Neurology

For most symptomatic patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), adding extracranial-intracranial (EC-IC) bypass surgery to medical therapy did not reduce stroke or death in comparison with medical therapy alone in the latest randomized trial comparing the two interventions.

However, subgroup analyses suggest a potential benefit of surgery for certain patients, such as those with MCA vs. ICA occlusion, mean transit time greater than 6 seconds, or regional blood flow of 0.8 or less.

“We were disappointed by the results,” Liqun Jiao, MD, of the National Center for Neurological Disorders in Beijing, told this news organization. “We were expecting to demonstrate a benefit from EC-IC bypass surgery over medical treatment alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, per our original hypothesis.”

Although the study showed improved efficacy and safety for the surgical procedure, he said, “The progress of medical treatment is even better.”

The study was published online in JAMA.
 

Subgroup analyses promising

Previous randomized clinical trials, including the EC/IC Bypass Study and the Carotid Occlusion Surgery Study (COSS), showed no benefit in stroke prevention for patients with atherosclerotic occlusion of the ICA or MCA.

However, in light of improvements over the years in surgical techniques and patient selection, the authors conducted the Carotid and Middle Cerebral Artery Occlusion Surgery Study (CMOSS), a multicenter, randomized, open-label trial comparing EC-IC bypass surgery plus medical therapy, consisting of antiplatelet therapy and control of stroke risk factors, with medical therapy alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, with refined patient and operator selection.

A total of 324 patients (median age, 52.7 years; 79% men) in 13 centers in China were included; 309 patients (95%) completed the study.

The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization.

Secondary outcomes included, among others, any stroke or death within 2 years and fatal stroke within 2 years.

No significant difference was found for the primary outcome between the surgical group (8.6%) and the medical group (12.3%).

The 30-day risk of stroke or death was 6.2% in the surgery group, versus 1.8% (3/163) for the medical group. The risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2%, versus 10.3% – nonsignificant differences.

Furthermore, none of the prespecified secondary endpoints showed a significant difference, including any stroke or death within 2 years (9.9% vs. 15.3%; hazard ratio, 0.69) and fatal stroke within 2 years (2% vs. none).

Despite the findings, “We are encouraged by the subgroup analysis and the trend of long-term outcomes,” Dr. Jiao said. “We will continue to finish 5-10 years of follow-up to see whether the benefit of bypass surgery can be identified.”

The team has also launched the CMOSS-2 trial with a refined study design based on the results of subgroup analysis of the CMOSS study.

CMOSS-2 is recruiting patients with symptomatic chronic occlusion of the MCA and severe hemodynamic insufficiency in 13 sites in China. The primary outcome is ischemic stroke in the territory of the target artery within 24 months after randomization.
 

Can’t exclude benefit

Thomas Jeerakathil, MD, a professor at the University of Alberta and Northern Stroke Lead, Cardiovascular and Stroke Strategic Clinical Network, Alberta Health Services, Edmonton, commented on the study for this news organization. Like the authors, he said, “I don’t consider this study to definitively exclude the benefit of EC/IC bypass. More studies are required.”

Dr. Jeerakathil would like to see a study of a higher-risk group based on both clinical and hemodynamic blood flow criteria. In the current study, he said, “The trial group overall may not have been at high enough stroke risk to justify the up-front risks of the EC-IC bypass procedure.”

In addition, “The analysis method of Cox proportional hazards regression for the primary outcome did not fit the data when the perioperative period was combined with the period beyond 30 days,” he noted. “The researchers were open about this and did pivot and included a post hoc relative risk-based analysis, but the validity of their primary analysis is questionable.”

Furthermore, the study was “somewhat underpowered with a relatively small sample size and had the potential to miss clinically significant differences between groups,” he said. “It would be good to see a longer follow-up period of at least 5 years added to this trial and used in future trials, rather than 2 years.”

“Lastly,” he said, “it’s difficult to ignore the reduction in recurrent stroke events over the 30-day to 2-year time period associated with EC-IC bypass (from 10.3% down to 2%). This reduction alone shows the procedure has some potential to prevent stroke and would argue for more trials.”

EC-IC could be considered for patients who have failed other medical therapies and have more substantial evidence of compromised blood flow to the brain than those in the CMOSS trial, he noted, as many of these patients have few other options. “In our center and many other centers, the approach to EC-IC bypass is probably much more selective than used in the trial.”

Dr. Jeerakathil concluded, “Clinicians should be cautious about offering the procedure to patients with just mildly delayed blood flow in the hemisphere affected by the occluded artery and those who have not yet failed maximal medical therapy.”

But Seemant Chaturvedi, MD, and J. Marc Simard, MD, PhD, both of the University of Maryland, Baltimore, are not as optimistic about the potential for EC-IC.

Writing in a related editorial, they conclude that the results with EC-IC bypass surgery in randomized trials “remain unimpressive. Until a better understanding of the unique hemodynamic features of the brain is achieved, it will be difficult for neurosurgeons to continue offering this procedure to patients with ICA or MCA occlusion. Intensive, multifaceted medical therapy remains the first-line treatment for [these] patients.”

The study was supported by a research grant from the National Health Commission of the People’s Republic of China. Dr. Jiao, Dr. Jeerakathil, Dr. Chaturvedi, and Dr. Simard reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

For most symptomatic patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), adding extracranial-intracranial (EC-IC) bypass surgery to medical therapy did not reduce stroke or death in comparison with medical therapy alone in the latest randomized trial comparing the two interventions.

However, subgroup analyses suggest a potential benefit of surgery for certain patients, such as those with MCA vs. ICA occlusion, mean transit time greater than 6 seconds, or regional blood flow of 0.8 or less.

“We were disappointed by the results,” Liqun Jiao, MD, of the National Center for Neurological Disorders in Beijing, told this news organization. “We were expecting to demonstrate a benefit from EC-IC bypass surgery over medical treatment alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, per our original hypothesis.”

Although the study showed improved efficacy and safety for the surgical procedure, he said, “The progress of medical treatment is even better.”

The study was published online in JAMA.
 

Subgroup analyses promising

Previous randomized clinical trials, including the EC/IC Bypass Study and the Carotid Occlusion Surgery Study (COSS), showed no benefit in stroke prevention for patients with atherosclerotic occlusion of the ICA or MCA.

However, in light of improvements over the years in surgical techniques and patient selection, the authors conducted the Carotid and Middle Cerebral Artery Occlusion Surgery Study (CMOSS), a multicenter, randomized, open-label trial comparing EC-IC bypass surgery plus medical therapy, consisting of antiplatelet therapy and control of stroke risk factors, with medical therapy alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, with refined patient and operator selection.

A total of 324 patients (median age, 52.7 years; 79% men) in 13 centers in China were included; 309 patients (95%) completed the study.

The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization.

Secondary outcomes included, among others, any stroke or death within 2 years and fatal stroke within 2 years.

No significant difference was found for the primary outcome between the surgical group (8.6%) and the medical group (12.3%).

The 30-day risk of stroke or death was 6.2% in the surgery group, versus 1.8% (3/163) for the medical group. The risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2%, versus 10.3% – nonsignificant differences.

Furthermore, none of the prespecified secondary endpoints showed a significant difference, including any stroke or death within 2 years (9.9% vs. 15.3%; hazard ratio, 0.69) and fatal stroke within 2 years (2% vs. none).

Despite the findings, “We are encouraged by the subgroup analysis and the trend of long-term outcomes,” Dr. Jiao said. “We will continue to finish 5-10 years of follow-up to see whether the benefit of bypass surgery can be identified.”

The team has also launched the CMOSS-2 trial with a refined study design based on the results of subgroup analysis of the CMOSS study.

CMOSS-2 is recruiting patients with symptomatic chronic occlusion of the MCA and severe hemodynamic insufficiency in 13 sites in China. The primary outcome is ischemic stroke in the territory of the target artery within 24 months after randomization.
 

Can’t exclude benefit

Thomas Jeerakathil, MD, a professor at the University of Alberta and Northern Stroke Lead, Cardiovascular and Stroke Strategic Clinical Network, Alberta Health Services, Edmonton, commented on the study for this news organization. Like the authors, he said, “I don’t consider this study to definitively exclude the benefit of EC/IC bypass. More studies are required.”

Dr. Jeerakathil would like to see a study of a higher-risk group based on both clinical and hemodynamic blood flow criteria. In the current study, he said, “The trial group overall may not have been at high enough stroke risk to justify the up-front risks of the EC-IC bypass procedure.”

In addition, “The analysis method of Cox proportional hazards regression for the primary outcome did not fit the data when the perioperative period was combined with the period beyond 30 days,” he noted. “The researchers were open about this and did pivot and included a post hoc relative risk-based analysis, but the validity of their primary analysis is questionable.”

Furthermore, the study was “somewhat underpowered with a relatively small sample size and had the potential to miss clinically significant differences between groups,” he said. “It would be good to see a longer follow-up period of at least 5 years added to this trial and used in future trials, rather than 2 years.”

“Lastly,” he said, “it’s difficult to ignore the reduction in recurrent stroke events over the 30-day to 2-year time period associated with EC-IC bypass (from 10.3% down to 2%). This reduction alone shows the procedure has some potential to prevent stroke and would argue for more trials.”

EC-IC could be considered for patients who have failed other medical therapies and have more substantial evidence of compromised blood flow to the brain than those in the CMOSS trial, he noted, as many of these patients have few other options. “In our center and many other centers, the approach to EC-IC bypass is probably much more selective than used in the trial.”

Dr. Jeerakathil concluded, “Clinicians should be cautious about offering the procedure to patients with just mildly delayed blood flow in the hemisphere affected by the occluded artery and those who have not yet failed maximal medical therapy.”

But Seemant Chaturvedi, MD, and J. Marc Simard, MD, PhD, both of the University of Maryland, Baltimore, are not as optimistic about the potential for EC-IC.

Writing in a related editorial, they conclude that the results with EC-IC bypass surgery in randomized trials “remain unimpressive. Until a better understanding of the unique hemodynamic features of the brain is achieved, it will be difficult for neurosurgeons to continue offering this procedure to patients with ICA or MCA occlusion. Intensive, multifaceted medical therapy remains the first-line treatment for [these] patients.”

The study was supported by a research grant from the National Health Commission of the People’s Republic of China. Dr. Jiao, Dr. Jeerakathil, Dr. Chaturvedi, and Dr. Simard reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

For most symptomatic patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), adding extracranial-intracranial (EC-IC) bypass surgery to medical therapy did not reduce stroke or death in comparison with medical therapy alone in the latest randomized trial comparing the two interventions.

However, subgroup analyses suggest a potential benefit of surgery for certain patients, such as those with MCA vs. ICA occlusion, mean transit time greater than 6 seconds, or regional blood flow of 0.8 or less.

“We were disappointed by the results,” Liqun Jiao, MD, of the National Center for Neurological Disorders in Beijing, told this news organization. “We were expecting to demonstrate a benefit from EC-IC bypass surgery over medical treatment alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, per our original hypothesis.”

Although the study showed improved efficacy and safety for the surgical procedure, he said, “The progress of medical treatment is even better.”

The study was published online in JAMA.
 

Subgroup analyses promising

Previous randomized clinical trials, including the EC/IC Bypass Study and the Carotid Occlusion Surgery Study (COSS), showed no benefit in stroke prevention for patients with atherosclerotic occlusion of the ICA or MCA.

However, in light of improvements over the years in surgical techniques and patient selection, the authors conducted the Carotid and Middle Cerebral Artery Occlusion Surgery Study (CMOSS), a multicenter, randomized, open-label trial comparing EC-IC bypass surgery plus medical therapy, consisting of antiplatelet therapy and control of stroke risk factors, with medical therapy alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, with refined patient and operator selection.

A total of 324 patients (median age, 52.7 years; 79% men) in 13 centers in China were included; 309 patients (95%) completed the study.

The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization.

Secondary outcomes included, among others, any stroke or death within 2 years and fatal stroke within 2 years.

No significant difference was found for the primary outcome between the surgical group (8.6%) and the medical group (12.3%).

The 30-day risk of stroke or death was 6.2% in the surgery group, versus 1.8% (3/163) for the medical group. The risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2%, versus 10.3% – nonsignificant differences.

Furthermore, none of the prespecified secondary endpoints showed a significant difference, including any stroke or death within 2 years (9.9% vs. 15.3%; hazard ratio, 0.69) and fatal stroke within 2 years (2% vs. none).

Despite the findings, “We are encouraged by the subgroup analysis and the trend of long-term outcomes,” Dr. Jiao said. “We will continue to finish 5-10 years of follow-up to see whether the benefit of bypass surgery can be identified.”

The team has also launched the CMOSS-2 trial with a refined study design based on the results of subgroup analysis of the CMOSS study.

CMOSS-2 is recruiting patients with symptomatic chronic occlusion of the MCA and severe hemodynamic insufficiency in 13 sites in China. The primary outcome is ischemic stroke in the territory of the target artery within 24 months after randomization.
 

Can’t exclude benefit

Thomas Jeerakathil, MD, a professor at the University of Alberta and Northern Stroke Lead, Cardiovascular and Stroke Strategic Clinical Network, Alberta Health Services, Edmonton, commented on the study for this news organization. Like the authors, he said, “I don’t consider this study to definitively exclude the benefit of EC/IC bypass. More studies are required.”

Dr. Jeerakathil would like to see a study of a higher-risk group based on both clinical and hemodynamic blood flow criteria. In the current study, he said, “The trial group overall may not have been at high enough stroke risk to justify the up-front risks of the EC-IC bypass procedure.”

In addition, “The analysis method of Cox proportional hazards regression for the primary outcome did not fit the data when the perioperative period was combined with the period beyond 30 days,” he noted. “The researchers were open about this and did pivot and included a post hoc relative risk-based analysis, but the validity of their primary analysis is questionable.”

Furthermore, the study was “somewhat underpowered with a relatively small sample size and had the potential to miss clinically significant differences between groups,” he said. “It would be good to see a longer follow-up period of at least 5 years added to this trial and used in future trials, rather than 2 years.”

“Lastly,” he said, “it’s difficult to ignore the reduction in recurrent stroke events over the 30-day to 2-year time period associated with EC-IC bypass (from 10.3% down to 2%). This reduction alone shows the procedure has some potential to prevent stroke and would argue for more trials.”

EC-IC could be considered for patients who have failed other medical therapies and have more substantial evidence of compromised blood flow to the brain than those in the CMOSS trial, he noted, as many of these patients have few other options. “In our center and many other centers, the approach to EC-IC bypass is probably much more selective than used in the trial.”

Dr. Jeerakathil concluded, “Clinicians should be cautious about offering the procedure to patients with just mildly delayed blood flow in the hemisphere affected by the occluded artery and those who have not yet failed maximal medical therapy.”

But Seemant Chaturvedi, MD, and J. Marc Simard, MD, PhD, both of the University of Maryland, Baltimore, are not as optimistic about the potential for EC-IC.

Writing in a related editorial, they conclude that the results with EC-IC bypass surgery in randomized trials “remain unimpressive. Until a better understanding of the unique hemodynamic features of the brain is achieved, it will be difficult for neurosurgeons to continue offering this procedure to patients with ICA or MCA occlusion. Intensive, multifaceted medical therapy remains the first-line treatment for [these] patients.”

The study was supported by a research grant from the National Health Commission of the People’s Republic of China. Dr. Jiao, Dr. Jeerakathil, Dr. Chaturvedi, and Dr. Simard reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Traumatic brain injury (TBI) that occurs in early adulthood is associated with cognitive decline in later life, results from a study of identical twins who served in World War II show.

The research, which included almost 9,000 individuals, showed that twins who had experienced a TBI were more likely to have lower cognitive function at age 70 versus their twin who did not experience a TBI, especially if they had lost consciousness or were older than age 24 at the time of injury. In addition, their cognitive decline occurred at a more rapid rate.

“We know that TBI increases the risk of developing Alzheimer’s disease and other dementias in later life, but we haven’t known about TBI’s effect on cognitive decline that does not quite meet the threshold for dementia,” study investigator Marianne Chanti-Ketterl, PhD, Duke University, Durham, N.C., said in an interview.

“We know that TBI increases the risk of dementia in later life, but we haven’t known if TBI affects cognitive function, causes cognitive decline that has not progressed to the point of severity with Alzheimer’s or dementia,” she added.

Being able to study the impact of TBI in monozygotic twins gives this study a unique strength, she noted.

“The important thing about this is that they are monozygotic twins, and we know they shared a lot of early life exposure, and almost 100% genetics,” Dr. Chanti-Ketterl said.

The study was published online in Neurology.

For the study, the investigators assessed 8,662 participants born between 1917 and 1927 who were part of the National Academy of Sciences National Research Council’s Twin Registry. The registry is composed of male veterans of World War II with a history of TBI, as reported by themselves or a caregiver.

The men were followed up for many years as part of the registry, but cognitive assessment only began in the 1990s. They were followed up at four different time points, at which time the Telephone Interview for Cognitive Status (TICS-m), an alternative to the Mini-Mental State Examination that must be given in person, was administered.

A total of 25% of participants had experienced concussion in their lifetime. Of this cohort, there were 589 pairs of monozygotic twins who were discordant (one twin had TBI and the other had not).

Among the monozygotic twin cohort, a history of any TBI and being older than age 24 at the time of TBI were associated with lower TICS-m scores.

A twin who experienced TBI after age 24 scored 0.59 points lower on the TICS-m at age 70 than his twin with no TBI, and cognitive function declined faster, by 0.05 points per year.
 

First study of its kind

Holly Elser, MD, PhD, MPH, an epidemiologist and resident physician in neurology at the University of Pennsylvania, Philadelphia, and coauthor of an accompanying editorial, said in an interview that the study’s twin design was a definite strength.

“There are lots of papers that have remarked on the apparent association between head injury and subsequent dementia or cognitive decline, but to my knowledge, this is one of the first, if not the first, to use a twin study design, which has the unique advantage of having better control over early life and genetic factors than would ever typically be possible in a dataset of unrelated adults,” said Dr. Elser.

She added that the study findings “strengthen our understanding of the relationship between TBI and later cognitive decline, so I think there is an etiologic value to the study.”

However, Dr. Elser noted that the composition of the study population may limit the extent to which the results apply to contemporary populations.

“This was a population of White male twins born between 1917 and 1927,” she noted. “However, does the experience of people who were in the military generalize to civilian populations? Are twins representative of the general population or are they unique in terms of their risk factors?”

It is always important to emphasize inclusivity in clinical research, and in dementia research in particular, Dr. Elser added.

“There are many examples of instances where racialized and otherwise economically marginalized groups have been excluded from analysis, which is problematic because there are already economically and socially marginalized groups who disproportionately bear the brunt of dementia.

“This is not a criticism of the authors’ work, that their data didn’t include a more diverse patient base, but I think it is an important reminder that we should always interpret study findings within the limitations of the data. It’s a reminder to be thoughtful about taking explicit steps to include more diverse groups in future research,” she said.

The study was funded by the National Institute on Aging/National Institutes of Health and the Department of Defense. Dr. Chanti-Ketterl and Dr. Elser have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research hints at the possibility that cerebral amyloid angiopathy (CAA), a cause of spontaneous brain hemorrhage, can be transmitted via blood transfusion, raising the risk for spontaneous intracerebral hemorrhage (ICH) in transfusion recipients.

In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.

“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.

“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.

The study was published online  in the Journal of the American Medical Association.
 

Novel finding

Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.

CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH. 

The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.

The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.

Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).

“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.

There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.

The findings were robust to several of the sensitivity analyses.

A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.

This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.

The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
 

Worrisome finding or false alarm?

In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”

“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.

Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.

Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.

He added the current study leaves him “squarely at the corner of anxiety and skepticism.”

With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.

“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.

Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.

“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”

“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.

The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research hints at the possibility that cerebral amyloid angiopathy (CAA), a cause of spontaneous brain hemorrhage, can be transmitted via blood transfusion, raising the risk for spontaneous intracerebral hemorrhage (ICH) in transfusion recipients.

In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.

“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.

“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.

The study was published online  in the Journal of the American Medical Association.
 

Novel finding

Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.

CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH. 

The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.

The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.

Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).

“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.

There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.

The findings were robust to several of the sensitivity analyses.

A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.

This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.

The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
 

Worrisome finding or false alarm?

In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”

“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.

Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.

Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.

He added the current study leaves him “squarely at the corner of anxiety and skepticism.”

With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.

“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.

Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.

“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”

“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.

The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research hints at the possibility that cerebral amyloid angiopathy (CAA), a cause of spontaneous brain hemorrhage, can be transmitted via blood transfusion, raising the risk for spontaneous intracerebral hemorrhage (ICH) in transfusion recipients.

In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.

“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.

“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.

The study was published online  in the Journal of the American Medical Association.
 

Novel finding

Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.

CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH. 

The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.

The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.

Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).

“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.

There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.

The findings were robust to several of the sensitivity analyses.

A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.

This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.

The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
 

Worrisome finding or false alarm?

In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”

“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.

Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.

Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.

He added the current study leaves him “squarely at the corner of anxiety and skepticism.”

With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.

“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.

Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.

“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”

“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.

The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.

METHODOLOGY:

• Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
• Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
• Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.

TAKEAWAY:

• Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
• The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
• These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
• The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.

IN PRACTICE:

Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.

STUDY DETAILS:

The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.

LIMITATIONS:

• Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
• Certain income projections and income losses are uncertain.
• Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.

DISCLOSURES:

The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

More than 10 hours a day of sedentary behavior significantly increases the risk of dementia in older adults, a new study suggests.

The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.

Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.

“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.

The findings were published online in JAMA.
 

A surprising find?

The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.

Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.

Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.

Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).

Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.

“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”

The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
 

More research welcome

Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”

“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.

It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.

“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”

The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than 10 hours a day of sedentary behavior significantly increases the risk of dementia in older adults, a new study suggests.

The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.

Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.

“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.

The findings were published online in JAMA.
 

A surprising find?

The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.

Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.

Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.

Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).

Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.

“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”

The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
 

More research welcome

Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”

“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.

It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.

“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”

The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than 10 hours a day of sedentary behavior significantly increases the risk of dementia in older adults, a new study suggests.

The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.

Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.

“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.

The findings were published online in JAMA.
 

A surprising find?

The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.

Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.

Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.

Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).

Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.

“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”

The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
 

More research welcome

Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”

“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.

It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.

“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”

The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended new measures designed to avoid topiramate (multiple brands) use during pregnancy.

While it’s well known that topiramate can cause major congenital malformations and fetal growth restriction when used during pregnancy, recent data also suggest a possibly increased risk for neurodevelopmental disorders when topiramate is used during pregnancy, the EMA said in a statement. 

The data include two observational studies that showed children born to mothers with epilepsy and who were exposed to topiramate in the womb may have a two- to threefold higher risk for neurodevelopmental disorders, in particular autism spectrum disorders (ASD), intellectual disability, or attention deficit hyperactivity disorder (ADHD), compared with children born to mothers with epilepsy not taking antiepileptic medication.

For patients using topiramate for the treatment of epilepsy, the PRAC now recommends that the medicine not be used during pregnancy unless no other suitable treatment is available.

The PRAC had also recommended a pregnancy prevention program to avoid exposure of the developing fetus to topiramate. “These measures will inform any woman or girl who is able to have children of the risks of taking topiramate during pregnancy and the need to avoid becoming pregnant while taking topiramate,” the EMA said.

Regardless of indication, the agency said topiramate should be used in women of childbearing age only when the following conditions of the pregnancy prevention program are met:

• A pregnancy test before starting treatment.
• Counseling about the risks of topiramate treatment and the need for highly effective contraception throughout treatment.
• A review of ongoing treatment at least annually by completion of a risk awareness form.

The PRAC recommends that health care professionals ensure women of childbearing age are fully aware of the risks of taking topiramate during pregnancy. The committee noted that alternative treatment options should be considered and the need for topiramate treatment should be reassessed at least annually.

The product information for topiramate-containing medicines will be updated to further highlight the risks for neurodevelopmental disorders and the additional safety measures to be taken.

Patients and health care professionals will be provided with educational materials regarding the risks of using topiramate during pregnancy, and a patient card will be provided to the patient with each medicine package. A visible warning will also be added to the outer packaging of the medicine.

The new PRAC recommendations will be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended new measures designed to avoid topiramate (multiple brands) use during pregnancy.

While it’s well known that topiramate can cause major congenital malformations and fetal growth restriction when used during pregnancy, recent data also suggest a possibly increased risk for neurodevelopmental disorders when topiramate is used during pregnancy, the EMA said in a statement. 

The data include two observational studies that showed children born to mothers with epilepsy and who were exposed to topiramate in the womb may have a two- to threefold higher risk for neurodevelopmental disorders, in particular autism spectrum disorders (ASD), intellectual disability, or attention deficit hyperactivity disorder (ADHD), compared with children born to mothers with epilepsy not taking antiepileptic medication.

For patients using topiramate for the treatment of epilepsy, the PRAC now recommends that the medicine not be used during pregnancy unless no other suitable treatment is available.

The PRAC had also recommended a pregnancy prevention program to avoid exposure of the developing fetus to topiramate. “These measures will inform any woman or girl who is able to have children of the risks of taking topiramate during pregnancy and the need to avoid becoming pregnant while taking topiramate,” the EMA said.

Regardless of indication, the agency said topiramate should be used in women of childbearing age only when the following conditions of the pregnancy prevention program are met:

• A pregnancy test before starting treatment.
• Counseling about the risks of topiramate treatment and the need for highly effective contraception throughout treatment.
• A review of ongoing treatment at least annually by completion of a risk awareness form.

The PRAC recommends that health care professionals ensure women of childbearing age are fully aware of the risks of taking topiramate during pregnancy. The committee noted that alternative treatment options should be considered and the need for topiramate treatment should be reassessed at least annually.

The product information for topiramate-containing medicines will be updated to further highlight the risks for neurodevelopmental disorders and the additional safety measures to be taken.

Patients and health care professionals will be provided with educational materials regarding the risks of using topiramate during pregnancy, and a patient card will be provided to the patient with each medicine package. A visible warning will also be added to the outer packaging of the medicine.

The new PRAC recommendations will be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended new measures designed to avoid topiramate (multiple brands) use during pregnancy.

While it’s well known that topiramate can cause major congenital malformations and fetal growth restriction when used during pregnancy, recent data also suggest a possibly increased risk for neurodevelopmental disorders when topiramate is used during pregnancy, the EMA said in a statement. 

The data include two observational studies that showed children born to mothers with epilepsy and who were exposed to topiramate in the womb may have a two- to threefold higher risk for neurodevelopmental disorders, in particular autism spectrum disorders (ASD), intellectual disability, or attention deficit hyperactivity disorder (ADHD), compared with children born to mothers with epilepsy not taking antiepileptic medication.

For patients using topiramate for the treatment of epilepsy, the PRAC now recommends that the medicine not be used during pregnancy unless no other suitable treatment is available.

The PRAC had also recommended a pregnancy prevention program to avoid exposure of the developing fetus to topiramate. “These measures will inform any woman or girl who is able to have children of the risks of taking topiramate during pregnancy and the need to avoid becoming pregnant while taking topiramate,” the EMA said.

Regardless of indication, the agency said topiramate should be used in women of childbearing age only when the following conditions of the pregnancy prevention program are met:

• A pregnancy test before starting treatment.
• Counseling about the risks of topiramate treatment and the need for highly effective contraception throughout treatment.
• A review of ongoing treatment at least annually by completion of a risk awareness form.

The PRAC recommends that health care professionals ensure women of childbearing age are fully aware of the risks of taking topiramate during pregnancy. The committee noted that alternative treatment options should be considered and the need for topiramate treatment should be reassessed at least annually.

The product information for topiramate-containing medicines will be updated to further highlight the risks for neurodevelopmental disorders and the additional safety measures to be taken.

Patients and health care professionals will be provided with educational materials regarding the risks of using topiramate during pregnancy, and a patient card will be provided to the patient with each medicine package. A visible warning will also be added to the outer packaging of the medicine.

The new PRAC recommendations will be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position.
 

A version of this article first appeared on Medscape.com.

Pediatric concussion is one of those rare phenomena in which we may be witnessing its emergence and clarification in a generation. When I was serving as the game doctor for our local high school football team in the 1970s, I and many other physicians had a very simplistic view of concussion. If the patient never lost conscious and had a reasonably intact short-term memory, we didn’t seriously entertain concussion as a diagnosis. “What’s the score and who is the president?” Were my favorite screening questions.

Obviously, we were underdiagnosing and mismanaging concussion. In part thanks to some high-profile athletes who suffered multiple concussions and eventually chronic traumatic encephalopathy (CTE) physicians began to realize that they should be looking more closely at children who sustained a head injury. The diagnostic criteria were expanded to include any injury that even temporarily effected brain function.

With the new appreciation for the risk of multiple concussions, the focus broadened to include the question of when is it safe for the athlete to return to competition. What signs or symptoms can the patient offer us so we can be sure his or her brain is sufficiently recovered? Here we stepped off into a deep abyss of ignorance. Fortunately, it became obvious fairly quickly that imaging studies weren’t going to help us, as they were invariably normal or at least didn’t tell us anything that wasn’t obvious on a physical exam.

If the patient had a headache, complained of dizziness, or manifested amnesia, monitoring the patient was fairly straightforward. But, in the absence of symptoms and no obvious way to determine the pace of recovery of an organ we couldn’t visualize, clinicians were pulling criteria and time tables out of thin air. Guessing that the concussed brain was in some ways like a torn muscle or overstretched tendon, “brain rest” was often suggested. So no TV, no reading, and certainly none of the cerebral challenging activity of school. Fortunately, we don’t hear much about the notion of brain rest anymore and there is at least one study that suggests that patients kept home from school recover more slowly.

But there remains a significant number of patients who have persistent symptoms and are unable to resume their usual activities, including school and sports. Sometimes they describe headache or dizziness but often they complain of a vague mental unwellness. “Brain fog,” a term that has emerged in the wake of the COVID pandemic, might be an apt descriptor. Management of these slow recoverers has been a challenge.

However, two recent articles in the journal Pediatrics may provide some clarity and offer guidance in their management. In a study coming from the psychology department at Georgia State University, researchers reported that they have been able to find “no evidence of clinical meaningful differences in IQ after pediatric concussion.” In their words there is “strong evidence against reduced intelligence in the first few weeks to month after pediatric concussion.”

While their findings may simply toss the IQ onto the pile of worthless measures of healing, a companion commentary by Talin Babikian, PhD, a psychologist at the Semel Institute for Neuroscience and Human Behavior at UCLA, provides a more nuanced interpretation. He writes that if we are looking for an explanation when a patient’s recovery is taking longer than we might expect we need to look beyond some structural damage. Maybe the patient has a previously undiagnosed premorbid condition effecting his or her intellectual, cognitive, or learning abilities. Could the stall in improvement be the result of other symptoms? Here fatigue and sleep deprivation may be the culprits. Could some underlying emotional factor such as anxiety or depression be the problem? For example, I have seen patients whose fear of re-injury has prevented their return to full function. And, finally, the patient may be avoiding a “nonpreferred or challenging situation” unrelated to the injury.

In other words, the concussion may simply be the most obvious rip in a fabric that was already frayed and under stress. This kind of broad holistic (a word I usually like to avoid) thinking may be what is lacking as we struggle to understand other mysterious and chronic conditions such as Lyme disease and chronic fatigue syndrome.

While these two papers help provide some clarity in the management of pediatric concussion, what they fail to address is the bigger question of the relationship between head injury and CTE. The answers to that conundrum are enshrouded in a mix of politics and publicity that I doubt will clear in the near future.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Pediatric concussion is one of those rare phenomena in which we may be witnessing its emergence and clarification in a generation. When I was serving as the game doctor for our local high school football team in the 1970s, I and many other physicians had a very simplistic view of concussion. If the patient never lost conscious and had a reasonably intact short-term memory, we didn’t seriously entertain concussion as a diagnosis. “What’s the score and who is the president?” Were my favorite screening questions.

Obviously, we were underdiagnosing and mismanaging concussion. In part thanks to some high-profile athletes who suffered multiple concussions and eventually chronic traumatic encephalopathy (CTE) physicians began to realize that they should be looking more closely at children who sustained a head injury. The diagnostic criteria were expanded to include any injury that even temporarily effected brain function.

With the new appreciation for the risk of multiple concussions, the focus broadened to include the question of when is it safe for the athlete to return to competition. What signs or symptoms can the patient offer us so we can be sure his or her brain is sufficiently recovered? Here we stepped off into a deep abyss of ignorance. Fortunately, it became obvious fairly quickly that imaging studies weren’t going to help us, as they were invariably normal or at least didn’t tell us anything that wasn’t obvious on a physical exam.

If the patient had a headache, complained of dizziness, or manifested amnesia, monitoring the patient was fairly straightforward. But, in the absence of symptoms and no obvious way to determine the pace of recovery of an organ we couldn’t visualize, clinicians were pulling criteria and time tables out of thin air. Guessing that the concussed brain was in some ways like a torn muscle or overstretched tendon, “brain rest” was often suggested. So no TV, no reading, and certainly none of the cerebral challenging activity of school. Fortunately, we don’t hear much about the notion of brain rest anymore and there is at least one study that suggests that patients kept home from school recover more slowly.

But there remains a significant number of patients who have persistent symptoms and are unable to resume their usual activities, including school and sports. Sometimes they describe headache or dizziness but often they complain of a vague mental unwellness. “Brain fog,” a term that has emerged in the wake of the COVID pandemic, might be an apt descriptor. Management of these slow recoverers has been a challenge.

However, two recent articles in the journal Pediatrics may provide some clarity and offer guidance in their management. In a study coming from the psychology department at Georgia State University, researchers reported that they have been able to find “no evidence of clinical meaningful differences in IQ after pediatric concussion.” In their words there is “strong evidence against reduced intelligence in the first few weeks to month after pediatric concussion.”

While their findings may simply toss the IQ onto the pile of worthless measures of healing, a companion commentary by Talin Babikian, PhD, a psychologist at the Semel Institute for Neuroscience and Human Behavior at UCLA, provides a more nuanced interpretation. He writes that if we are looking for an explanation when a patient’s recovery is taking longer than we might expect we need to look beyond some structural damage. Maybe the patient has a previously undiagnosed premorbid condition effecting his or her intellectual, cognitive, or learning abilities. Could the stall in improvement be the result of other symptoms? Here fatigue and sleep deprivation may be the culprits. Could some underlying emotional factor such as anxiety or depression be the problem? For example, I have seen patients whose fear of re-injury has prevented their return to full function. And, finally, the patient may be avoiding a “nonpreferred or challenging situation” unrelated to the injury.

In other words, the concussion may simply be the most obvious rip in a fabric that was already frayed and under stress. This kind of broad holistic (a word I usually like to avoid) thinking may be what is lacking as we struggle to understand other mysterious and chronic conditions such as Lyme disease and chronic fatigue syndrome.

While these two papers help provide some clarity in the management of pediatric concussion, what they fail to address is the bigger question of the relationship between head injury and CTE. The answers to that conundrum are enshrouded in a mix of politics and publicity that I doubt will clear in the near future.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Pediatric concussion is one of those rare phenomena in which we may be witnessing its emergence and clarification in a generation. When I was serving as the game doctor for our local high school football team in the 1970s, I and many other physicians had a very simplistic view of concussion. If the patient never lost conscious and had a reasonably intact short-term memory, we didn’t seriously entertain concussion as a diagnosis. “What’s the score and who is the president?” Were my favorite screening questions.

Obviously, we were underdiagnosing and mismanaging concussion. In part thanks to some high-profile athletes who suffered multiple concussions and eventually chronic traumatic encephalopathy (CTE) physicians began to realize that they should be looking more closely at children who sustained a head injury. The diagnostic criteria were expanded to include any injury that even temporarily effected brain function.

With the new appreciation for the risk of multiple concussions, the focus broadened to include the question of when is it safe for the athlete to return to competition. What signs or symptoms can the patient offer us so we can be sure his or her brain is sufficiently recovered? Here we stepped off into a deep abyss of ignorance. Fortunately, it became obvious fairly quickly that imaging studies weren’t going to help us, as they were invariably normal or at least didn’t tell us anything that wasn’t obvious on a physical exam.

If the patient had a headache, complained of dizziness, or manifested amnesia, monitoring the patient was fairly straightforward. But, in the absence of symptoms and no obvious way to determine the pace of recovery of an organ we couldn’t visualize, clinicians were pulling criteria and time tables out of thin air. Guessing that the concussed brain was in some ways like a torn muscle or overstretched tendon, “brain rest” was often suggested. So no TV, no reading, and certainly none of the cerebral challenging activity of school. Fortunately, we don’t hear much about the notion of brain rest anymore and there is at least one study that suggests that patients kept home from school recover more slowly.

But there remains a significant number of patients who have persistent symptoms and are unable to resume their usual activities, including school and sports. Sometimes they describe headache or dizziness but often they complain of a vague mental unwellness. “Brain fog,” a term that has emerged in the wake of the COVID pandemic, might be an apt descriptor. Management of these slow recoverers has been a challenge.

However, two recent articles in the journal Pediatrics may provide some clarity and offer guidance in their management. In a study coming from the psychology department at Georgia State University, researchers reported that they have been able to find “no evidence of clinical meaningful differences in IQ after pediatric concussion.” In their words there is “strong evidence against reduced intelligence in the first few weeks to month after pediatric concussion.”

While their findings may simply toss the IQ onto the pile of worthless measures of healing, a companion commentary by Talin Babikian, PhD, a psychologist at the Semel Institute for Neuroscience and Human Behavior at UCLA, provides a more nuanced interpretation. He writes that if we are looking for an explanation when a patient’s recovery is taking longer than we might expect we need to look beyond some structural damage. Maybe the patient has a previously undiagnosed premorbid condition effecting his or her intellectual, cognitive, or learning abilities. Could the stall in improvement be the result of other symptoms? Here fatigue and sleep deprivation may be the culprits. Could some underlying emotional factor such as anxiety or depression be the problem? For example, I have seen patients whose fear of re-injury has prevented their return to full function. And, finally, the patient may be avoiding a “nonpreferred or challenging situation” unrelated to the injury.

In other words, the concussion may simply be the most obvious rip in a fabric that was already frayed and under stress. This kind of broad holistic (a word I usually like to avoid) thinking may be what is lacking as we struggle to understand other mysterious and chronic conditions such as Lyme disease and chronic fatigue syndrome.

While these two papers help provide some clarity in the management of pediatric concussion, what they fail to address is the bigger question of the relationship between head injury and CTE. The answers to that conundrum are enshrouded in a mix of politics and publicity that I doubt will clear in the near future.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].