Jeff Evans

One of the 24 freezers used by the Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Mass., has failed without triggering appropriate alarms, leaving 147 brains stored for research on autism, psychiatric disorders, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease to thaw.

The thawed brains included 54 from people with autism - about one-third of the Center's total collection on the neurodevelopmental disorder - which could set back research on the condition.

Courtesy NIH

The circumstances of the freezer's failure has left some suspicion of foul play. A decision on whether to ask law enforcement officials to investigate will be based on the completion of an internal investigation, said Dr. Francine Benes, the Center's director.

Read the news story at the Boston Globe: Freezer Failure.

One of the 24 freezers used by the Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Mass., has failed without triggering appropriate alarms, leaving 147 brains stored for research on autism, psychiatric disorders, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease to thaw.

The thawed brains included 54 from people with autism - about one-third of the Center's total collection on the neurodevelopmental disorder - which could set back research on the condition.

Courtesy NIH

The circumstances of the freezer's failure has left some suspicion of foul play. A decision on whether to ask law enforcement officials to investigate will be based on the completion of an internal investigation, said Dr. Francine Benes, the Center's director.

Read the news story at the Boston Globe: Freezer Failure.

One of the 24 freezers used by the Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Mass., has failed without triggering appropriate alarms, leaving 147 brains stored for research on autism, psychiatric disorders, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease to thaw.

The thawed brains included 54 from people with autism - about one-third of the Center's total collection on the neurodevelopmental disorder - which could set back research on the condition.

Courtesy NIH

The circumstances of the freezer's failure has left some suspicion of foul play. A decision on whether to ask law enforcement officials to investigate will be based on the completion of an internal investigation, said Dr. Francine Benes, the Center's director.

Read the news story at the Boston Globe: Freezer Failure.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

NEW ORLEANS – The incidence of hospitalizations for status epilepticus rose nearly fourfold during 1980-2009, according to researchers who analyzed the National Center for Health Statistics’ National Hospital Database Survey.

The population-adjusted incidence increased from 3.7/100,000 to 14.2/100,000, although the median hospital length of stay for status epilepticus (SE) remained relatively stable at a median of 4-5 days. Hospitalizations for SE also tended to follow a bimodal distribution with the greatest incidence in the first decade of life and between the 5th and 6th decades.

The data on the epidemiology of SE are "quite limited" and come mainly from small, population-based studies, which often do not have findings that are generalizable to the U.S. population and do not provide temporal trends, said Dr. Bhavpreet Dham of the University of Medicine and Dentistry of New Jersey, Camden.

Dr. Dham also noted that it is estimated that $4 billion is spent each year in the United States on status epilepticus hospitalizations, which is even more than is spent on myocardial infarctions or heart failure (Seizure 2005;14:46-51).

He and his colleagues analyzed 699,690 patient discharges in the study’s 30-year time span. These hospitalizations accounted for just 0.07% of about 1 billion hospitalizations in the database. The database covers hospitals in all 50 states and the District of Columbia and uses abstracted ICD-9 codes for diagnoses.

"We believe that this is one of the largest epidemiological studies of SE," Dr. Dham said.

In most of the years, the incidence of SE was about 10% higher in men than in women, and nonwhite patients also had a higher incidence than did whites.

In-hospital mortality (about 8.4% overall) did not differ between the sexes. Although mortality was lowest among patients aged 10 years or younger (2.7%) and highest among those older than 80 years (19%), the incidence of hospitalizations was lowest for patients in the first decade of life and highest in those older than 80 years.

These changes may be the result of a temporal shift in population age distribution during the past 30 years because of more adults living to an older age than there were 30 years ago. In recent years more people have been diagnosed with SE, Dr. Dham noted.

He said that the study is limited by the investigators’ inability to audit the database to review patient charts and the lack of morbidity and mortality data for patients once they left the hospital. Furthermore, the investigators could not differentiate between convulsive, nonconvulsive, and refractory SE because the ICD-9 coding does not allow it.

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

NEW ORLEANS – The incidence of hospitalizations for status epilepticus rose nearly fourfold during 1980-2009, according to researchers who analyzed the National Center for Health Statistics’ National Hospital Database Survey.

The population-adjusted incidence increased from 3.7/100,000 to 14.2/100,000, although the median hospital length of stay for status epilepticus (SE) remained relatively stable at a median of 4-5 days. Hospitalizations for SE also tended to follow a bimodal distribution with the greatest incidence in the first decade of life and between the 5th and 6th decades.

The data on the epidemiology of SE are "quite limited" and come mainly from small, population-based studies, which often do not have findings that are generalizable to the U.S. population and do not provide temporal trends, said Dr. Bhavpreet Dham of the University of Medicine and Dentistry of New Jersey, Camden.

Dr. Dham also noted that it is estimated that $4 billion is spent each year in the United States on status epilepticus hospitalizations, which is even more than is spent on myocardial infarctions or heart failure (Seizure 2005;14:46-51).

He and his colleagues analyzed 699,690 patient discharges in the study’s 30-year time span. These hospitalizations accounted for just 0.07% of about 1 billion hospitalizations in the database. The database covers hospitals in all 50 states and the District of Columbia and uses abstracted ICD-9 codes for diagnoses.

"We believe that this is one of the largest epidemiological studies of SE," Dr. Dham said.

In most of the years, the incidence of SE was about 10% higher in men than in women, and nonwhite patients also had a higher incidence than did whites.

In-hospital mortality (about 8.4% overall) did not differ between the sexes. Although mortality was lowest among patients aged 10 years or younger (2.7%) and highest among those older than 80 years (19%), the incidence of hospitalizations was lowest for patients in the first decade of life and highest in those older than 80 years.

These changes may be the result of a temporal shift in population age distribution during the past 30 years because of more adults living to an older age than there were 30 years ago. In recent years more people have been diagnosed with SE, Dr. Dham noted.

He said that the study is limited by the investigators’ inability to audit the database to review patient charts and the lack of morbidity and mortality data for patients once they left the hospital. Furthermore, the investigators could not differentiate between convulsive, nonconvulsive, and refractory SE because the ICD-9 coding does not allow it.

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

NEW ORLEANS – The incidence of hospitalizations for status epilepticus rose nearly fourfold during 1980-2009, according to researchers who analyzed the National Center for Health Statistics’ National Hospital Database Survey.

The population-adjusted incidence increased from 3.7/100,000 to 14.2/100,000, although the median hospital length of stay for status epilepticus (SE) remained relatively stable at a median of 4-5 days. Hospitalizations for SE also tended to follow a bimodal distribution with the greatest incidence in the first decade of life and between the 5th and 6th decades.

The data on the epidemiology of SE are "quite limited" and come mainly from small, population-based studies, which often do not have findings that are generalizable to the U.S. population and do not provide temporal trends, said Dr. Bhavpreet Dham of the University of Medicine and Dentistry of New Jersey, Camden.

Dr. Dham also noted that it is estimated that $4 billion is spent each year in the United States on status epilepticus hospitalizations, which is even more than is spent on myocardial infarctions or heart failure (Seizure 2005;14:46-51).

He and his colleagues analyzed 699,690 patient discharges in the study’s 30-year time span. These hospitalizations accounted for just 0.07% of about 1 billion hospitalizations in the database. The database covers hospitals in all 50 states and the District of Columbia and uses abstracted ICD-9 codes for diagnoses.

"We believe that this is one of the largest epidemiological studies of SE," Dr. Dham said.

In most of the years, the incidence of SE was about 10% higher in men than in women, and nonwhite patients also had a higher incidence than did whites.

In-hospital mortality (about 8.4% overall) did not differ between the sexes. Although mortality was lowest among patients aged 10 years or younger (2.7%) and highest among those older than 80 years (19%), the incidence of hospitalizations was lowest for patients in the first decade of life and highest in those older than 80 years.

These changes may be the result of a temporal shift in population age distribution during the past 30 years because of more adults living to an older age than there were 30 years ago. In recent years more people have been diagnosed with SE, Dr. Dham noted.

He said that the study is limited by the investigators’ inability to audit the database to review patient charts and the lack of morbidity and mortality data for patients once they left the hospital. Furthermore, the investigators could not differentiate between convulsive, nonconvulsive, and refractory SE because the ICD-9 coding does not allow it.

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

NEW ORLEANS – Women with epilepsy appear to have a significantly greater number of unintended pregnancies than does the general population and cite a wide variety of reasons for discontinuing different contraceptive methods, according to preliminary results from the Epilepsy Birth Control Registry.

In the survey of 350 women with epilepsy, pregnancy was unintended in 125 (86%) of the 146 women who had pregnancies and in 215 (63%) of the 340 total pregnancies. This was significantly higher than the rate of 49% observed in a general U.S. population survey of 7,643 women.

Jeff Evans/IMNG Medical Media

This was surprising to senior study investigator Dr. Andrew G. Herzog, director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center, Wellesley, Mass. "The epilepsy population, which is thought to have a lower fertility rate [than the general population], nevertheless had the higher unintended pregnancy rate," he said in an interview.

The frequency of unintended pregnancy differed significantly between various combinations of contraceptive methods and types of antiepileptic drug (AED), and was highest for those who used enzyme-inducing AEDs (EIAEDs) and hormonal birth control such as depot medroxyprogesterone acetate. EIAEDs also proved to be the only significant AED-related reason for stopping contraception, at least for women who were using hormonal birth control.

"There are some reciprocal interactions between antiepileptic drugs and contraceptive hormones, which can compromise both contraceptive efficacy and also seizure control," Dr. Herzog noted. "We now know that enzyme-inducing and glucuronidated AEDs such as lamotrigine interact with hormonal contraceptives." For instance, high estrogen levels decrease levels of lamotrigine but increase levels of EIAEDs.

Studies have shown that many women with epilepsy who take hormonal contraceptives also do not know that they can interact with AEDs or that some AEDs have a high teratogenic potential.

"Our goal is to get enough information so that we can develop some meaningful guidelines for safe and effective contraception for women with epilepsy ... and also for their health care providers," Dr. Herzog said. "Neurologists need to be informed and knowledgeable about the interactions between hormones and the antiepileptic drugs, and need to be comfortable in talking to their patients about contraception and these interactions because gynecologists are comfortable in discussing contraception, but they have a limited number of patients with epilepsy, like 1% perhaps."

The investigators promoted the Epilepsy Birth Control Registry through online advertisements and Facebook as an educational website for epilepsy birth control in which women could get educational material after taking a 30-question survey. It is the first community-based study of contraceptive methods and AED use in women with epilepsy.

Demographic characteristics of the survey respondents, aged 18-47 years, indicated that they were "somewhat younger than the general epilepsy population and somewhat better educated," Dr. Herzog said at the annual meeting of the American Academy of Neurology.

Respondents reported contraceptive methods including withdrawal, barrier, hormonal, hormonal-depot, and intrauterine device (IUD). AEDs were grouped into enzyme-inducing, non–enzyme-inducing, glucuronidated (lamotrigine), enzyme-inhibiting (valproate), or none.

All of the expected frequencies for contraceptive methods and AED categories assumed equal risk of stoppage and unintended pregnancies because no data are available to set expected values. In statistical comparisons, the contraceptive methods and AED categories were adjusted for differences in frequency of their use in the survey population.

Of 408 total stoppages of contraceptives, 214 (53%) were for adverse reasons – not because of a desire to become pregnant, sexual inactivity, or tubal ligation. Participants cited 22 different reasons for stopping their contraceptive method, which the investigators collated into 8 categories: menstrual disorder, increasing seizures, logistical issues related to the method, pregnancy on the method, concerns about the reliability of the method, headache, emotional changes, and concern about AED interaction.

Respondents stopped birth control for an adverse reason most often with depot medroxyprogesterone acetate (56%); followed by hormonal (oral pill, patch, or vaginal ring) (47%); withdrawal (38%); IUD (28%); and barrier (condom or diaphragm) (21%). Frequencies of stoppage for each of the categories of adverse reasons differed significantly between the contraceptive methods, Arielle Saporta, a research assistant in Dr. Herzog’s lab, reported at the meeting.

The reasons for stoppage varied from method to method. For withdrawal and barrier methods, they included reliability and pregnancy (as well as logistical concerns for barrier). Hormonal contraception was stopped over concerns about seizures and menstrual disorder (irregular cycles, heavy menses, or irregular bleeding). Depot medroxyprogesterone acetate was often stopped because of menstrual disorder and logistical reasons. IUDs were discontinued largely because of menstrual disorder.

Among the different types of AEDs, only EIAEDs were significantly associated with a reason for stopping birth control. For example, menstrual disorder as a reason for stopping birth control was significantly associated with use of EIAEDs. Overall, 29% of respondents who used EIAEDs and hormonal birth control cited menstrual disorder as a reason for stopping, which was twice as often as for women not taking AEDs.

An earlier report from the registry showed that 18% of women on hormonal contraceptives had worsening of their seizures, compared with 3% of women on nonhormonal contraceptives.

These results also led some audience members to wonder who was prescribing AEDs to women on unreliable contraceptive methods such as withdrawal. Indeed, only one-fourth of women who completed the survey consulted a neurologist about what contraceptive methods might be most appropriate for their type of epilepsy and treatment. This was a "surprise," Dr. Herzog said. "Either they don’t think their neurologist know about the topic, or maybe they are correct that [we] don’t know about the topic. And for gynecologists, epilepsy makes up only about 1% of their practice, so it’s not their major focus either."

The investigators now have 550 completed surveys and hope to get 1,000. They are planning to set up a prospective arm of the study in which patients can check back into the registry every 3 months, which will hopefully provide rates of unintended pregnancy for each kind of contraceptive in terms of woman-years of contraceptive use, which is the standard measurement for contraceptive efficacy.

The registry is funded in part by the Epilepsy Foundation. Dr. Herzog and Ms. Saporta had no relevant disclosures.

NEW ORLEANS – Women with epilepsy appear to have a significantly greater number of unintended pregnancies than does the general population and cite a wide variety of reasons for discontinuing different contraceptive methods, according to preliminary results from the Epilepsy Birth Control Registry.

In the survey of 350 women with epilepsy, pregnancy was unintended in 125 (86%) of the 146 women who had pregnancies and in 215 (63%) of the 340 total pregnancies. This was significantly higher than the rate of 49% observed in a general U.S. population survey of 7,643 women.

Jeff Evans/IMNG Medical Media

This was surprising to senior study investigator Dr. Andrew G. Herzog, director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center, Wellesley, Mass. "The epilepsy population, which is thought to have a lower fertility rate [than the general population], nevertheless had the higher unintended pregnancy rate," he said in an interview.

The frequency of unintended pregnancy differed significantly between various combinations of contraceptive methods and types of antiepileptic drug (AED), and was highest for those who used enzyme-inducing AEDs (EIAEDs) and hormonal birth control such as depot medroxyprogesterone acetate. EIAEDs also proved to be the only significant AED-related reason for stopping contraception, at least for women who were using hormonal birth control.

"There are some reciprocal interactions between antiepileptic drugs and contraceptive hormones, which can compromise both contraceptive efficacy and also seizure control," Dr. Herzog noted. "We now know that enzyme-inducing and glucuronidated AEDs such as lamotrigine interact with hormonal contraceptives." For instance, high estrogen levels decrease levels of lamotrigine but increase levels of EIAEDs.

Studies have shown that many women with epilepsy who take hormonal contraceptives also do not know that they can interact with AEDs or that some AEDs have a high teratogenic potential.

"Our goal is to get enough information so that we can develop some meaningful guidelines for safe and effective contraception for women with epilepsy ... and also for their health care providers," Dr. Herzog said. "Neurologists need to be informed and knowledgeable about the interactions between hormones and the antiepileptic drugs, and need to be comfortable in talking to their patients about contraception and these interactions because gynecologists are comfortable in discussing contraception, but they have a limited number of patients with epilepsy, like 1% perhaps."

The investigators promoted the Epilepsy Birth Control Registry through online advertisements and Facebook as an educational website for epilepsy birth control in which women could get educational material after taking a 30-question survey. It is the first community-based study of contraceptive methods and AED use in women with epilepsy.

Demographic characteristics of the survey respondents, aged 18-47 years, indicated that they were "somewhat younger than the general epilepsy population and somewhat better educated," Dr. Herzog said at the annual meeting of the American Academy of Neurology.

Respondents reported contraceptive methods including withdrawal, barrier, hormonal, hormonal-depot, and intrauterine device (IUD). AEDs were grouped into enzyme-inducing, non–enzyme-inducing, glucuronidated (lamotrigine), enzyme-inhibiting (valproate), or none.

All of the expected frequencies for contraceptive methods and AED categories assumed equal risk of stoppage and unintended pregnancies because no data are available to set expected values. In statistical comparisons, the contraceptive methods and AED categories were adjusted for differences in frequency of their use in the survey population.

Of 408 total stoppages of contraceptives, 214 (53%) were for adverse reasons – not because of a desire to become pregnant, sexual inactivity, or tubal ligation. Participants cited 22 different reasons for stopping their contraceptive method, which the investigators collated into 8 categories: menstrual disorder, increasing seizures, logistical issues related to the method, pregnancy on the method, concerns about the reliability of the method, headache, emotional changes, and concern about AED interaction.

Respondents stopped birth control for an adverse reason most often with depot medroxyprogesterone acetate (56%); followed by hormonal (oral pill, patch, or vaginal ring) (47%); withdrawal (38%); IUD (28%); and barrier (condom or diaphragm) (21%). Frequencies of stoppage for each of the categories of adverse reasons differed significantly between the contraceptive methods, Arielle Saporta, a research assistant in Dr. Herzog’s lab, reported at the meeting.

The reasons for stoppage varied from method to method. For withdrawal and barrier methods, they included reliability and pregnancy (as well as logistical concerns for barrier). Hormonal contraception was stopped over concerns about seizures and menstrual disorder (irregular cycles, heavy menses, or irregular bleeding). Depot medroxyprogesterone acetate was often stopped because of menstrual disorder and logistical reasons. IUDs were discontinued largely because of menstrual disorder.

Among the different types of AEDs, only EIAEDs were significantly associated with a reason for stopping birth control. For example, menstrual disorder as a reason for stopping birth control was significantly associated with use of EIAEDs. Overall, 29% of respondents who used EIAEDs and hormonal birth control cited menstrual disorder as a reason for stopping, which was twice as often as for women not taking AEDs.

An earlier report from the registry showed that 18% of women on hormonal contraceptives had worsening of their seizures, compared with 3% of women on nonhormonal contraceptives.

These results also led some audience members to wonder who was prescribing AEDs to women on unreliable contraceptive methods such as withdrawal. Indeed, only one-fourth of women who completed the survey consulted a neurologist about what contraceptive methods might be most appropriate for their type of epilepsy and treatment. This was a "surprise," Dr. Herzog said. "Either they don’t think their neurologist know about the topic, or maybe they are correct that [we] don’t know about the topic. And for gynecologists, epilepsy makes up only about 1% of their practice, so it’s not their major focus either."

The investigators now have 550 completed surveys and hope to get 1,000. They are planning to set up a prospective arm of the study in which patients can check back into the registry every 3 months, which will hopefully provide rates of unintended pregnancy for each kind of contraceptive in terms of woman-years of contraceptive use, which is the standard measurement for contraceptive efficacy.

The registry is funded in part by the Epilepsy Foundation. Dr. Herzog and Ms. Saporta had no relevant disclosures.

NEW ORLEANS – Women with epilepsy appear to have a significantly greater number of unintended pregnancies than does the general population and cite a wide variety of reasons for discontinuing different contraceptive methods, according to preliminary results from the Epilepsy Birth Control Registry.

In the survey of 350 women with epilepsy, pregnancy was unintended in 125 (86%) of the 146 women who had pregnancies and in 215 (63%) of the 340 total pregnancies. This was significantly higher than the rate of 49% observed in a general U.S. population survey of 7,643 women.

Jeff Evans/IMNG Medical Media

This was surprising to senior study investigator Dr. Andrew G. Herzog, director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center, Wellesley, Mass. "The epilepsy population, which is thought to have a lower fertility rate [than the general population], nevertheless had the higher unintended pregnancy rate," he said in an interview.

The frequency of unintended pregnancy differed significantly between various combinations of contraceptive methods and types of antiepileptic drug (AED), and was highest for those who used enzyme-inducing AEDs (EIAEDs) and hormonal birth control such as depot medroxyprogesterone acetate. EIAEDs also proved to be the only significant AED-related reason for stopping contraception, at least for women who were using hormonal birth control.

"There are some reciprocal interactions between antiepileptic drugs and contraceptive hormones, which can compromise both contraceptive efficacy and also seizure control," Dr. Herzog noted. "We now know that enzyme-inducing and glucuronidated AEDs such as lamotrigine interact with hormonal contraceptives." For instance, high estrogen levels decrease levels of lamotrigine but increase levels of EIAEDs.

Studies have shown that many women with epilepsy who take hormonal contraceptives also do not know that they can interact with AEDs or that some AEDs have a high teratogenic potential.

"Our goal is to get enough information so that we can develop some meaningful guidelines for safe and effective contraception for women with epilepsy ... and also for their health care providers," Dr. Herzog said. "Neurologists need to be informed and knowledgeable about the interactions between hormones and the antiepileptic drugs, and need to be comfortable in talking to their patients about contraception and these interactions because gynecologists are comfortable in discussing contraception, but they have a limited number of patients with epilepsy, like 1% perhaps."

The investigators promoted the Epilepsy Birth Control Registry through online advertisements and Facebook as an educational website for epilepsy birth control in which women could get educational material after taking a 30-question survey. It is the first community-based study of contraceptive methods and AED use in women with epilepsy.

Demographic characteristics of the survey respondents, aged 18-47 years, indicated that they were "somewhat younger than the general epilepsy population and somewhat better educated," Dr. Herzog said at the annual meeting of the American Academy of Neurology.

Respondents reported contraceptive methods including withdrawal, barrier, hormonal, hormonal-depot, and intrauterine device (IUD). AEDs were grouped into enzyme-inducing, non–enzyme-inducing, glucuronidated (lamotrigine), enzyme-inhibiting (valproate), or none.

All of the expected frequencies for contraceptive methods and AED categories assumed equal risk of stoppage and unintended pregnancies because no data are available to set expected values. In statistical comparisons, the contraceptive methods and AED categories were adjusted for differences in frequency of their use in the survey population.

Of 408 total stoppages of contraceptives, 214 (53%) were for adverse reasons – not because of a desire to become pregnant, sexual inactivity, or tubal ligation. Participants cited 22 different reasons for stopping their contraceptive method, which the investigators collated into 8 categories: menstrual disorder, increasing seizures, logistical issues related to the method, pregnancy on the method, concerns about the reliability of the method, headache, emotional changes, and concern about AED interaction.

Respondents stopped birth control for an adverse reason most often with depot medroxyprogesterone acetate (56%); followed by hormonal (oral pill, patch, or vaginal ring) (47%); withdrawal (38%); IUD (28%); and barrier (condom or diaphragm) (21%). Frequencies of stoppage for each of the categories of adverse reasons differed significantly between the contraceptive methods, Arielle Saporta, a research assistant in Dr. Herzog’s lab, reported at the meeting.

The reasons for stoppage varied from method to method. For withdrawal and barrier methods, they included reliability and pregnancy (as well as logistical concerns for barrier). Hormonal contraception was stopped over concerns about seizures and menstrual disorder (irregular cycles, heavy menses, or irregular bleeding). Depot medroxyprogesterone acetate was often stopped because of menstrual disorder and logistical reasons. IUDs were discontinued largely because of menstrual disorder.

Among the different types of AEDs, only EIAEDs were significantly associated with a reason for stopping birth control. For example, menstrual disorder as a reason for stopping birth control was significantly associated with use of EIAEDs. Overall, 29% of respondents who used EIAEDs and hormonal birth control cited menstrual disorder as a reason for stopping, which was twice as often as for women not taking AEDs.

An earlier report from the registry showed that 18% of women on hormonal contraceptives had worsening of their seizures, compared with 3% of women on nonhormonal contraceptives.

These results also led some audience members to wonder who was prescribing AEDs to women on unreliable contraceptive methods such as withdrawal. Indeed, only one-fourth of women who completed the survey consulted a neurologist about what contraceptive methods might be most appropriate for their type of epilepsy and treatment. This was a "surprise," Dr. Herzog said. "Either they don’t think their neurologist know about the topic, or maybe they are correct that [we] don’t know about the topic. And for gynecologists, epilepsy makes up only about 1% of their practice, so it’s not their major focus either."

The investigators now have 550 completed surveys and hope to get 1,000. They are planning to set up a prospective arm of the study in which patients can check back into the registry every 3 months, which will hopefully provide rates of unintended pregnancy for each kind of contraceptive in terms of woman-years of contraceptive use, which is the standard measurement for contraceptive efficacy.

The registry is funded in part by the Epilepsy Foundation. Dr. Herzog and Ms. Saporta had no relevant disclosures.

NEW ORLEANS – The total defined daily dose of antiepileptic drugs was the best predictor of medication side effects in a clinical prediction rule developed from a single-center, cross-sectional study of 801 patients with epilepsy.

The finding stands in contrast to a previous study that found overall antiepileptic drug (AED) burden, also calculated by defined daily dose (DDD), was not a significant predictor of the risk of side effects (Epilepsia 2010;51:797-804).

But the lead author of the current study, Jonathan Dykeman, and his associates used recursive partitioning to develop a clinical decision model that classifies patients into subgroups based on their risk of side effects, whereas the earlier report used standard multivariate linear progression to model patients’ scores on the Adverse Event Profile questionnaire. Disentangling the number of AEDs a person used from the overall AED burden on standard linear regression is not easy because the two are highly correlated, he said.

The investigators aim to help guide therapy and clinical decision making with their clinical prediction rule. "To our knowledge, there isn’t a clinical prediction rule that’s used because a lot of the focus is on reduction of seizures," said Mr. Dykeman, an MD/PhD student in the department of clinical neurosciences at the University of Calgary (Alta.) at the annual meeting of the American Academy of Neurology.

Drug burden was high in the group of 801 patients; they took 17 different AEDs, and there were 132 possible combinations of drugs. Instead of modeling that complex scenario, Mr. Dykeman and his colleagues converted AED burden into the World Health Organization’s definition of DDD, which is the average total that a person would take in 1 day for the drug’s main indication. The investigators also included a number of other characteristics that broadly fit into the categories of AED type, sociodemographic factors, and clinical factors. Patients reported side effects during clinical interviews.

The recursive partitioning method hierarchically organized the risk factors associated with side effects from strongest to weakest. Overall, 18% of the cohort experienced side effects. A DDD of greater than 3.5 was the best predictor of side effects. Of 46 patients with a DDD greater than 3.5, 33% reported side effects, compared with 17% of 755 patients with a lower DDD.

A history of psychiatric treatment with medication or counseling also carried about a threefold higher risk for side effects than did the absence of such history. Among patients with the higher DDD, side effects occurred in 8 (57%) of 14 patients with a history of psychiatric treatment, compared with 22% of low DDD patients without a history of psychiatric treatment.

"We have a side study going that’s going to try to tease out whether that’s an interaction with the psychiatric drugs or the fact that they have a psychiatric illness," Mr. Dykeman said in an interview.

Also, side effects reportedly occurred significantly less often among patients on a low DDD with a history of a learning disability (9% of 111) than in patients without such history (18% of 644). "We highly suspect this is related more to the reporting of side effects than actually the occurrence of side effects," said Mr. Dykeman. It might have been more difficult to convey that the patients were having side effects because of their learning disorders as opposed to not actually having them, he said.

The group of patients without learning disabilities could be further partitioned for side-effect risk based on whether they used topiramate (35% of 37) or not (17% of 607). Age was used to further refine the risk for side effects among patients who did not take topiramate. Patients aged 45 years or younger (6 of 27, or 22%) had a lower risk for side effects, compared with patients older than 45 years (7 of 10, or 70%).

Mr. Dykeman said the conclusions that can be drawn from the study are limited by the lack of ascertainment of self-reported side effects, the cross-sectional nature of the data, and the small sizes of subgroups used in comparisons.

Next, the researchers plan to validate their ascertainment of side effects against the Adverse Event Profile questionnaire and conduct the same analysis in a larger, external set of patients at another tertiary referral center before testing it in the general epilepsy population.

None of the authors had relevant disclosures.

NEW ORLEANS – The total defined daily dose of antiepileptic drugs was the best predictor of medication side effects in a clinical prediction rule developed from a single-center, cross-sectional study of 801 patients with epilepsy.

The finding stands in contrast to a previous study that found overall antiepileptic drug (AED) burden, also calculated by defined daily dose (DDD), was not a significant predictor of the risk of side effects (Epilepsia 2010;51:797-804).

But the lead author of the current study, Jonathan Dykeman, and his associates used recursive partitioning to develop a clinical decision model that classifies patients into subgroups based on their risk of side effects, whereas the earlier report used standard multivariate linear progression to model patients’ scores on the Adverse Event Profile questionnaire. Disentangling the number of AEDs a person used from the overall AED burden on standard linear regression is not easy because the two are highly correlated, he said.

The investigators aim to help guide therapy and clinical decision making with their clinical prediction rule. "To our knowledge, there isn’t a clinical prediction rule that’s used because a lot of the focus is on reduction of seizures," said Mr. Dykeman, an MD/PhD student in the department of clinical neurosciences at the University of Calgary (Alta.) at the annual meeting of the American Academy of Neurology.

Drug burden was high in the group of 801 patients; they took 17 different AEDs, and there were 132 possible combinations of drugs. Instead of modeling that complex scenario, Mr. Dykeman and his colleagues converted AED burden into the World Health Organization’s definition of DDD, which is the average total that a person would take in 1 day for the drug’s main indication. The investigators also included a number of other characteristics that broadly fit into the categories of AED type, sociodemographic factors, and clinical factors. Patients reported side effects during clinical interviews.

The recursive partitioning method hierarchically organized the risk factors associated with side effects from strongest to weakest. Overall, 18% of the cohort experienced side effects. A DDD of greater than 3.5 was the best predictor of side effects. Of 46 patients with a DDD greater than 3.5, 33% reported side effects, compared with 17% of 755 patients with a lower DDD.

A history of psychiatric treatment with medication or counseling also carried about a threefold higher risk for side effects than did the absence of such history. Among patients with the higher DDD, side effects occurred in 8 (57%) of 14 patients with a history of psychiatric treatment, compared with 22% of low DDD patients without a history of psychiatric treatment.

"We have a side study going that’s going to try to tease out whether that’s an interaction with the psychiatric drugs or the fact that they have a psychiatric illness," Mr. Dykeman said in an interview.

Also, side effects reportedly occurred significantly less often among patients on a low DDD with a history of a learning disability (9% of 111) than in patients without such history (18% of 644). "We highly suspect this is related more to the reporting of side effects than actually the occurrence of side effects," said Mr. Dykeman. It might have been more difficult to convey that the patients were having side effects because of their learning disorders as opposed to not actually having them, he said.

The group of patients without learning disabilities could be further partitioned for side-effect risk based on whether they used topiramate (35% of 37) or not (17% of 607). Age was used to further refine the risk for side effects among patients who did not take topiramate. Patients aged 45 years or younger (6 of 27, or 22%) had a lower risk for side effects, compared with patients older than 45 years (7 of 10, or 70%).

Mr. Dykeman said the conclusions that can be drawn from the study are limited by the lack of ascertainment of self-reported side effects, the cross-sectional nature of the data, and the small sizes of subgroups used in comparisons.

Next, the researchers plan to validate their ascertainment of side effects against the Adverse Event Profile questionnaire and conduct the same analysis in a larger, external set of patients at another tertiary referral center before testing it in the general epilepsy population.

None of the authors had relevant disclosures.

NEW ORLEANS – The total defined daily dose of antiepileptic drugs was the best predictor of medication side effects in a clinical prediction rule developed from a single-center, cross-sectional study of 801 patients with epilepsy.

The finding stands in contrast to a previous study that found overall antiepileptic drug (AED) burden, also calculated by defined daily dose (DDD), was not a significant predictor of the risk of side effects (Epilepsia 2010;51:797-804).

But the lead author of the current study, Jonathan Dykeman, and his associates used recursive partitioning to develop a clinical decision model that classifies patients into subgroups based on their risk of side effects, whereas the earlier report used standard multivariate linear progression to model patients’ scores on the Adverse Event Profile questionnaire. Disentangling the number of AEDs a person used from the overall AED burden on standard linear regression is not easy because the two are highly correlated, he said.

The investigators aim to help guide therapy and clinical decision making with their clinical prediction rule. "To our knowledge, there isn’t a clinical prediction rule that’s used because a lot of the focus is on reduction of seizures," said Mr. Dykeman, an MD/PhD student in the department of clinical neurosciences at the University of Calgary (Alta.) at the annual meeting of the American Academy of Neurology.

Drug burden was high in the group of 801 patients; they took 17 different AEDs, and there were 132 possible combinations of drugs. Instead of modeling that complex scenario, Mr. Dykeman and his colleagues converted AED burden into the World Health Organization’s definition of DDD, which is the average total that a person would take in 1 day for the drug’s main indication. The investigators also included a number of other characteristics that broadly fit into the categories of AED type, sociodemographic factors, and clinical factors. Patients reported side effects during clinical interviews.

The recursive partitioning method hierarchically organized the risk factors associated with side effects from strongest to weakest. Overall, 18% of the cohort experienced side effects. A DDD of greater than 3.5 was the best predictor of side effects. Of 46 patients with a DDD greater than 3.5, 33% reported side effects, compared with 17% of 755 patients with a lower DDD.

A history of psychiatric treatment with medication or counseling also carried about a threefold higher risk for side effects than did the absence of such history. Among patients with the higher DDD, side effects occurred in 8 (57%) of 14 patients with a history of psychiatric treatment, compared with 22% of low DDD patients without a history of psychiatric treatment.

"We have a side study going that’s going to try to tease out whether that’s an interaction with the psychiatric drugs or the fact that they have a psychiatric illness," Mr. Dykeman said in an interview.

Also, side effects reportedly occurred significantly less often among patients on a low DDD with a history of a learning disability (9% of 111) than in patients without such history (18% of 644). "We highly suspect this is related more to the reporting of side effects than actually the occurrence of side effects," said Mr. Dykeman. It might have been more difficult to convey that the patients were having side effects because of their learning disorders as opposed to not actually having them, he said.

The group of patients without learning disabilities could be further partitioned for side-effect risk based on whether they used topiramate (35% of 37) or not (17% of 607). Age was used to further refine the risk for side effects among patients who did not take topiramate. Patients aged 45 years or younger (6 of 27, or 22%) had a lower risk for side effects, compared with patients older than 45 years (7 of 10, or 70%).

Mr. Dykeman said the conclusions that can be drawn from the study are limited by the lack of ascertainment of self-reported side effects, the cross-sectional nature of the data, and the small sizes of subgroups used in comparisons.

Next, the researchers plan to validate their ascertainment of side effects against the Adverse Event Profile questionnaire and conduct the same analysis in a larger, external set of patients at another tertiary referral center before testing it in the general epilepsy population.

None of the authors had relevant disclosures.

An update to the American Heart Association and American Stroke Association guidelines for the management of aneurysmal subarachnoid hemorrhage places new emphasis on treating patients at high-volume centers with multidisciplinary teams and following up with patients after treatment to detect rebleeding and delayed cerebral ischemia, along with other potential complications.

Those changes are among 21 new recommendations made by the guidelines’ multidisciplinary writing committee, including five class I recommendations where there is high confidence that the benefit from a procedure or treatment greatly outweighs the potential risks. Another nine recommendations from the 2009 guidelines were changed.

"The guidelines in 2009 had to summarize the literature of 15 years [since the first guidelines were published in 1994], and so the development of those guidelines was very complex. It achieved its goal to a good degree, but obviously there were a few aspects to be refined," said Dr. Alejandro A. Rabinstein, vice chair of the guidelines writing committee. He is a vascular neurologist and neurocritical care specialist at the Mayo Clinic, Rochester, Minn.

The revised document primarily covers the literature published between Nov. 1, 2006 – the last date covered in the 2009 guidelines – and May 1, 2010, and does not discuss ongoing studies. The associations plan to update the guidelines every 3 years because "the data presented ... only begin to scratch the surface of the burgeoning knowledge in this fast-developing field," according to the writing committee.

The panel required a consensus to make recommendations "even where there is the best quality of evidence because there may be some difference of opinion even with good research," Dr. Rabinstein said in an interview. The use of a multidisciplinary panel "allows for the possibility of arriving at the same types of positions that you get with the patient at the bedside. It is a multidisciplinary group treating these patients; it is not a single specialty."

The guidelines recommend that low-volume hospitals, such as those with fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year, should consider early transfer of patients to high-volume centers, such as those with more than 35 cases per year, that have experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neurointensive care services. Hospitals should also perform annual monitoring of complication rates as well as have a credentialing process to make sure that proper training standards have been met by individual physicians treating brain aneurysms (Stroke 2012 May 3 [doi:10.1161/STR.0b013e3182587839]).

"We do not have, like other American Heart Association stroke guidelines, a track record that we can follow. We don’t know exactly how the guidelines are being followed across institutions. Hopefully that’s going to become available by the time the next set of guidelines gets published. But certainly we do know that there is great variation," Dr. Rabinstein said.

Although the panel noted that there "have been only minor changes in imaging technology for this condition" since the previous guidelines, Dr. Rabinstein pointed out that new recommendations clarify the value of noninvasive angiography vs. invasive angiography. CT angiography (CTA) may be considered in diagnosing an aneurysm and may help in deciding which method to repair it with, but when CTA is inconclusive, digital subtraction angiography with three-dimensional rotational angiography is recommended in most cases. MRI modalities may be reasonable if CTA is nondiagnostic, but negative results do not preclude an analysis of cerebrospinal fluid.

Between symptom onset and repair of the aneurysm, the guidelines recommend controlling blood pressure (to a systolic BP of less than 160 mm Hg) with a titratable drug to balance the risk of stroke, hypertension-related rebleeding, and maintaining cerebral perfusion pressure.

Treatment of the ruptured aneurysm with endovascular coiling should be considered when it is judged to be technically amenable to both coiling and microsurgical clipping. Stenting of the ruptured aneurysm should be avoided because of increased morbidity and mortality associated with the procedure.

Dr. Rabinstein noted that the panel put "emphasis on the importance of following up with these patients after their subarachnoid aneurysm is treated to make sure they do not have what we call remnant rebleeding of the aneurysm that could require retreatment," particularly for patients with aneurysms treated with endovascular coiling.

When cerebral vasospasm occurs, new emphasis has been placed on maintaining euvolemia and normal circulating blood volume rather than hypervolemia to prevent delayed cerebral ischemia. Evidence for the use of oral nimodipine for vasodilation is even stronger than before, making it recommended for use in all aSAH patients. Recommendations now suggest that use of transcranial Doppler imaging is reasonable to conduct surveillance for vasospasm and that perfusion imaging with CT or MRI may identify regions of ischemia. Delayed cerebral ischemia should be treated with induced hypertension unless it is elevated at baseline or cardiac status contraindicates its use.

When hydrocephalus occurs acutely, the guidelines now advise diverting cerebrospinal fluid (CSF) by external ventricular drainage or lumbar drainage. Weaning from external drainage over a period longer than 24 hours does not appear to reduce the need for ventricular shunt placement. Permanent CSF diversion should be reserved for chronic, symptomatic hydrocephalus.

Recommendations on the management of seizures associated with aSAH and anesthesia during surgical and endovascular treatment remain unchanged from the previous guidelines.

The committee added a new section of recommendations on how to manage medical complications associated with aSAH, including hyponatremia and fluid imbalance, fever, elevated blood glucose levels, anemia, heparin-induced thrombocytopenia, and deep vein thrombosis. "For all of these, the areas may not be conclusive, but these are important topics that people often seek guidance for," Dr. Rabinstein said.

Dr. Rabinstein had no relevant disclosures. Some of the other members of the writing committee reported serving as consultants to or on the advisory boards of device manufacturers.

An update to the American Heart Association and American Stroke Association guidelines for the management of aneurysmal subarachnoid hemorrhage places new emphasis on treating patients at high-volume centers with multidisciplinary teams and following up with patients after treatment to detect rebleeding and delayed cerebral ischemia, along with other potential complications.

Those changes are among 21 new recommendations made by the guidelines’ multidisciplinary writing committee, including five class I recommendations where there is high confidence that the benefit from a procedure or treatment greatly outweighs the potential risks. Another nine recommendations from the 2009 guidelines were changed.

"The guidelines in 2009 had to summarize the literature of 15 years [since the first guidelines were published in 1994], and so the development of those guidelines was very complex. It achieved its goal to a good degree, but obviously there were a few aspects to be refined," said Dr. Alejandro A. Rabinstein, vice chair of the guidelines writing committee. He is a vascular neurologist and neurocritical care specialist at the Mayo Clinic, Rochester, Minn.

The revised document primarily covers the literature published between Nov. 1, 2006 – the last date covered in the 2009 guidelines – and May 1, 2010, and does not discuss ongoing studies. The associations plan to update the guidelines every 3 years because "the data presented ... only begin to scratch the surface of the burgeoning knowledge in this fast-developing field," according to the writing committee.

The panel required a consensus to make recommendations "even where there is the best quality of evidence because there may be some difference of opinion even with good research," Dr. Rabinstein said in an interview. The use of a multidisciplinary panel "allows for the possibility of arriving at the same types of positions that you get with the patient at the bedside. It is a multidisciplinary group treating these patients; it is not a single specialty."

The guidelines recommend that low-volume hospitals, such as those with fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year, should consider early transfer of patients to high-volume centers, such as those with more than 35 cases per year, that have experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neurointensive care services. Hospitals should also perform annual monitoring of complication rates as well as have a credentialing process to make sure that proper training standards have been met by individual physicians treating brain aneurysms (Stroke 2012 May 3 [doi:10.1161/STR.0b013e3182587839]).

"We do not have, like other American Heart Association stroke guidelines, a track record that we can follow. We don’t know exactly how the guidelines are being followed across institutions. Hopefully that’s going to become available by the time the next set of guidelines gets published. But certainly we do know that there is great variation," Dr. Rabinstein said.

Although the panel noted that there "have been only minor changes in imaging technology for this condition" since the previous guidelines, Dr. Rabinstein pointed out that new recommendations clarify the value of noninvasive angiography vs. invasive angiography. CT angiography (CTA) may be considered in diagnosing an aneurysm and may help in deciding which method to repair it with, but when CTA is inconclusive, digital subtraction angiography with three-dimensional rotational angiography is recommended in most cases. MRI modalities may be reasonable if CTA is nondiagnostic, but negative results do not preclude an analysis of cerebrospinal fluid.

Between symptom onset and repair of the aneurysm, the guidelines recommend controlling blood pressure (to a systolic BP of less than 160 mm Hg) with a titratable drug to balance the risk of stroke, hypertension-related rebleeding, and maintaining cerebral perfusion pressure.

Treatment of the ruptured aneurysm with endovascular coiling should be considered when it is judged to be technically amenable to both coiling and microsurgical clipping. Stenting of the ruptured aneurysm should be avoided because of increased morbidity and mortality associated with the procedure.

Dr. Rabinstein noted that the panel put "emphasis on the importance of following up with these patients after their subarachnoid aneurysm is treated to make sure they do not have what we call remnant rebleeding of the aneurysm that could require retreatment," particularly for patients with aneurysms treated with endovascular coiling.

When cerebral vasospasm occurs, new emphasis has been placed on maintaining euvolemia and normal circulating blood volume rather than hypervolemia to prevent delayed cerebral ischemia. Evidence for the use of oral nimodipine for vasodilation is even stronger than before, making it recommended for use in all aSAH patients. Recommendations now suggest that use of transcranial Doppler imaging is reasonable to conduct surveillance for vasospasm and that perfusion imaging with CT or MRI may identify regions of ischemia. Delayed cerebral ischemia should be treated with induced hypertension unless it is elevated at baseline or cardiac status contraindicates its use.

When hydrocephalus occurs acutely, the guidelines now advise diverting cerebrospinal fluid (CSF) by external ventricular drainage or lumbar drainage. Weaning from external drainage over a period longer than 24 hours does not appear to reduce the need for ventricular shunt placement. Permanent CSF diversion should be reserved for chronic, symptomatic hydrocephalus.

Recommendations on the management of seizures associated with aSAH and anesthesia during surgical and endovascular treatment remain unchanged from the previous guidelines.

The committee added a new section of recommendations on how to manage medical complications associated with aSAH, including hyponatremia and fluid imbalance, fever, elevated blood glucose levels, anemia, heparin-induced thrombocytopenia, and deep vein thrombosis. "For all of these, the areas may not be conclusive, but these are important topics that people often seek guidance for," Dr. Rabinstein said.

Dr. Rabinstein had no relevant disclosures. Some of the other members of the writing committee reported serving as consultants to or on the advisory boards of device manufacturers.

An update to the American Heart Association and American Stroke Association guidelines for the management of aneurysmal subarachnoid hemorrhage places new emphasis on treating patients at high-volume centers with multidisciplinary teams and following up with patients after treatment to detect rebleeding and delayed cerebral ischemia, along with other potential complications.

Those changes are among 21 new recommendations made by the guidelines’ multidisciplinary writing committee, including five class I recommendations where there is high confidence that the benefit from a procedure or treatment greatly outweighs the potential risks. Another nine recommendations from the 2009 guidelines were changed.

"The guidelines in 2009 had to summarize the literature of 15 years [since the first guidelines were published in 1994], and so the development of those guidelines was very complex. It achieved its goal to a good degree, but obviously there were a few aspects to be refined," said Dr. Alejandro A. Rabinstein, vice chair of the guidelines writing committee. He is a vascular neurologist and neurocritical care specialist at the Mayo Clinic, Rochester, Minn.

The revised document primarily covers the literature published between Nov. 1, 2006 – the last date covered in the 2009 guidelines – and May 1, 2010, and does not discuss ongoing studies. The associations plan to update the guidelines every 3 years because "the data presented ... only begin to scratch the surface of the burgeoning knowledge in this fast-developing field," according to the writing committee.

The panel required a consensus to make recommendations "even where there is the best quality of evidence because there may be some difference of opinion even with good research," Dr. Rabinstein said in an interview. The use of a multidisciplinary panel "allows for the possibility of arriving at the same types of positions that you get with the patient at the bedside. It is a multidisciplinary group treating these patients; it is not a single specialty."

The guidelines recommend that low-volume hospitals, such as those with fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year, should consider early transfer of patients to high-volume centers, such as those with more than 35 cases per year, that have experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neurointensive care services. Hospitals should also perform annual monitoring of complication rates as well as have a credentialing process to make sure that proper training standards have been met by individual physicians treating brain aneurysms (Stroke 2012 May 3 [doi:10.1161/STR.0b013e3182587839]).

"We do not have, like other American Heart Association stroke guidelines, a track record that we can follow. We don’t know exactly how the guidelines are being followed across institutions. Hopefully that’s going to become available by the time the next set of guidelines gets published. But certainly we do know that there is great variation," Dr. Rabinstein said.

Although the panel noted that there "have been only minor changes in imaging technology for this condition" since the previous guidelines, Dr. Rabinstein pointed out that new recommendations clarify the value of noninvasive angiography vs. invasive angiography. CT angiography (CTA) may be considered in diagnosing an aneurysm and may help in deciding which method to repair it with, but when CTA is inconclusive, digital subtraction angiography with three-dimensional rotational angiography is recommended in most cases. MRI modalities may be reasonable if CTA is nondiagnostic, but negative results do not preclude an analysis of cerebrospinal fluid.

Between symptom onset and repair of the aneurysm, the guidelines recommend controlling blood pressure (to a systolic BP of less than 160 mm Hg) with a titratable drug to balance the risk of stroke, hypertension-related rebleeding, and maintaining cerebral perfusion pressure.

Treatment of the ruptured aneurysm with endovascular coiling should be considered when it is judged to be technically amenable to both coiling and microsurgical clipping. Stenting of the ruptured aneurysm should be avoided because of increased morbidity and mortality associated with the procedure.

Dr. Rabinstein noted that the panel put "emphasis on the importance of following up with these patients after their subarachnoid aneurysm is treated to make sure they do not have what we call remnant rebleeding of the aneurysm that could require retreatment," particularly for patients with aneurysms treated with endovascular coiling.

When cerebral vasospasm occurs, new emphasis has been placed on maintaining euvolemia and normal circulating blood volume rather than hypervolemia to prevent delayed cerebral ischemia. Evidence for the use of oral nimodipine for vasodilation is even stronger than before, making it recommended for use in all aSAH patients. Recommendations now suggest that use of transcranial Doppler imaging is reasonable to conduct surveillance for vasospasm and that perfusion imaging with CT or MRI may identify regions of ischemia. Delayed cerebral ischemia should be treated with induced hypertension unless it is elevated at baseline or cardiac status contraindicates its use.

When hydrocephalus occurs acutely, the guidelines now advise diverting cerebrospinal fluid (CSF) by external ventricular drainage or lumbar drainage. Weaning from external drainage over a period longer than 24 hours does not appear to reduce the need for ventricular shunt placement. Permanent CSF diversion should be reserved for chronic, symptomatic hydrocephalus.

Recommendations on the management of seizures associated with aSAH and anesthesia during surgical and endovascular treatment remain unchanged from the previous guidelines.

The committee added a new section of recommendations on how to manage medical complications associated with aSAH, including hyponatremia and fluid imbalance, fever, elevated blood glucose levels, anemia, heparin-induced thrombocytopenia, and deep vein thrombosis. "For all of these, the areas may not be conclusive, but these are important topics that people often seek guidance for," Dr. Rabinstein said.

Dr. Rabinstein had no relevant disclosures. Some of the other members of the writing committee reported serving as consultants to or on the advisory boards of device manufacturers.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

A high level of an enzyme that causes the deacetylation of histones associated with genes important for learning and memory may be a common feature that mediates the cognitive impairment seen in animal models of Alzheimer’s disease and human patients with the disease.

Inhibition of this gene, which codes for histone deacetylase 2 (HDAC2), may be a good approach to test therapeutically in further studies of animal models of Alzheimer’s disease, noted Johannes Gräff, Ph.D., and his colleagues, who were led by Li-Huei Tsai, Ph.D., of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, Cambridge.

Courtesy of Dr. Li-Huei Tsai

Over the past decade, other studies have noted sporadic cases of reduced histone acetylation in animal models of neurodegeneration that are characterized by cognitive decline, including Alzheimer’s disease. These studies have shown success in reducing cognitive decline in mouse models of Alzheimer’s through the use of nonselective HDAC inhibitors. The results of the current study by Dr. Tsai and her associates suggest that HDAC2 likely was the target of the nonselective inhibitors in earlier studies (Nature 2012;483:222-6).

"I really think this points to a new direction in thinking about therapeutic intervention or prevention" with a strategy that does not directly target amyloid-beta levels, Dr. Tsai said in an interview. While amyloid-beta plays a very early and important role in the disease, she suggested that once the pathogenic cascade of events is triggered, "there are a lot of biological processes that may become amyloid-independent."

Prior studies have shown how amyloid-beta can acutely impair synaptic plasticity by decreasing N-methyl-d-aspartate receptor functions, she said, but it may have a more profound and chronic effect on memory by inducing a blockade of the expression of many genes involved in different steps of memory formation and consolidation, she said.

In two different mouse models of Alzheimer’s disease, the investigators found elevated HDAC2 protein levels in neurodegenerating areas of the mice’s brains, including part of the hippocampus and in the prefrontal cortex. HDAC2 protein in the hippocampus of these mice was found bound to genes implicated in learning, memory, and synaptic plasticity. The investigators found that certain amino acids in the histones that bind to these genes had reduced acetylation, which is known to be important for learning, memory, and synaptic plasticity. All of these genes had reduced expression.

"Taken together, these results indicate that HDAC2 mediates a local chromatin compaction of neuroplasticity genes, which decreases their expression and may contribute to cognitive decline during neurodegeneration," Dr. Tsai and her associates wrote.

When the researchers blocked the expression of HDAC2, the acetylation of neuroplasticity genes increased. The regained expression of these genes induced morphological changes that increased synaptic density and the number of dendrites on surviving neurons, but did not alter neuronal survival.

Blocking HDAC2 in a mouse model of Alzheimer’s led to an improvement in associative and spatial memory – two types of hippocampus-dependent memory – indicating "that elevated HDAC2 levels are causally involved in the cognitive decline associated with neurodegeneration [in the mouse model], but that the prevention of HDAC2 upregulation rescues memory capabilities," the authors wrote.

The transcription of HDAC2 increased in primary hippocampal neurons after they were exposed in vitro to hydrogen peroxide and amyloid-beta oligomers – neurotoxic stimuli that are characteristic of Alzheimer’s disease–related neurodegeneration – as well as in the hippocampus of the mouse model. The effect of these stimuli on HDAC2 suggested to the researchers that transcriptional mechanisms might be involved. They found a binding site for the transcriptional regulator glucocorticoid receptor 1 within the HDAC2 gene. Activation of the glucocorticoid receptor is accomplished through phosphorylation, which the investigators detected in the hippocampi of the mouse model and in cultured hippocampal neurons after exposure to hydrogen peroxide and amyloid-beta oligomers. The hippocampi of these mice, as well as cultured hippocampal neurons stimulated with amyloid-beta oligomers, contained the phosphorylated glucocorticoid receptor 1 attached to the binding site on HDAC2. The binding site of glucocorticoid receptor 1 on HDAC2 was necessary for the transcriptional activation of HDAC2.

Post mortem brain specimens from patients at different stages of Alzheimer’s disease contained significantly elevated HDAC2 levels in the entorhinal cortex and a part of the hippocampus. The elevation of HDAC2 also was an early event in the progression of Alzheimer’s, judging from patients who died in Braak stage I and II.

Robert D. Moir, Ph.D., who studies biochemical and cellular mechanisms involved in neurodegeneration in Alzheimer’s disease and aging at MassGeneral Institute for Neurodegenerative Disease, Boston, said in an interview that the study is "terrific for supporting a role for HDAC2 in memory," but may be a "bit of an overreach in claiming that it is proof of blocking cognitive decline in the neurodegenerating brain. It may be true, but I think there needs to be a lot more work before that assertion can be really made."

The finding of increased levels of HDAC2 in the Alzheimer’s disease brain doesn’t necessarily indicate that it is the cause of cognitive decline, he said. "The AD brain is a mess. You’ve got increased and decreased levels of all sorts of things."

Dr. Moir also noted that there’s not a lot of genetics that point in the direction of HDAC2 for Alzheimer’s.

The research was partly supported by the Stanley Medical Research Institution, the National Institute on Drug Abuse, and the National Institute for Neurological Disorders and Stroke. The authors declared having no financial disclosures.

A high level of an enzyme that causes the deacetylation of histones associated with genes important for learning and memory may be a common feature that mediates the cognitive impairment seen in animal models of Alzheimer’s disease and human patients with the disease.

Inhibition of this gene, which codes for histone deacetylase 2 (HDAC2), may be a good approach to test therapeutically in further studies of animal models of Alzheimer’s disease, noted Johannes Gräff, Ph.D., and his colleagues, who were led by Li-Huei Tsai, Ph.D., of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, Cambridge.

Courtesy of Dr. Li-Huei Tsai

Over the past decade, other studies have noted sporadic cases of reduced histone acetylation in animal models of neurodegeneration that are characterized by cognitive decline, including Alzheimer’s disease. These studies have shown success in reducing cognitive decline in mouse models of Alzheimer’s through the use of nonselective HDAC inhibitors. The results of the current study by Dr. Tsai and her associates suggest that HDAC2 likely was the target of the nonselective inhibitors in earlier studies (Nature 2012;483:222-6).

"I really think this points to a new direction in thinking about therapeutic intervention or prevention" with a strategy that does not directly target amyloid-beta levels, Dr. Tsai said in an interview. While amyloid-beta plays a very early and important role in the disease, she suggested that once the pathogenic cascade of events is triggered, "there are a lot of biological processes that may become amyloid-independent."

Prior studies have shown how amyloid-beta can acutely impair synaptic plasticity by decreasing N-methyl-d-aspartate receptor functions, she said, but it may have a more profound and chronic effect on memory by inducing a blockade of the expression of many genes involved in different steps of memory formation and consolidation, she said.

In two different mouse models of Alzheimer’s disease, the investigators found elevated HDAC2 protein levels in neurodegenerating areas of the mice’s brains, including part of the hippocampus and in the prefrontal cortex. HDAC2 protein in the hippocampus of these mice was found bound to genes implicated in learning, memory, and synaptic plasticity. The investigators found that certain amino acids in the histones that bind to these genes had reduced acetylation, which is known to be important for learning, memory, and synaptic plasticity. All of these genes had reduced expression.

"Taken together, these results indicate that HDAC2 mediates a local chromatin compaction of neuroplasticity genes, which decreases their expression and may contribute to cognitive decline during neurodegeneration," Dr. Tsai and her associates wrote.

When the researchers blocked the expression of HDAC2, the acetylation of neuroplasticity genes increased. The regained expression of these genes induced morphological changes that increased synaptic density and the number of dendrites on surviving neurons, but did not alter neuronal survival.

Blocking HDAC2 in a mouse model of Alzheimer’s led to an improvement in associative and spatial memory – two types of hippocampus-dependent memory – indicating "that elevated HDAC2 levels are causally involved in the cognitive decline associated with neurodegeneration [in the mouse model], but that the prevention of HDAC2 upregulation rescues memory capabilities," the authors wrote.

The transcription of HDAC2 increased in primary hippocampal neurons after they were exposed in vitro to hydrogen peroxide and amyloid-beta oligomers – neurotoxic stimuli that are characteristic of Alzheimer’s disease–related neurodegeneration – as well as in the hippocampus of the mouse model. The effect of these stimuli on HDAC2 suggested to the researchers that transcriptional mechanisms might be involved. They found a binding site for the transcriptional regulator glucocorticoid receptor 1 within the HDAC2 gene. Activation of the glucocorticoid receptor is accomplished through phosphorylation, which the investigators detected in the hippocampi of the mouse model and in cultured hippocampal neurons after exposure to hydrogen peroxide and amyloid-beta oligomers. The hippocampi of these mice, as well as cultured hippocampal neurons stimulated with amyloid-beta oligomers, contained the phosphorylated glucocorticoid receptor 1 attached to the binding site on HDAC2. The binding site of glucocorticoid receptor 1 on HDAC2 was necessary for the transcriptional activation of HDAC2.

Post mortem brain specimens from patients at different stages of Alzheimer’s disease contained significantly elevated HDAC2 levels in the entorhinal cortex and a part of the hippocampus. The elevation of HDAC2 also was an early event in the progression of Alzheimer’s, judging from patients who died in Braak stage I and II.

Robert D. Moir, Ph.D., who studies biochemical and cellular mechanisms involved in neurodegeneration in Alzheimer’s disease and aging at MassGeneral Institute for Neurodegenerative Disease, Boston, said in an interview that the study is "terrific for supporting a role for HDAC2 in memory," but may be a "bit of an overreach in claiming that it is proof of blocking cognitive decline in the neurodegenerating brain. It may be true, but I think there needs to be a lot more work before that assertion can be really made."

The finding of increased levels of HDAC2 in the Alzheimer’s disease brain doesn’t necessarily indicate that it is the cause of cognitive decline, he said. "The AD brain is a mess. You’ve got increased and decreased levels of all sorts of things."

Dr. Moir also noted that there’s not a lot of genetics that point in the direction of HDAC2 for Alzheimer’s.

The research was partly supported by the Stanley Medical Research Institution, the National Institute on Drug Abuse, and the National Institute for Neurological Disorders and Stroke. The authors declared having no financial disclosures.

A high level of an enzyme that causes the deacetylation of histones associated with genes important for learning and memory may be a common feature that mediates the cognitive impairment seen in animal models of Alzheimer’s disease and human patients with the disease.

Inhibition of this gene, which codes for histone deacetylase 2 (HDAC2), may be a good approach to test therapeutically in further studies of animal models of Alzheimer’s disease, noted Johannes Gräff, Ph.D., and his colleagues, who were led by Li-Huei Tsai, Ph.D., of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, Cambridge.

Courtesy of Dr. Li-Huei Tsai

Over the past decade, other studies have noted sporadic cases of reduced histone acetylation in animal models of neurodegeneration that are characterized by cognitive decline, including Alzheimer’s disease. These studies have shown success in reducing cognitive decline in mouse models of Alzheimer’s through the use of nonselective HDAC inhibitors. The results of the current study by Dr. Tsai and her associates suggest that HDAC2 likely was the target of the nonselective inhibitors in earlier studies (Nature 2012;483:222-6).

"I really think this points to a new direction in thinking about therapeutic intervention or prevention" with a strategy that does not directly target amyloid-beta levels, Dr. Tsai said in an interview. While amyloid-beta plays a very early and important role in the disease, she suggested that once the pathogenic cascade of events is triggered, "there are a lot of biological processes that may become amyloid-independent."

Prior studies have shown how amyloid-beta can acutely impair synaptic plasticity by decreasing N-methyl-d-aspartate receptor functions, she said, but it may have a more profound and chronic effect on memory by inducing a blockade of the expression of many genes involved in different steps of memory formation and consolidation, she said.

In two different mouse models of Alzheimer’s disease, the investigators found elevated HDAC2 protein levels in neurodegenerating areas of the mice’s brains, including part of the hippocampus and in the prefrontal cortex. HDAC2 protein in the hippocampus of these mice was found bound to genes implicated in learning, memory, and synaptic plasticity. The investigators found that certain amino acids in the histones that bind to these genes had reduced acetylation, which is known to be important for learning, memory, and synaptic plasticity. All of these genes had reduced expression.

"Taken together, these results indicate that HDAC2 mediates a local chromatin compaction of neuroplasticity genes, which decreases their expression and may contribute to cognitive decline during neurodegeneration," Dr. Tsai and her associates wrote.

When the researchers blocked the expression of HDAC2, the acetylation of neuroplasticity genes increased. The regained expression of these genes induced morphological changes that increased synaptic density and the number of dendrites on surviving neurons, but did not alter neuronal survival.

Blocking HDAC2 in a mouse model of Alzheimer’s led to an improvement in associative and spatial memory – two types of hippocampus-dependent memory – indicating "that elevated HDAC2 levels are causally involved in the cognitive decline associated with neurodegeneration [in the mouse model], but that the prevention of HDAC2 upregulation rescues memory capabilities," the authors wrote.

The transcription of HDAC2 increased in primary hippocampal neurons after they were exposed in vitro to hydrogen peroxide and amyloid-beta oligomers – neurotoxic stimuli that are characteristic of Alzheimer’s disease–related neurodegeneration – as well as in the hippocampus of the mouse model. The effect of these stimuli on HDAC2 suggested to the researchers that transcriptional mechanisms might be involved. They found a binding site for the transcriptional regulator glucocorticoid receptor 1 within the HDAC2 gene. Activation of the glucocorticoid receptor is accomplished through phosphorylation, which the investigators detected in the hippocampi of the mouse model and in cultured hippocampal neurons after exposure to hydrogen peroxide and amyloid-beta oligomers. The hippocampi of these mice, as well as cultured hippocampal neurons stimulated with amyloid-beta oligomers, contained the phosphorylated glucocorticoid receptor 1 attached to the binding site on HDAC2. The binding site of glucocorticoid receptor 1 on HDAC2 was necessary for the transcriptional activation of HDAC2.

Post mortem brain specimens from patients at different stages of Alzheimer’s disease contained significantly elevated HDAC2 levels in the entorhinal cortex and a part of the hippocampus. The elevation of HDAC2 also was an early event in the progression of Alzheimer’s, judging from patients who died in Braak stage I and II.

Robert D. Moir, Ph.D., who studies biochemical and cellular mechanisms involved in neurodegeneration in Alzheimer’s disease and aging at MassGeneral Institute for Neurodegenerative Disease, Boston, said in an interview that the study is "terrific for supporting a role for HDAC2 in memory," but may be a "bit of an overreach in claiming that it is proof of blocking cognitive decline in the neurodegenerating brain. It may be true, but I think there needs to be a lot more work before that assertion can be really made."

The finding of increased levels of HDAC2 in the Alzheimer’s disease brain doesn’t necessarily indicate that it is the cause of cognitive decline, he said. "The AD brain is a mess. You’ve got increased and decreased levels of all sorts of things."

Dr. Moir also noted that there’s not a lot of genetics that point in the direction of HDAC2 for Alzheimer’s.

The research was partly supported by the Stanley Medical Research Institution, the National Institute on Drug Abuse, and the National Institute for Neurological Disorders and Stroke. The authors declared having no financial disclosures.

The results of a randomized, open-label, and blinded trial of tenecteplase vs. alteplase (tissue plasminogen activator) for thrombolysis in patients with acute ischemic stroke are now published in full in the March 22 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:1099-1107). We previously reported on the results of the trial when they were presented at this year’s International Stroke Conference. (See "Related News" item at left.) The full paper does not contain any notable revisions from our original report.

The results of a randomized, open-label, and blinded trial of tenecteplase vs. alteplase (tissue plasminogen activator) for thrombolysis in patients with acute ischemic stroke are now published in full in the March 22 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:1099-1107). We previously reported on the results of the trial when they were presented at this year’s International Stroke Conference. (See "Related News" item at left.) The full paper does not contain any notable revisions from our original report.

The results of a randomized, open-label, and blinded trial of tenecteplase vs. alteplase (tissue plasminogen activator) for thrombolysis in patients with acute ischemic stroke are now published in full in the March 22 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:1099-1107). We previously reported on the results of the trial when they were presented at this year’s International Stroke Conference. (See "Related News" item at left.) The full paper does not contain any notable revisions from our original report.

The results of the ALLEGRO phase III trial of laquinimod for relapsing-remitting multiple sclerosis are now published in full in the March 15 New England Journal of Medicine (N. Engl. J. Med. 2012;366:1000-9). We previously reported on the results of ALLEGRO at last year’s annual meeting of the American Academy of Neurology (See sidebar). The full paper does not contain any notable revisions from our original report.

Last fall, we also reported (see sidebar, as well) on the results of the second phase III trial of laquinimod, BRAVO, at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis. The results have not been published yet.

The results of the ALLEGRO phase III trial of laquinimod for relapsing-remitting multiple sclerosis are now published in full in the March 15 New England Journal of Medicine (N. Engl. J. Med. 2012;366:1000-9). We previously reported on the results of ALLEGRO at last year’s annual meeting of the American Academy of Neurology (See sidebar). The full paper does not contain any notable revisions from our original report.

Last fall, we also reported (see sidebar, as well) on the results of the second phase III trial of laquinimod, BRAVO, at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis. The results have not been published yet.

The results of the ALLEGRO phase III trial of laquinimod for relapsing-remitting multiple sclerosis are now published in full in the March 15 New England Journal of Medicine (N. Engl. J. Med. 2012;366:1000-9). We previously reported on the results of ALLEGRO at last year’s annual meeting of the American Academy of Neurology (See sidebar). The full paper does not contain any notable revisions from our original report.

Last fall, we also reported (see sidebar, as well) on the results of the second phase III trial of laquinimod, BRAVO, at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis. The results have not been published yet.