with concussion), and severe (loss of consciousness for longer than 24 hours with hematoma and/or fracture), there is at least a trend for a dose response, whether the trauma was sustained during combat or elsewhere. According to Dr. Lowenstein, TBI is one of the most common etiologies of acquired epilepsy. In general, individuals with TBI have about 30 times the risk for epilepsy compared with the healthy population, but the risk may be far greater regarding severe TBI acquired in combat. Data from the Vietnam War suggested that the relative risk was more than 500-fold greater in the first year after injury and 25 times greater 10 to 15 years after injury.

Imaging tools, such as EEG, CT, and MRI, have not been effective for predicting which patients with TBI will progress to epilepsy. Clonic and partial seizures are particularly common after TBI, but Dr. Lowenstein noted that essentially all forms of epilepsy are represented.

Mechanism of Epilepsy After TBI Is Uncertain
There are a number of theories regarding the mechanism of epilepsy after TBI, but the precise mechanism or mechanisms have not been isolated, Dr. Lowenstein explained. One theory is that changes in iron metabolism and deposition increase free radical damage and an excessive release of glutamine that alters electrical activity. In animal models, even brief trauma to the dura mater results in selective loss in neuronal populations, including those considered to be important to inhibition of electrical signaling. In addition, surviving neurons often undergo a change in architecture that includes increases in axon length and the number of axon collaterals. This can also contribute to enhanced excitability.

“This is an area that is ripe for translational research,” said Dr. Lowenstein, who indicated that this step is likely to be critical in the effort to develop targets for prophylaxis. The need for prophylaxis is especially acute. For soldiers, an increasing incidence of epilepsy is predicted by the higher rate of survival after head injury in the Iraq War. Wounded soldiers are reaching hospitals in Germany or the United States within two or three days, versus two or more weeks in the Vietnam War, Dr. Lowenstein pointed out. Of the 30,200 soldiers wounded in Iraq, more than 2,000 have had significant TBI. The long-term care costs of these injuries are expected to be substantial.

Treating TBI-Induced Epilepsy
Commonly used therapies for epilepsy can be effective against TBI-induced epilepsy in some but not all patients, according to Dr. Lowenstein. So far, he said, there have been no well-controlled trials to compare specific treatment strategies to determine whether one antiepileptic drug or one class of drugs is superior to another in controlling TBI-induced epilepsy, but there is evidence that effective treatment in the acute phase of TBI-induced epilepsy can reduce the risk of death or disability.

As a significant cause of epilepsy even outside the confines of war, TBI is a reasonable target for additional study, commented Dr. Lowenstein. However, the urgency to identify effective prophylaxis has been increased by the Iraq War. The high risk for TBI-induced epilepsy is remarkably consistent when the rates in World War I, World War II, and the Vietnam War are compared, and there is no reason to believe the current conflict will be any  different, he said.

“The data on the rate of epilepsy among soldiers returning from Iraq are not very reliable, so we really do not know how many cases there are so far. However, based on what we know of TBI, we expect the rate to be substantial,” Dr. Lowenstein concluded.

SALT LAKE CITY—The incidence of epilepsy among soldiers who have experienced head trauma in the Iraq War is expected to increase, with no clearly effective strategy available to treat or prevent it, according to Daniel H. Lowenstein, MD. Although traumatic brain injury (TBI)-induced epilepsy has been a well-documented phenomenon after combat, the rate is expected to be particularly high in veterans of the Iraq conflict due to the nature of the weaponry, with explosive devices being a key source of injury.

“Brain trauma has been the signature injury of the Iraq War,” said Dr. Lowenstein, Professor and Vice Chairman of the Department of Neurology at the University of California, San Francisco (UCSF). Although the rate of thoracic injuries has been much lower among American soldiers in Iraq than that observed in previous conflicts, including Vietnam and World War II, concussive explosions are a common phenomenon, he reported at the 133rd Annual Meeting of the American Neurological Association.

No Clear Evidence for Preventive Measures
Seizures can usually be controlled in those who experience them immediately (within the first week) after TBI, noted Dr. Lowenstein, who is also Director of the UCSF Epilepsy Center and Director of Physician-Scientist and Education Training Programs for the UCSF School of Medicine. However, it is estimated that between 25% and 50% of individuals who have a severe brain injury will eventually develop epilepsy. Although more than half will develop seizures within the first year of the injury, a substantial number will not experience their first seizure for years or as much as a decade later. Various studies have looked at prophylaxis, usually with conventional antiepileptic drugs, but there is no clear evidence of protection.

Dr. Lowenstein characterized results of the four placebo-controlled trials that have been conducted thus far as “quite sobering.” Not only was there no clear-cut preventive effect with such drugs as phenytoin, but “the more troubling result was that in the two most carefully controlled studies, there was a suggestion that the intervention was actually increasing the relative risk of epilepsy after TBI.” Although some noncontrolled studies have associated antiepileptic agents with potential protection from trauma-induced seizures, a meta-analysis of the placebo-controlled trials also indicated an absence of preventive effect.

When stratifying head injuries by mild (loss of consciousness for less than 30 minutes and no fracture), moderate (loss of consciousness from 30 minutes to 24 hours with concussion), and severe (loss of consciousness for longer than 24 hours with hematoma and/or fracture), there is at least a trend for a dose response, whether the trauma was sustained during combat or elsewhere. According to Dr. Lowenstein, TBI is one of the most common etiologies of acquired epilepsy. In general, individuals with TBI have about 30 times the risk for epilepsy compared with the healthy population, but the risk may be far greater regarding severe TBI acquired in combat. Data from the Vietnam War suggested that the relative risk was more than 500-fold greater in the first year after injury and 25 times greater 10 to 15 years after injury.

Imaging tools, such as EEG, CT, and MRI, have not been effective for predicting which patients with TBI will progress to epilepsy. Clonic and partial seizures are particularly common after TBI, but Dr. Lowenstein noted that essentially all forms of epilepsy are represented.

Mechanism of Epilepsy After TBI Is Uncertain
There are a number of theories regarding the mechanism of epilepsy after TBI, but the precise mechanism or mechanisms have not been isolated, Dr. Lowenstein explained. One theory is that changes in iron metabolism and deposition increase free radical damage and an excessive release of glutamine that alters electrical activity. In animal models, even brief trauma to the dura mater results in selective loss in neuronal populations, including those considered to be important to inhibition of electrical signaling. In addition, surviving neurons often undergo a change in architecture that includes increases in axon length and the number of axon collaterals. This can also contribute to enhanced excitability.

“This is an area that is ripe for translational research,” said Dr. Lowenstein, who indicated that this step is likely to be critical in the effort to develop targets for prophylaxis. The need for prophylaxis is especially acute. For soldiers, an increasing incidence of epilepsy is predicted by the higher rate of survival after head injury in the Iraq War. Wounded soldiers are reaching hospitals in Germany or the United States within two or three days, versus two or more weeks in the Vietnam War, Dr. Lowenstein pointed out. Of the 30,200 soldiers wounded in Iraq, more than 2,000 have had significant TBI. The long-term care costs of these injuries are expected to be substantial.

Treating TBI-Induced Epilepsy
Commonly used therapies for epilepsy can be effective against TBI-induced epilepsy in some but not all patients, according to Dr. Lowenstein. So far, he said, there have been no well-controlled trials to compare specific treatment strategies to determine whether one antiepileptic drug or one class of drugs is superior to another in controlling TBI-induced epilepsy, but there is evidence that effective treatment in the acute phase of TBI-induced epilepsy can reduce the risk of death or disability.

As a significant cause of epilepsy even outside the confines of war, TBI is a reasonable target for additional study, commented Dr. Lowenstein. However, the urgency to identify effective prophylaxis has been increased by the Iraq War. The high risk for TBI-induced epilepsy is remarkably consistent when the rates in World War I, World War II, and the Vietnam War are compared, and there is no reason to believe the current conflict will be any  different, he said.

“The data on the rate of epilepsy among soldiers returning from Iraq are not very reliable, so we really do not know how many cases there are so far. However, based on what we know of TBI, we expect the rate to be substantial,” Dr. Lowenstein concluded.

SALT LAKE CITY—The incidence of epilepsy among soldiers who have experienced head trauma in the Iraq War is expected to increase, with no clearly effective strategy available to treat or prevent it, according to Daniel H. Lowenstein, MD. Although traumatic brain injury (TBI)-induced epilepsy has been a well-documented phenomenon after combat, the rate is expected to be particularly high in veterans of the Iraq conflict due to the nature of the weaponry, with explosive devices being a key source of injury.

“Brain trauma has been the signature injury of the Iraq War,” said Dr. Lowenstein, Professor and Vice Chairman of the Department of Neurology at the University of California, San Francisco (UCSF). Although the rate of thoracic injuries has been much lower among American soldiers in Iraq than that observed in previous conflicts, including Vietnam and World War II, concussive explosions are a common phenomenon, he reported at the 133rd Annual Meeting of the American Neurological Association.

No Clear Evidence for Preventive Measures
Seizures can usually be controlled in those who experience them immediately (within the first week) after TBI, noted Dr. Lowenstein, who is also Director of the UCSF Epilepsy Center and Director of Physician-Scientist and Education Training Programs for the UCSF School of Medicine. However, it is estimated that between 25% and 50% of individuals who have a severe brain injury will eventually develop epilepsy. Although more than half will develop seizures within the first year of the injury, a substantial number will not experience their first seizure for years or as much as a decade later. Various studies have looked at prophylaxis, usually with conventional antiepileptic drugs, but there is no clear evidence of protection.

Dr. Lowenstein characterized results of the four placebo-controlled trials that have been conducted thus far as “quite sobering.” Not only was there no clear-cut preventive effect with such drugs as phenytoin, but “the more troubling result was that in the two most carefully controlled studies, there was a suggestion that the intervention was actually increasing the relative risk of epilepsy after TBI.” Although some noncontrolled studies have associated antiepileptic agents with potential protection from trauma-induced seizures, a meta-analysis of the placebo-controlled trials also indicated an absence of preventive effect.

When stratifying head injuries by mild (loss of consciousness for less than 30 minutes and no fracture), moderate (loss of consciousness from 30 minutes to 24 hours with concussion), and severe (loss of consciousness for longer than 24 hours with hematoma and/or fracture), there is at least a trend for a dose response, whether the trauma was sustained during combat or elsewhere. According to Dr. Lowenstein, TBI is one of the most common etiologies of acquired epilepsy. In general, individuals with TBI have about 30 times the risk for epilepsy compared with the healthy population, but the risk may be far greater regarding severe TBI acquired in combat. Data from the Vietnam War suggested that the relative risk was more than 500-fold greater in the first year after injury and 25 times greater 10 to 15 years after injury.

Imaging tools, such as EEG, CT, and MRI, have not been effective for predicting which patients with TBI will progress to epilepsy. Clonic and partial seizures are particularly common after TBI, but Dr. Lowenstein noted that essentially all forms of epilepsy are represented.

Mechanism of Epilepsy After TBI Is Uncertain
There are a number of theories regarding the mechanism of epilepsy after TBI, but the precise mechanism or mechanisms have not been isolated, Dr. Lowenstein explained. One theory is that changes in iron metabolism and deposition increase free radical damage and an excessive release of glutamine that alters electrical activity. In animal models, even brief trauma to the dura mater results in selective loss in neuronal populations, including those considered to be important to inhibition of electrical signaling. In addition, surviving neurons often undergo a change in architecture that includes increases in axon length and the number of axon collaterals. This can also contribute to enhanced excitability.

“This is an area that is ripe for translational research,” said Dr. Lowenstein, who indicated that this step is likely to be critical in the effort to develop targets for prophylaxis. The need for prophylaxis is especially acute. For soldiers, an increasing incidence of epilepsy is predicted by the higher rate of survival after head injury in the Iraq War. Wounded soldiers are reaching hospitals in Germany or the United States within two or three days, versus two or more weeks in the Vietnam War, Dr. Lowenstein pointed out. Of the 30,200 soldiers wounded in Iraq, more than 2,000 have had significant TBI. The long-term care costs of these injuries are expected to be substantial.

Treating TBI-Induced Epilepsy
Commonly used therapies for epilepsy can be effective against TBI-induced epilepsy in some but not all patients, according to Dr. Lowenstein. So far, he said, there have been no well-controlled trials to compare specific treatment strategies to determine whether one antiepileptic drug or one class of drugs is superior to another in controlling TBI-induced epilepsy, but there is evidence that effective treatment in the acute phase of TBI-induced epilepsy can reduce the risk of death or disability.

As a significant cause of epilepsy even outside the confines of war, TBI is a reasonable target for additional study, commented Dr. Lowenstein. However, the urgency to identify effective prophylaxis has been increased by the Iraq War. The high risk for TBI-induced epilepsy is remarkably consistent when the rates in World War I, World War II, and the Vietnam War are compared, and there is no reason to believe the current conflict will be any  different, he said.

“The data on the rate of epilepsy among soldiers returning from Iraq are not very reliable, so we really do not know how many cases there are so far. However, based on what we know of TBI, we expect the rate to be substantial,” Dr. Lowenstein concluded.

ORLANDO—Soccer players with a history of concussion perform worse on certain aspects of initial postconcussion neurocognitive testing than those without such a history, and female players perform worse than their male counterparts, according to research reported at the 2008 Annual Meeting of the American Orthopaedic Society for Sports Medicine. Alexis Chiang Colvin, MD, urged physicians to take an individualized approach to treating patients with concussion.
“Concussion used to be managed according to the number of minutes of lost consciousness,” stated Dr. Colvin. “However, an athlete does not need to lose consciousness to have a concussion, and this is a message that we as clinicians need to get across to everyone involved in sports—coaches, trainers, team physicians, parents, and athletes.” Dr. Colvin, who conducted this research as a Sports Medicine Fellow in the Department of Orthopaedics at the University of Pittsburgh Medical Center, is now Assistant Professor of Sports Medicine at Mount Sinai School of Medicine in New York City.
Gender Differences in Recovery From Concussion
Dr. Colvin and colleagues defined a concussion, based on standard American Academy of Neurology classification, as a traumatically induced alteration in mental status with or without a loss of consciousness. Athletes were diagnosed with concussion if they reported symptoms such as headache, dizziness, balance problems, or nausea after a blow to the head or body. The investigators chose to examine concussion recovery patterns in soccer players primarily because soccer is a nonhelmeted sport with identical rules at all participation levels for both genders.
The study included 234 soccer players (60% female), ages 8 to 24, who underwent clinical evaluation at the University of Pittsburgh following a diagnosis of a sports-related concussion. None had a history of seizures, attention-deficit disorder, or a psychiatric disorder for which they were taking medication. All patients were tested within 13 days of their concussion with the ImPACT test battery. ImPACT is a computer-based neuropsychologic test that measures attention, memory, visual motor processing speed, and reaction time. The ImPACT inventory also queries athletes about their subjective experience of symptoms such as headaches, nausea, dizziness, and memory loss.
The researchers analyzed whether there were group differences in performance between male and female participants with or without a history of prior concussion. They found that following concussion, females performed significantly worse than males on tests of reaction time and were significantly more symptomatic. In particular, females had longer-lasting headaches.
A nonsignificant trend was also observed regarding greater deficits in verbal memory and processing speed in females, compared with males. Regardless of gender, however, soccer players with a history of concussion performed significantly worse on verbal memory testing after another concussion.
Does BMI Affect Postconcussion Outcomes?
Differences in postinjury neurocognitive outcomes were not attributable to differences in BMI, according to Dr. Colvin. “Our study demonstrated that gender may be more important than the mass of the player in postconcussive testing,” she said.
“There’s a theory that males typically have a stronger neck and torso that can handle forces better,” she commented. “However, there are differences in recovery between genders that cannot simply be attributed to size difference. More studies are needed to determine the reason for differences in recovery between males and females.”
An Individualized Approach
“The results of this study suggest that physicians should not be taking a one-size-fits-all approach to treating concussions,” Dr. Colvin concluded. “Our study shows that patients with a history of a previous concussion perform worse than patients without a previous history on neurocognitive tests taken after they sustain a concussion. Furthermore, females perform worse than males on postconcussion testing.”

ORLANDO—Soccer players with a history of concussion perform worse on certain aspects of initial postconcussion neurocognitive testing than those without such a history, and female players perform worse than their male counterparts, according to research reported at the 2008 Annual Meeting of the American Orthopaedic Society for Sports Medicine. Alexis Chiang Colvin, MD, urged physicians to take an individualized approach to treating patients with concussion.
“Concussion used to be managed according to the number of minutes of lost consciousness,” stated Dr. Colvin. “However, an athlete does not need to lose consciousness to have a concussion, and this is a message that we as clinicians need to get across to everyone involved in sports—coaches, trainers, team physicians, parents, and athletes.” Dr. Colvin, who conducted this research as a Sports Medicine Fellow in the Department of Orthopaedics at the University of Pittsburgh Medical Center, is now Assistant Professor of Sports Medicine at Mount Sinai School of Medicine in New York City.
Gender Differences in Recovery From Concussion
Dr. Colvin and colleagues defined a concussion, based on standard American Academy of Neurology classification, as a traumatically induced alteration in mental status with or without a loss of consciousness. Athletes were diagnosed with concussion if they reported symptoms such as headache, dizziness, balance problems, or nausea after a blow to the head or body. The investigators chose to examine concussion recovery patterns in soccer players primarily because soccer is a nonhelmeted sport with identical rules at all participation levels for both genders.
The study included 234 soccer players (60% female), ages 8 to 24, who underwent clinical evaluation at the University of Pittsburgh following a diagnosis of a sports-related concussion. None had a history of seizures, attention-deficit disorder, or a psychiatric disorder for which they were taking medication. All patients were tested within 13 days of their concussion with the ImPACT test battery. ImPACT is a computer-based neuropsychologic test that measures attention, memory, visual motor processing speed, and reaction time. The ImPACT inventory also queries athletes about their subjective experience of symptoms such as headaches, nausea, dizziness, and memory loss.
The researchers analyzed whether there were group differences in performance between male and female participants with or without a history of prior concussion. They found that following concussion, females performed significantly worse than males on tests of reaction time and were significantly more symptomatic. In particular, females had longer-lasting headaches.
A nonsignificant trend was also observed regarding greater deficits in verbal memory and processing speed in females, compared with males. Regardless of gender, however, soccer players with a history of concussion performed significantly worse on verbal memory testing after another concussion.
Does BMI Affect Postconcussion Outcomes?
Differences in postinjury neurocognitive outcomes were not attributable to differences in BMI, according to Dr. Colvin. “Our study demonstrated that gender may be more important than the mass of the player in postconcussive testing,” she said.
“There’s a theory that males typically have a stronger neck and torso that can handle forces better,” she commented. “However, there are differences in recovery between genders that cannot simply be attributed to size difference. More studies are needed to determine the reason for differences in recovery between males and females.”
An Individualized Approach
“The results of this study suggest that physicians should not be taking a one-size-fits-all approach to treating concussions,” Dr. Colvin concluded. “Our study shows that patients with a history of a previous concussion perform worse than patients without a previous history on neurocognitive tests taken after they sustain a concussion. Furthermore, females perform worse than males on postconcussion testing.”

ORLANDO—Soccer players with a history of concussion perform worse on certain aspects of initial postconcussion neurocognitive testing than those without such a history, and female players perform worse than their male counterparts, according to research reported at the 2008 Annual Meeting of the American Orthopaedic Society for Sports Medicine. Alexis Chiang Colvin, MD, urged physicians to take an individualized approach to treating patients with concussion.
“Concussion used to be managed according to the number of minutes of lost consciousness,” stated Dr. Colvin. “However, an athlete does not need to lose consciousness to have a concussion, and this is a message that we as clinicians need to get across to everyone involved in sports—coaches, trainers, team physicians, parents, and athletes.” Dr. Colvin, who conducted this research as a Sports Medicine Fellow in the Department of Orthopaedics at the University of Pittsburgh Medical Center, is now Assistant Professor of Sports Medicine at Mount Sinai School of Medicine in New York City.
Gender Differences in Recovery From Concussion
Dr. Colvin and colleagues defined a concussion, based on standard American Academy of Neurology classification, as a traumatically induced alteration in mental status with or without a loss of consciousness. Athletes were diagnosed with concussion if they reported symptoms such as headache, dizziness, balance problems, or nausea after a blow to the head or body. The investigators chose to examine concussion recovery patterns in soccer players primarily because soccer is a nonhelmeted sport with identical rules at all participation levels for both genders.
The study included 234 soccer players (60% female), ages 8 to 24, who underwent clinical evaluation at the University of Pittsburgh following a diagnosis of a sports-related concussion. None had a history of seizures, attention-deficit disorder, or a psychiatric disorder for which they were taking medication. All patients were tested within 13 days of their concussion with the ImPACT test battery. ImPACT is a computer-based neuropsychologic test that measures attention, memory, visual motor processing speed, and reaction time. The ImPACT inventory also queries athletes about their subjective experience of symptoms such as headaches, nausea, dizziness, and memory loss.
The researchers analyzed whether there were group differences in performance between male and female participants with or without a history of prior concussion. They found that following concussion, females performed significantly worse than males on tests of reaction time and were significantly more symptomatic. In particular, females had longer-lasting headaches.
A nonsignificant trend was also observed regarding greater deficits in verbal memory and processing speed in females, compared with males. Regardless of gender, however, soccer players with a history of concussion performed significantly worse on verbal memory testing after another concussion.
Does BMI Affect Postconcussion Outcomes?
Differences in postinjury neurocognitive outcomes were not attributable to differences in BMI, according to Dr. Colvin. “Our study demonstrated that gender may be more important than the mass of the player in postconcussive testing,” she said.
“There’s a theory that males typically have a stronger neck and torso that can handle forces better,” she commented. “However, there are differences in recovery between genders that cannot simply be attributed to size difference. More studies are needed to determine the reason for differences in recovery between males and females.”
An Individualized Approach
“The results of this study suggest that physicians should not be taking a one-size-fits-all approach to treating concussions,” Dr. Colvin concluded. “Our study shows that patients with a history of a previous concussion perform worse than patients without a previous history on neurocognitive tests taken after they sustain a concussion. Furthermore, females perform worse than males on postconcussion testing.”

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.