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Chemotherapy Linked to Brain Atrophy in Patients With Breast Cancer
Patients with breast cancer who undergo chemotherapy may face an increased risk for brain atrophy and cognitive decline, new findings from a pilot study suggest.
Memory problems in patients with cancer may not stem solely from stress or anxiety related to their diagnosis but could reflect underlying changes in brain structure, study investigator Paul Edison, PhD, MPhil, professor of neuroscience and clinical professor of neurology at Imperial College London, England, told this news organization.
While the findings suggest that chemotherapy may contribute to neuronal damage, the researchers noted that many aspects of the relationship between treatment and brain changes remain unclear.
Edison highlighted three key areas that require further investigation — uncovering the mechanisms driving brain atrophy, determining the proportion of patients affected, and identifying effective prevention strategies.
Another investigator on the study, Laura Kenny, MD, PhD, associate professor and consultant medical oncologist at Imperial College London, noted that the issue has received limited attention to date but expressed hope that the findings will raise awareness and encourage further research, given its clinical importance.
The findings were presented on July 29 at the Alzheimer’s Association International Conference (AAIC) 2025.
Investigating Cognitive Impact
Advances in chemotherapeutic agents have improved survival rates in patients with cancer. However, challenges persist regarding the long-term impact of these drugs.
Chemotherapy-associated cognitive impairment, often referred to as “brain fog” or “chemobrain,” affects approximately one third of patients with breast cancer following treatment.
While cognitive decline resolves within 12 months for some patients, others experience persistent effects that may elevate the risk for neurodegenerative conditions, Edison explained.
To evaluate the impact of chemotherapy on the brain, investigators studied 328 women with nonmetastatic breast cancer who had undergone chemotherapy within the past 12 months.
Patients received either anthracycline — a drug derived from the Streptomyces peucetius bacterium — or taxanes such as docetaxel and paclitaxel, both commonly used in breast cancer treatment, or a combination of these agents. In addition, some patients may also have had hormone therapy at some point during treatment, said Kenny.
Participants completed neurocognitive prescreening tests every 3 months using a specialized artificial intelligence–driven platform, allowing them to take detailed memory assessments online from home.
Among those prescreened, 18 individuals with lower neurocognitive scores (mean age, 55 years) and 19 cognitively normal control individuals without breast cancer (mean age, 67 years) underwent comprehensive, in-person, neurocognitive evaluations and MRI scans.
Researchers analyzed the scans using region of interest (ROI) and voxel-based morphometry (VBM), which uses sophisticated computer software, to assess gray matter volumes and surface areas.
The ROI analysis revealed significant reductions in gray matter volume (measured in mm3) and surface area (measured in mm2) among patients experiencing chemobrain, particularly affecting the isthmus cingulate and pars opercularis, with changes extending into the orbitofrontal and temporal regions.
Significant Atrophy
The VBM analysis confirmed significant atrophy in the frontal, parietal, and cingulate regions of patients with chemobrain compared with control individuals (P < .05). Edison noted that this pattern overlaps with brain changes typically observed in Alzheimer’s disease and vascular cognitive impairment.
For both analyses, “we demonstrated there is some amount of shrinkage in the brain among patients with chemobrain,” he said. “The fact that controls are older means the results are even more significant as there’s more brain atrophy as people age.”
Some of the affected brain regions may be linked to impaired memory, a hallmark of Alzheimer’s disease, but Edison cautioned that given the small sample size this finding should be interpreted with caution.
While the analysis demonstrated overall lower brain volumes in patients with “chemobrain” compared with controls, Edison emphasized that this finding reflects a single time point and does not indicate brain shrinkage over time.
Other events, including stroke — can also cause brain changes.
Edison highlighted the importance of determining the significance of these brain changes, how they affect patients and whether they can be prevented.
In-person neurocognitive testing revealed significantly reduced semantic and verbal fluency, as well as lower Mini-Mental State Examination scores in patients with chemobrain. Edison noted that these results support the MRI findings.
The team plans to follow patients to track brain changes and memory recovery, Kenny said. While patients with breast cancer are a common focus, the researchers intend to expand the study to other cancers in both men and women, said Kenny.
Based on discussions with her oncology colleagues, Kenny noted that many patients anecdotally report experiencing memory problems during chemotherapy.
More Research Needed
Commenting for this news organization, Rebecca M. Edelmayer, PhD, vice president, scientific engagement, at the Alzheimer’s Association, said the research may help shed light on why women are more likely to develop dementia than men.
For years now, experts have been trying to figure out what puts women at higher risk for AD and other dementias, said Edelmayer.
“We still don’t understand whether this involves biologically driven risk factors or socially driven risk factors.”
Research linking treatments for other health conditions to increased memory problems may offer some clues, she noted, suggesting a potential avenue for further investigation into the intersection of chemotherapy and neurodegenerative diseases such as Alzheimer’s.
However, Edelmayer emphasized that this line of research is still in its infancy. Much more work is needed to determine whether there is a direct cause-and-effect relationship with specific chemotherapy drugs, and whether some patients may already be predisposed or at higher risk for cognitive decline, she said.
Also commenting for this news organization, Eric Brown, MD, associate scientist and associate chief of geriatric psychiatry at the Centre for Addiction and Mental Health in Toronto, raised concerns about the study’s design.
One issue, he noted, is that the researchers did not image all patients who received chemotherapy but instead selected those with the most significant cognitive impairment. As a result, the findings may not have reflected outcomes in the average post-chemotherapy patients but rather represent the most severely affected subgroup.
Brown pointed out that the study did not clarify whether this subgroup had comorbid conditions. It’s possible, he said, that some individuals may have had Alzheimer’s disease or other forms of dementia unrelated to chemotherapy.
He agreed that tracking longitudinal changes in both cognitive scores and neuroimaging — comparing patients who receive chemotherapy with those who do not — would be a valuable next step.
The investigators, Edelmayer, and Brown reported no relevant conflicts of interest. A version of this article first appeared on Medscape.com.
Patients with breast cancer who undergo chemotherapy may face an increased risk for brain atrophy and cognitive decline, new findings from a pilot study suggest.
Memory problems in patients with cancer may not stem solely from stress or anxiety related to their diagnosis but could reflect underlying changes in brain structure, study investigator Paul Edison, PhD, MPhil, professor of neuroscience and clinical professor of neurology at Imperial College London, England, told this news organization.
While the findings suggest that chemotherapy may contribute to neuronal damage, the researchers noted that many aspects of the relationship between treatment and brain changes remain unclear.
Edison highlighted three key areas that require further investigation — uncovering the mechanisms driving brain atrophy, determining the proportion of patients affected, and identifying effective prevention strategies.
Another investigator on the study, Laura Kenny, MD, PhD, associate professor and consultant medical oncologist at Imperial College London, noted that the issue has received limited attention to date but expressed hope that the findings will raise awareness and encourage further research, given its clinical importance.
The findings were presented on July 29 at the Alzheimer’s Association International Conference (AAIC) 2025.
Investigating Cognitive Impact
Advances in chemotherapeutic agents have improved survival rates in patients with cancer. However, challenges persist regarding the long-term impact of these drugs.
Chemotherapy-associated cognitive impairment, often referred to as “brain fog” or “chemobrain,” affects approximately one third of patients with breast cancer following treatment.
While cognitive decline resolves within 12 months for some patients, others experience persistent effects that may elevate the risk for neurodegenerative conditions, Edison explained.
To evaluate the impact of chemotherapy on the brain, investigators studied 328 women with nonmetastatic breast cancer who had undergone chemotherapy within the past 12 months.
Patients received either anthracycline — a drug derived from the Streptomyces peucetius bacterium — or taxanes such as docetaxel and paclitaxel, both commonly used in breast cancer treatment, or a combination of these agents. In addition, some patients may also have had hormone therapy at some point during treatment, said Kenny.
Participants completed neurocognitive prescreening tests every 3 months using a specialized artificial intelligence–driven platform, allowing them to take detailed memory assessments online from home.
Among those prescreened, 18 individuals with lower neurocognitive scores (mean age, 55 years) and 19 cognitively normal control individuals without breast cancer (mean age, 67 years) underwent comprehensive, in-person, neurocognitive evaluations and MRI scans.
Researchers analyzed the scans using region of interest (ROI) and voxel-based morphometry (VBM), which uses sophisticated computer software, to assess gray matter volumes and surface areas.
The ROI analysis revealed significant reductions in gray matter volume (measured in mm3) and surface area (measured in mm2) among patients experiencing chemobrain, particularly affecting the isthmus cingulate and pars opercularis, with changes extending into the orbitofrontal and temporal regions.
Significant Atrophy
The VBM analysis confirmed significant atrophy in the frontal, parietal, and cingulate regions of patients with chemobrain compared with control individuals (P < .05). Edison noted that this pattern overlaps with brain changes typically observed in Alzheimer’s disease and vascular cognitive impairment.
For both analyses, “we demonstrated there is some amount of shrinkage in the brain among patients with chemobrain,” he said. “The fact that controls are older means the results are even more significant as there’s more brain atrophy as people age.”
Some of the affected brain regions may be linked to impaired memory, a hallmark of Alzheimer’s disease, but Edison cautioned that given the small sample size this finding should be interpreted with caution.
While the analysis demonstrated overall lower brain volumes in patients with “chemobrain” compared with controls, Edison emphasized that this finding reflects a single time point and does not indicate brain shrinkage over time.
Other events, including stroke — can also cause brain changes.
Edison highlighted the importance of determining the significance of these brain changes, how they affect patients and whether they can be prevented.
In-person neurocognitive testing revealed significantly reduced semantic and verbal fluency, as well as lower Mini-Mental State Examination scores in patients with chemobrain. Edison noted that these results support the MRI findings.
The team plans to follow patients to track brain changes and memory recovery, Kenny said. While patients with breast cancer are a common focus, the researchers intend to expand the study to other cancers in both men and women, said Kenny.
Based on discussions with her oncology colleagues, Kenny noted that many patients anecdotally report experiencing memory problems during chemotherapy.
More Research Needed
Commenting for this news organization, Rebecca M. Edelmayer, PhD, vice president, scientific engagement, at the Alzheimer’s Association, said the research may help shed light on why women are more likely to develop dementia than men.
For years now, experts have been trying to figure out what puts women at higher risk for AD and other dementias, said Edelmayer.
“We still don’t understand whether this involves biologically driven risk factors or socially driven risk factors.”
Research linking treatments for other health conditions to increased memory problems may offer some clues, she noted, suggesting a potential avenue for further investigation into the intersection of chemotherapy and neurodegenerative diseases such as Alzheimer’s.
However, Edelmayer emphasized that this line of research is still in its infancy. Much more work is needed to determine whether there is a direct cause-and-effect relationship with specific chemotherapy drugs, and whether some patients may already be predisposed or at higher risk for cognitive decline, she said.
Also commenting for this news organization, Eric Brown, MD, associate scientist and associate chief of geriatric psychiatry at the Centre for Addiction and Mental Health in Toronto, raised concerns about the study’s design.
One issue, he noted, is that the researchers did not image all patients who received chemotherapy but instead selected those with the most significant cognitive impairment. As a result, the findings may not have reflected outcomes in the average post-chemotherapy patients but rather represent the most severely affected subgroup.
Brown pointed out that the study did not clarify whether this subgroup had comorbid conditions. It’s possible, he said, that some individuals may have had Alzheimer’s disease or other forms of dementia unrelated to chemotherapy.
He agreed that tracking longitudinal changes in both cognitive scores and neuroimaging — comparing patients who receive chemotherapy with those who do not — would be a valuable next step.
The investigators, Edelmayer, and Brown reported no relevant conflicts of interest. A version of this article first appeared on Medscape.com.
Patients with breast cancer who undergo chemotherapy may face an increased risk for brain atrophy and cognitive decline, new findings from a pilot study suggest.
Memory problems in patients with cancer may not stem solely from stress or anxiety related to their diagnosis but could reflect underlying changes in brain structure, study investigator Paul Edison, PhD, MPhil, professor of neuroscience and clinical professor of neurology at Imperial College London, England, told this news organization.
While the findings suggest that chemotherapy may contribute to neuronal damage, the researchers noted that many aspects of the relationship between treatment and brain changes remain unclear.
Edison highlighted three key areas that require further investigation — uncovering the mechanisms driving brain atrophy, determining the proportion of patients affected, and identifying effective prevention strategies.
Another investigator on the study, Laura Kenny, MD, PhD, associate professor and consultant medical oncologist at Imperial College London, noted that the issue has received limited attention to date but expressed hope that the findings will raise awareness and encourage further research, given its clinical importance.
The findings were presented on July 29 at the Alzheimer’s Association International Conference (AAIC) 2025.
Investigating Cognitive Impact
Advances in chemotherapeutic agents have improved survival rates in patients with cancer. However, challenges persist regarding the long-term impact of these drugs.
Chemotherapy-associated cognitive impairment, often referred to as “brain fog” or “chemobrain,” affects approximately one third of patients with breast cancer following treatment.
While cognitive decline resolves within 12 months for some patients, others experience persistent effects that may elevate the risk for neurodegenerative conditions, Edison explained.
To evaluate the impact of chemotherapy on the brain, investigators studied 328 women with nonmetastatic breast cancer who had undergone chemotherapy within the past 12 months.
Patients received either anthracycline — a drug derived from the Streptomyces peucetius bacterium — or taxanes such as docetaxel and paclitaxel, both commonly used in breast cancer treatment, or a combination of these agents. In addition, some patients may also have had hormone therapy at some point during treatment, said Kenny.
Participants completed neurocognitive prescreening tests every 3 months using a specialized artificial intelligence–driven platform, allowing them to take detailed memory assessments online from home.
Among those prescreened, 18 individuals with lower neurocognitive scores (mean age, 55 years) and 19 cognitively normal control individuals without breast cancer (mean age, 67 years) underwent comprehensive, in-person, neurocognitive evaluations and MRI scans.
Researchers analyzed the scans using region of interest (ROI) and voxel-based morphometry (VBM), which uses sophisticated computer software, to assess gray matter volumes and surface areas.
The ROI analysis revealed significant reductions in gray matter volume (measured in mm3) and surface area (measured in mm2) among patients experiencing chemobrain, particularly affecting the isthmus cingulate and pars opercularis, with changes extending into the orbitofrontal and temporal regions.
Significant Atrophy
The VBM analysis confirmed significant atrophy in the frontal, parietal, and cingulate regions of patients with chemobrain compared with control individuals (P < .05). Edison noted that this pattern overlaps with brain changes typically observed in Alzheimer’s disease and vascular cognitive impairment.
For both analyses, “we demonstrated there is some amount of shrinkage in the brain among patients with chemobrain,” he said. “The fact that controls are older means the results are even more significant as there’s more brain atrophy as people age.”
Some of the affected brain regions may be linked to impaired memory, a hallmark of Alzheimer’s disease, but Edison cautioned that given the small sample size this finding should be interpreted with caution.
While the analysis demonstrated overall lower brain volumes in patients with “chemobrain” compared with controls, Edison emphasized that this finding reflects a single time point and does not indicate brain shrinkage over time.
Other events, including stroke — can also cause brain changes.
Edison highlighted the importance of determining the significance of these brain changes, how they affect patients and whether they can be prevented.
In-person neurocognitive testing revealed significantly reduced semantic and verbal fluency, as well as lower Mini-Mental State Examination scores in patients with chemobrain. Edison noted that these results support the MRI findings.
The team plans to follow patients to track brain changes and memory recovery, Kenny said. While patients with breast cancer are a common focus, the researchers intend to expand the study to other cancers in both men and women, said Kenny.
Based on discussions with her oncology colleagues, Kenny noted that many patients anecdotally report experiencing memory problems during chemotherapy.
More Research Needed
Commenting for this news organization, Rebecca M. Edelmayer, PhD, vice president, scientific engagement, at the Alzheimer’s Association, said the research may help shed light on why women are more likely to develop dementia than men.
For years now, experts have been trying to figure out what puts women at higher risk for AD and other dementias, said Edelmayer.
“We still don’t understand whether this involves biologically driven risk factors or socially driven risk factors.”
Research linking treatments for other health conditions to increased memory problems may offer some clues, she noted, suggesting a potential avenue for further investigation into the intersection of chemotherapy and neurodegenerative diseases such as Alzheimer’s.
However, Edelmayer emphasized that this line of research is still in its infancy. Much more work is needed to determine whether there is a direct cause-and-effect relationship with specific chemotherapy drugs, and whether some patients may already be predisposed or at higher risk for cognitive decline, she said.
Also commenting for this news organization, Eric Brown, MD, associate scientist and associate chief of geriatric psychiatry at the Centre for Addiction and Mental Health in Toronto, raised concerns about the study’s design.
One issue, he noted, is that the researchers did not image all patients who received chemotherapy but instead selected those with the most significant cognitive impairment. As a result, the findings may not have reflected outcomes in the average post-chemotherapy patients but rather represent the most severely affected subgroup.
Brown pointed out that the study did not clarify whether this subgroup had comorbid conditions. It’s possible, he said, that some individuals may have had Alzheimer’s disease or other forms of dementia unrelated to chemotherapy.
He agreed that tracking longitudinal changes in both cognitive scores and neuroimaging — comparing patients who receive chemotherapy with those who do not — would be a valuable next step.
The investigators, Edelmayer, and Brown reported no relevant conflicts of interest. A version of this article first appeared on Medscape.com.
FROM AAIC 2025
Gestational Eclampsia Linked to Fivefold Epilepsy Risk
Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.
The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.
“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.
The findings were published online in JAMA Neurology.
Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.
“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.
The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.
Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.
Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.
The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.
Fivefold Epilepsy Risk
Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).
Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.
Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.
The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.
“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.
In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”
Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.
Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).
Common Vascular Component
The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.
“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.
The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.
The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.
Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.
This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.
She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.
Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.
In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.
“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.
Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.
As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.
The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.
The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.
“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.
The findings were published online in JAMA Neurology.
Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.
“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.
The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.
Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.
Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.
The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.
Fivefold Epilepsy Risk
Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).
Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.
Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.
The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.
“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.
In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”
Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.
Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).
Common Vascular Component
The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.
“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.
The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.
The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.
Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.
This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.
She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.
Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.
In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.
“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.
Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.
As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.
The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.
The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.
“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.
The findings were published online in JAMA Neurology.
Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.
“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.
The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.
Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.
Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.
The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.
Fivefold Epilepsy Risk
Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).
Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.
Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.
The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.
“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.
In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”
Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.
Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).
Common Vascular Component
The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.
“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.
The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.
The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.
Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.
This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.
She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.
Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.
In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.
“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.
Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.
As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.
The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM JAMA NEUROLOGY
Brain Changes in Youth Who Use Substances: Cause or Effect?
A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.
But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.
The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests
The findings were published online in JAMA Network Open.
Neuroanatomy a Predisposing Risk Factor?
Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.
To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.
The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.
Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.
The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.
Significant Brain Differences
Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10–8), total intracranial (beta = 0.04; P = 3.49 × 10−6), cortical (beta = 0.05; P = 4.31 × 10–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10–7).
The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.
The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.
Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.
Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.
Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.
The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”
Associations Precede Substance Use
A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.
“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.
A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.
The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.
“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.
Reevaluating Causal Assumptions
In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.
Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”
The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.
Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.
“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”
The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.
The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.
But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.
The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests
The findings were published online in JAMA Network Open.
Neuroanatomy a Predisposing Risk Factor?
Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.
To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.
The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.
Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.
The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.
Significant Brain Differences
Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10–8), total intracranial (beta = 0.04; P = 3.49 × 10−6), cortical (beta = 0.05; P = 4.31 × 10–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10–7).
The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.
The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.
Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.
Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.
Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.
The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”
Associations Precede Substance Use
A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.
“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.
A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.
The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.
“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.
Reevaluating Causal Assumptions
In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.
Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”
The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.
Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.
“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”
The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.
The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.
But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.
The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests
The findings were published online in JAMA Network Open.
Neuroanatomy a Predisposing Risk Factor?
Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.
To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.
The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.
Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.
The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.
Significant Brain Differences
Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10–8), total intracranial (beta = 0.04; P = 3.49 × 10−6), cortical (beta = 0.05; P = 4.31 × 10–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10–7).
The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.
The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.
Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.
Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.
Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.
The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”
Associations Precede Substance Use
A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.
“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.
A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.
The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.
“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.
Reevaluating Causal Assumptions
In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.
Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”
The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.
Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.
“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”
The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.
The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Common Gut Infection Tied to Alzheimer’s Disease
Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).
Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.
“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.
The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.
“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.
The study was published on December 19, 2024, in Alzheimer’s & Dementia.
Vagus Nerve a Potential Pathway?
CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.
It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.
Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.
The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.
The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.
Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.
From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.
They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.
The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.
Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.
HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.
This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”
The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.
“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.
Accelerated AD Pathology
The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.
As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.
In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.
But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”
Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.
Tipping the Balance
A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.
Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”
Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”
Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”
The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”
The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.
The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.
A version of this article first appeared on Medscape.com.
Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).
Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.
“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.
The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.
“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.
The study was published on December 19, 2024, in Alzheimer’s & Dementia.
Vagus Nerve a Potential Pathway?
CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.
It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.
Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.
The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.
The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.
Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.
From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.
They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.
The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.
Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.
HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.
This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”
The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.
“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.
Accelerated AD Pathology
The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.
As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.
In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.
But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”
Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.
Tipping the Balance
A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.
Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”
Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”
Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”
The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”
The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.
The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.
A version of this article first appeared on Medscape.com.
Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).
Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.
“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.
The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.
“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.
The study was published on December 19, 2024, in Alzheimer’s & Dementia.
Vagus Nerve a Potential Pathway?
CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.
It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.
Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.
The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.
The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.
Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.
From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.
They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.
The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.
Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.
HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.
This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”
The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.
“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.
Accelerated AD Pathology
The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.
As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.
In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.
But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”
Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.
Tipping the Balance
A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.
Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”
Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”
Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”
The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”
The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.
The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.
A version of this article first appeared on Medscape.com.
FROM ALZHEIMER’S & DEMENTIA
Angiotensin Receptor Blockers Cut Epilepsy Risk in Patients With Hypertension
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — (PSE), new research showed.
Investigators found angiotensin receptor blockers are better at cutting the PSE risk in individuals with high blood pressure than angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers.
The results suggested angiotensin receptor blockers could be a frontline strategy to proactively forestall development of epilepsy in patients with a history of stroke and hypertension, said the study’s co-lead investigator Giacomo Evangelista, MD, PhD, a resident in neurology at the Epilepsy Center at “G. d’Annunzio” University of Chieti-Pescara, Italy.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Stroke and Seizures Tightly Linked
Stroke is the most common cause of seizures in patients older than 60 years. About 6%-8% of new epilepsy diagnoses in older adult patients are associated with a brain ischemic event.
Hypertension is among the most common risk factors for both epilepsy and stroke. The European Society of Cardiology recommends ACE inhibitors and angiotensin receptor blockers be considered first-line hypertension treatments.
Angiotensin receptor blockers seem to provide a protective effect in terms of seizures in the general population, but their possible preventive role in PSE has not been clear.
The retrospective, observational study included 528 patients (mean age, 71.4 years; 57.19% men) with hypertension and ischemic stroke without a history of epilepsy.
Researchers divided patients into those who developed PSE during the 2-year follow-up and those who didn’t. The main outcome was incidence of PSE associated with angiotensin receptor blocker therapy compared with other antihypertensive drug classes (ACE inhibitors, calcium channel blockers, and beta blockers).
Of the total, 7.2% of patients developed PSE. The study found patients treated with an angiotensin receptor blockers had a lower risk for PSE (P = .009). PSE incidence was higher among patients receiving calcium channel blockers (P = .019) and beta blockers (P = .008), but ACE inhibitors did not appear to affect PSE risk.
Further analysis showed that patients taking a beta blocker were 120% more likely to develop PSE, and those taking a calcium channel blocker were 110% more likely to develop PSE than those taking an angiotensin receptor blocker. The corresponding comparison was 65% for those taking an ACE inhibitor.
Potential Mechanisms
Angiotensin receptor blockers block the angiotensin II type 1 receptor, which may lead to numerous neuroprotective benefits such as improved blood flow to the brain and less neuroinflammation. The blockage may also reduce epilepsy severity and seizure frequency.
ACE inhibitors work in the same system as angiotensin receptor blockers but don’t bind directly to the angiotensin receptor. Experts believe these drugs may lead to inflammation that raises the risk for PSE.
Calcium channel blockers and beta blockers may increase the likelihood of seizures by inducing excessive excitability in the brain, which can trigger seizures.
Other research presented at the meeting found that angiotensin receptor blockers reduce the risk for epilepsy in patients with hypertension even in the absence of stroke.
Using data from an US national administrative database, the retrospective cohort study included 2,261,964 eligible adult beneficiaries diagnosed with hypertension and dispensed at least one angiotensin receptor blocker, ACE inhibitor, beta blocker, or calcium channel blocker from 2010 to 2017.
The study found angiotensin receptor blockers were associated with lower epilepsy incidence than ACE inhibitors (hazard ratio [HR], 0.75; 95% CI, 0.58-0.96), beta blockers (HR, 0.70; 95% CI, 0.54-0.90), and calcium channel blockers (HR, 0.80; 95% CI, 0.61-1.04).
The effect was most robust for the angiotensin receptor blocker losartan and among patients with no preexisting stroke or cardiovascular conditions.
Researchers ran the analysis excluding stroke and the association was still there, said lead study author Kimford Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California. “People with hypertension who use angiotensin receptor blockers — even if they don’t have a stroke — are less likely to develop epilepsy than if they use other major anti-hypertensives.”
Exciting and Suggestive
These new studies are “exciting” and “very suggestive,” said Meador. “We don’t have any true antiepileptic drugs; we have antiseizure medications. If we could reduce the incidence of epilepsy, that would be a very big thing.”
But the research to date hasn’t been “definitive” and is subject to bias, he said. “What we really need is a large randomized controlled trial to see if this is real because any observational study in humans has the potential for confounding from unmeasured variables.”
If such a study does show the effect is real, “that would change clinical practice,” said Meador.
As angiotensin receptor blockers have anti-inflammatory effects, researchers are now investigating whether this class of drugs might be useful in other diseases linked to inflammation such as multiple sclerosis, said Meador.
Commenting on the research, Alain Zingraff Looti, MD, assistant professor of neurology and public health sciences, Penn State College of Medicine, Hershey, Pennsylvania, said this new research is “important” although still at a “very preliminary stage.”
As the studies so far have all been observational, “they showed an association, but that doesn’t mean causality,” said Looti. These studies just looked at known potential confounders, “and there may be some unknown confounders that could explain the association,” he added.
But he acknowledged the results make sense from a biological standpoint. He noted that infusing angiotensin receptor blockers into rats causes a “cascade reaction” leading to reduced inflammation in the brain and then to less epilepsy. “Inflammation plays a major role in several models of epilepsy,” he added.
While these new results are important, Looti, too, would like to see a randomized controlled trial to confirm the findings.
Looti and Meador reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
FROM AES 2024
‘Urgent Need’ to Examine Anti-Seizure Medication Pricing
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
LOS ANGELES — results of a new study showed.
These findings highlight an “urgent need” to examine ASM pricing, said study investigator Pradeep Javarayee, MD, MBA, assistant professor, Department of Neurology, Medical College of Wisconsin, Milwaukee.
“The price disparity between generic and brand-name anti-seizure medications is growing,” said Javarayee. “Understanding these trends is essential for clinicians to make cost-conscious prescribing decisions and to advocate for policies that ensure equitable access to treatment for patients with epilepsy.”
The findings were presented at American Epilepsy Society (AES) 78th Annual Meeting 2024.
Concerning Trends
Researchers analyzed prices of ASMs using National Average Drug Acquisition Cost (NADAC) data provided by the Centers for Medicare & Medicaid Services from November 2013 to July 2023.
A publicly available resource, NADAC is widely regarded as the most reliable benchmark for drug reimbursement in the United States, said Javarayee. It is based on the price/unit of Medicaid-covered outpatient drugs collected though monthly surveys of retail community pharmacies across the United States.
The database includes medication names, strengths, formulations, and National Drug Codes.
The study examined 23 US Food and Drug Administration–approved ASMs, encompassing 223 oral formulations, which included 112 brand-name and 111 generic products.
To account for inflation, researchers adjusted ASM prices using the Consumer Price Index for Medicinal Drugs–Seasonally Adjusted. They also explored the effects of the COVID-19 pandemic on drug pricing.
The study uncovered trends that Javarayee found concerning. For example, between 2013 and 2023, the average price of brand-name ASMs increased from $8.71 to $15.43, whereas the average price of generic ASMs decreased from $1.39 to $1.26.
Most generic ASMs remained in the low-cost range ($0-$0.25) during the study period, whereas the proportion of higher-priced brand-name ASMs ($10-$50) increased.
The number of brand-name ASMs with a mean price exceeding $15 rose from two (2013-2016) to six (2017-2019) and then to eight (2020-2023).
Unsustainable Price Increases
The study uncovered examples of what Javarayee called “extreme” price differences. For instance, matched brand-name and generic ASMs with price differences of 1000%-9999% increased from 32.88% in 2013-2016 to 41.43% in 2020-2023.
Among brand-name ASMs, cenobamate (Xcopri), which is approved in the United States for partial-onset seizures, had the highest mean price between 2020 and 2023 ($35.59). For generic ASMs, topiramate had the highest mean price in the same time period ($6.64).
Looking at formulation-based cost differences, the study found generic immediate-release formulations were significantly cheaper than extended-release or delayed-release counterparts, with cost differences reaching as high as 7751.20%.
The study also showed the COVID-19 pandemic led to a 24.4% increase in brand-name ASM prices and a 23.1% decrease in generic ASM prices.
The results underscore the need to raise awareness of drug pricing dynamics and call for targeted policy interventions to alleviate the rising cost burden on patients, said Javarayee.
He emphasized that such price increases are unsustainable. “Addressing these disparities is critical not only for improving patient adherence and outcomes but also for reducing the overall economic strain on the healthcare system.”
‘Tip of the Iceberg’
Reached for a comment, Tim Welty, a pharmacist in Des Moines, Iowa, who specializes in epilepsy drugs, agreed that the issue of medication costs needs to be addressed.
“I absolutely think physicians and others need to advocate for transparency in pricing,” he said. It’s not unusual for physician requests to have newer ASMs covered for their patients to be denied, he added.
Welty also noted Congress is currently considering bills that address the lack of transparency in the way medications are reimbursed.
This new study doesn’t reveal what patients are paying for their medications, he said. “These data tell me the national average of the cost to the pharmacy, but don’t tell me what the patient is actually paying, or what the insurance companies are actually paying for these medications.”
A “hot topic” in the industry is the role of pharmacy benefit managers, who are contracted by health insurance companies to manage medication portfolios, in influencing drug prices.
Drug pricing is a complicated topic. “There’s a lot more behind this; this is just like a tip of the iceberg,” said Welty.
Also commenting, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center, New York City, said the much higher ASM prices are “very problematic,” particularly for drugs that don’t have a generic.
“I wonder how much the drugs for orphan indications, which are usually higher priced, influenced the numbers.”
The good news, though, is that many people “can safely take generics if they’re available,” said French.
The investigators and Welty reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM AES 2024
Women Largely Unaware of Anti-Seizure Med Risks, More Education Needed
LOS ANGELES — The majority of women with epilepsy are inadequately educated about the potential risks associated with anti-seizure medications (ASMs), which include teratogenicity and a reduction in the efficacy of hormonal birth control, early results of a new survey suggested.
In addition, only about a third of survey respondents indicated that they were taking folic acid if pregnant or planning to be or using an effective contraceptive if they wanted to avoid pregnancy.
“Physicians should see it as inside their scope to ask about the family planning aspect of things because it’s relevant to their patients’ neurologic care,” first study author Tori Valachovic, a fourth-year medical student at the University of Rochester School of Medicine, New York, told this news organization.
She noted patients may be taking ASMs not just for seizures but potentially to manage migraines or a mood disorder.
The findings were presented on December 8 at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Unique Survey
Research shows that about half of pregnancies in the United States are unplanned, and the number is even higher among people with epilepsy, said senior author Sarah Betstadt, MD, associate professor of obstetrics and gynecology, University of Rochester. That may be because women aren’t appropriately counseled about ASMs, possibly reducing the effectiveness of their hormonal birth control, she said.
The American Academy of Neurology recommends women with seizure disorders who could become pregnant receive yearly counseling about reproductive health, including ASM teratogenicity and interactions with hormonal contraceptive medications.
The study included 107 women aged 18-49 years at two general neurology outpatient clinics who were taking an ASM and completed a survey between July 2023 and May 2024. Of these, six were pregnant or planning to become pregnant, and 69 were using a barrier, hormonal, or implant form of contraception.
Researchers collected medical histories for each respondent, including how long they had had a seizure disorder, how often they experienced seizures, what anti-seizure drugs they were taking, the type of birth control they used, their pregnancy intentions, and whether they were taking folic acid.
The survey was unique in that questions were personalized. Previous surveys have asked general questions, but for the current survey, patients were required to input their specific ASM and specific birth control, so it was also a test of their knowledge of their specific medications, said Valachovic.
When responding to questions about the safety of their ASMs for pregnancy or whether there were interactions between ASMs and birth control, about two thirds (67.3%) of the participants answered at least one question incorrectly.
The study found 36.2% of those using a barrier, hormonal, or implant contraceptive answered at least one question incorrectly regarding whether their ASM decreased birth control effectiveness.
ASMs such as carbamazepine, phenytoin, phenobarbital, higher doses of topiramate (over 200 mg daily), and oxcarbazepine can make hormonal contraceptives such as pills, patches, and rings less effective, noted Valachovic.
There’s also a bidirectional relationship at play, she added. Hormonal contraceptives can make ASMs such as lamotrigine, valproate, zonisamide, and rufinamide less effective because they decrease the levels of the ASMs.
For questions specifically about the teratogenicity of their medications, about 56.1% of participants did not answer correctly.
ASMs that increase the risk for birth defects include valproic acid (a drug that would be at the top of the list), topiramate, carbamazepine, phenobarbital, and phenytoin, said Valachovic.
However, she added, “It’s a little bit more nuanced” than simply saying, “Don’t take this medication during pregnancy” because the first aim is to control seizures. “Uncontrolled seizures are more dangerous for the fetus and the expectant mother than any ASM,” she explained.
Neurologists and reproductive healthcare providers should work together to better disseminate relevant information to their female patients who could become pregnant, said Betstadt. “We need to have better ways to collaborate. And I think we have to start with educating neurologists,” who care for these women throughout their journey with epilepsy and who during that time may become pregnant.
They “should be talking to their patients annually about whether they plan to be pregnant,” so they can educate them and make them aware of dangers to the fetus with certain medications and the effect of ASMs on birth control, added Betstadt, whose practice focuses on complex family planning.
“Our hope is that patients will have better care that’s in line with their reproductive goals,” she said.
No Trickle-Down Effect
Commenting for this news organization, Alison M. Pack, MD, professor of neurology and Epilepsy Division Chief, Columbia University, New York City, said the study underlines an important quandary: Despite guidelines on risks of combining ASMs and hormonal birth control, this information doesn’t seem to be “trickling down” to women with epilepsy.
“I think part of it is just the state of healthcare delivery these days,” where clinicians are expected to accomplish more and more within a 20-30–minute follow-up visit. It’s tough, too, to keep up with all the potential drug interactions involved with newer ASMs, she said.
“I also think it speaks to the complexity” of healthcare for young women with epilepsy, which involves not just neurologists but obstetricians, gynecologists, and primary care doctors, she added.
Pack doesn’t think epilepsy specialists “integrate” enough with these other specialties. “You need to communicate with the gynecologist; you need to open that line of communication.”
She believes advanced practice providers could play a role in reducing the complexity of treating young women with epilepsy by regularly reviewing how patients are adhering to recommended protocols.
But she pointed out that “in the overall picture, most women with epilepsy do have normal, healthy pregnancies.”
The investigators and Pack reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
LOS ANGELES — The majority of women with epilepsy are inadequately educated about the potential risks associated with anti-seizure medications (ASMs), which include teratogenicity and a reduction in the efficacy of hormonal birth control, early results of a new survey suggested.
In addition, only about a third of survey respondents indicated that they were taking folic acid if pregnant or planning to be or using an effective contraceptive if they wanted to avoid pregnancy.
“Physicians should see it as inside their scope to ask about the family planning aspect of things because it’s relevant to their patients’ neurologic care,” first study author Tori Valachovic, a fourth-year medical student at the University of Rochester School of Medicine, New York, told this news organization.
She noted patients may be taking ASMs not just for seizures but potentially to manage migraines or a mood disorder.
The findings were presented on December 8 at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Unique Survey
Research shows that about half of pregnancies in the United States are unplanned, and the number is even higher among people with epilepsy, said senior author Sarah Betstadt, MD, associate professor of obstetrics and gynecology, University of Rochester. That may be because women aren’t appropriately counseled about ASMs, possibly reducing the effectiveness of their hormonal birth control, she said.
The American Academy of Neurology recommends women with seizure disorders who could become pregnant receive yearly counseling about reproductive health, including ASM teratogenicity and interactions with hormonal contraceptive medications.
The study included 107 women aged 18-49 years at two general neurology outpatient clinics who were taking an ASM and completed a survey between July 2023 and May 2024. Of these, six were pregnant or planning to become pregnant, and 69 were using a barrier, hormonal, or implant form of contraception.
Researchers collected medical histories for each respondent, including how long they had had a seizure disorder, how often they experienced seizures, what anti-seizure drugs they were taking, the type of birth control they used, their pregnancy intentions, and whether they were taking folic acid.
The survey was unique in that questions were personalized. Previous surveys have asked general questions, but for the current survey, patients were required to input their specific ASM and specific birth control, so it was also a test of their knowledge of their specific medications, said Valachovic.
When responding to questions about the safety of their ASMs for pregnancy or whether there were interactions between ASMs and birth control, about two thirds (67.3%) of the participants answered at least one question incorrectly.
The study found 36.2% of those using a barrier, hormonal, or implant contraceptive answered at least one question incorrectly regarding whether their ASM decreased birth control effectiveness.
ASMs such as carbamazepine, phenytoin, phenobarbital, higher doses of topiramate (over 200 mg daily), and oxcarbazepine can make hormonal contraceptives such as pills, patches, and rings less effective, noted Valachovic.
There’s also a bidirectional relationship at play, she added. Hormonal contraceptives can make ASMs such as lamotrigine, valproate, zonisamide, and rufinamide less effective because they decrease the levels of the ASMs.
For questions specifically about the teratogenicity of their medications, about 56.1% of participants did not answer correctly.
ASMs that increase the risk for birth defects include valproic acid (a drug that would be at the top of the list), topiramate, carbamazepine, phenobarbital, and phenytoin, said Valachovic.
However, she added, “It’s a little bit more nuanced” than simply saying, “Don’t take this medication during pregnancy” because the first aim is to control seizures. “Uncontrolled seizures are more dangerous for the fetus and the expectant mother than any ASM,” she explained.
Neurologists and reproductive healthcare providers should work together to better disseminate relevant information to their female patients who could become pregnant, said Betstadt. “We need to have better ways to collaborate. And I think we have to start with educating neurologists,” who care for these women throughout their journey with epilepsy and who during that time may become pregnant.
They “should be talking to their patients annually about whether they plan to be pregnant,” so they can educate them and make them aware of dangers to the fetus with certain medications and the effect of ASMs on birth control, added Betstadt, whose practice focuses on complex family planning.
“Our hope is that patients will have better care that’s in line with their reproductive goals,” she said.
No Trickle-Down Effect
Commenting for this news organization, Alison M. Pack, MD, professor of neurology and Epilepsy Division Chief, Columbia University, New York City, said the study underlines an important quandary: Despite guidelines on risks of combining ASMs and hormonal birth control, this information doesn’t seem to be “trickling down” to women with epilepsy.
“I think part of it is just the state of healthcare delivery these days,” where clinicians are expected to accomplish more and more within a 20-30–minute follow-up visit. It’s tough, too, to keep up with all the potential drug interactions involved with newer ASMs, she said.
“I also think it speaks to the complexity” of healthcare for young women with epilepsy, which involves not just neurologists but obstetricians, gynecologists, and primary care doctors, she added.
Pack doesn’t think epilepsy specialists “integrate” enough with these other specialties. “You need to communicate with the gynecologist; you need to open that line of communication.”
She believes advanced practice providers could play a role in reducing the complexity of treating young women with epilepsy by regularly reviewing how patients are adhering to recommended protocols.
But she pointed out that “in the overall picture, most women with epilepsy do have normal, healthy pregnancies.”
The investigators and Pack reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
LOS ANGELES — The majority of women with epilepsy are inadequately educated about the potential risks associated with anti-seizure medications (ASMs), which include teratogenicity and a reduction in the efficacy of hormonal birth control, early results of a new survey suggested.
In addition, only about a third of survey respondents indicated that they were taking folic acid if pregnant or planning to be or using an effective contraceptive if they wanted to avoid pregnancy.
“Physicians should see it as inside their scope to ask about the family planning aspect of things because it’s relevant to their patients’ neurologic care,” first study author Tori Valachovic, a fourth-year medical student at the University of Rochester School of Medicine, New York, told this news organization.
She noted patients may be taking ASMs not just for seizures but potentially to manage migraines or a mood disorder.
The findings were presented on December 8 at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Unique Survey
Research shows that about half of pregnancies in the United States are unplanned, and the number is even higher among people with epilepsy, said senior author Sarah Betstadt, MD, associate professor of obstetrics and gynecology, University of Rochester. That may be because women aren’t appropriately counseled about ASMs, possibly reducing the effectiveness of their hormonal birth control, she said.
The American Academy of Neurology recommends women with seizure disorders who could become pregnant receive yearly counseling about reproductive health, including ASM teratogenicity and interactions with hormonal contraceptive medications.
The study included 107 women aged 18-49 years at two general neurology outpatient clinics who were taking an ASM and completed a survey between July 2023 and May 2024. Of these, six were pregnant or planning to become pregnant, and 69 were using a barrier, hormonal, or implant form of contraception.
Researchers collected medical histories for each respondent, including how long they had had a seizure disorder, how often they experienced seizures, what anti-seizure drugs they were taking, the type of birth control they used, their pregnancy intentions, and whether they were taking folic acid.
The survey was unique in that questions were personalized. Previous surveys have asked general questions, but for the current survey, patients were required to input their specific ASM and specific birth control, so it was also a test of their knowledge of their specific medications, said Valachovic.
When responding to questions about the safety of their ASMs for pregnancy or whether there were interactions between ASMs and birth control, about two thirds (67.3%) of the participants answered at least one question incorrectly.
The study found 36.2% of those using a barrier, hormonal, or implant contraceptive answered at least one question incorrectly regarding whether their ASM decreased birth control effectiveness.
ASMs such as carbamazepine, phenytoin, phenobarbital, higher doses of topiramate (over 200 mg daily), and oxcarbazepine can make hormonal contraceptives such as pills, patches, and rings less effective, noted Valachovic.
There’s also a bidirectional relationship at play, she added. Hormonal contraceptives can make ASMs such as lamotrigine, valproate, zonisamide, and rufinamide less effective because they decrease the levels of the ASMs.
For questions specifically about the teratogenicity of their medications, about 56.1% of participants did not answer correctly.
ASMs that increase the risk for birth defects include valproic acid (a drug that would be at the top of the list), topiramate, carbamazepine, phenobarbital, and phenytoin, said Valachovic.
However, she added, “It’s a little bit more nuanced” than simply saying, “Don’t take this medication during pregnancy” because the first aim is to control seizures. “Uncontrolled seizures are more dangerous for the fetus and the expectant mother than any ASM,” she explained.
Neurologists and reproductive healthcare providers should work together to better disseminate relevant information to their female patients who could become pregnant, said Betstadt. “We need to have better ways to collaborate. And I think we have to start with educating neurologists,” who care for these women throughout their journey with epilepsy and who during that time may become pregnant.
They “should be talking to their patients annually about whether they plan to be pregnant,” so they can educate them and make them aware of dangers to the fetus with certain medications and the effect of ASMs on birth control, added Betstadt, whose practice focuses on complex family planning.
“Our hope is that patients will have better care that’s in line with their reproductive goals,” she said.
No Trickle-Down Effect
Commenting for this news organization, Alison M. Pack, MD, professor of neurology and Epilepsy Division Chief, Columbia University, New York City, said the study underlines an important quandary: Despite guidelines on risks of combining ASMs and hormonal birth control, this information doesn’t seem to be “trickling down” to women with epilepsy.
“I think part of it is just the state of healthcare delivery these days,” where clinicians are expected to accomplish more and more within a 20-30–minute follow-up visit. It’s tough, too, to keep up with all the potential drug interactions involved with newer ASMs, she said.
“I also think it speaks to the complexity” of healthcare for young women with epilepsy, which involves not just neurologists but obstetricians, gynecologists, and primary care doctors, she added.
Pack doesn’t think epilepsy specialists “integrate” enough with these other specialties. “You need to communicate with the gynecologist; you need to open that line of communication.”
She believes advanced practice providers could play a role in reducing the complexity of treating young women with epilepsy by regularly reviewing how patients are adhering to recommended protocols.
But she pointed out that “in the overall picture, most women with epilepsy do have normal, healthy pregnancies.”
The investigators and Pack reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM AES 2024
Few Focal Epilepsy Cases Controlled by Initial ASM Treatment
LOS ANGELES — Only about 27% of patients newly diagnosed with focal epilepsy are seizure-free on initial anti-seizure medications (ASMs), new research suggested.
This is sobering information to pass on to patients with focal epilepsy who may have high expectations based on prior data. “Patients tend to expect things to happen quickly, said study investigator Sarah Barnard, MD, a research fellow at the School of Translational Medicine, Monash University, Melbourne, Australia.
The study was presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
An International Collaboration
The study is part of the International Human Epilepsy Project (HEP), which focuses on new-onset focal epilepsy, one of the most common forms of the disorder. The researchers are aiming to identify factors that influence treatment response in this population.
For example, they will investigate how specific medications and coexisting conditions affect treatment outcomes. Ultimately, the goal is to enable the development of individualized treatment plans for patients, leading to faster and more effective improvements or potential cures for the condition.
“The investigators wanted to focus in on focal epilepsy and exclude patients with more severe phenotypes, such as those with developmental delays or significant brain injury,” said Barnard. Individuals with focal epilepsy are generally healthy, she added.
In addition, previous studies may have used differing definitions of seizure freedom, said Barnard.
The study included 448 patients, median age about 33 years and 60% women, with focal epilepsy who were enrolled at 34 tertiary epilepsy centers in the United States, Europe, and Australia within 4 months of initiating ASM treatment.
Participants were followed for up to 6 years (the median was 3.13 years). The median age at seizure onset was 29 years, and the median age of treatment initiation was 32 years. The most common first-line ASMs were levetiracetam (56.9%) and lamotrigine (16.5%).
Researchers used updated International League Against Epilepsy definitions. Seizure freedom is defined as no seizures for 12 months or three times the longest pretreatment seizure-free interval, whichever is longer.
Results showed that only 27% of patients were seizure-free in the first year after diagnosis even accounting for a 2-month “medication adjustment” period.
Managing Expectations
Although the study excluded individuals with more severe types of epilepsy, “we still identified a substantial proportion of treatment-resistant cases, suggesting that much more complex factors are at play,” said Jacqueline French, MD, a study coinvestigator and professor at the NYU Langone’s Comprehensive Epilepsy Center in New York City.
“I don’t think we adequately prepare our patients for the challenges of the first year, which can be quite turbulent,” French said.
However, the seizure freedom rate in this study is lower than previous estimates. “It’s much less than what was predicted in other studies, some of which quote around 50%-55% seizure freedom on the first ASM,” said Barnard.
It’s not clear why there’s such a difference, although it may be related to a predominance in the HEP study of patients taking levetiracetam as the first-line ASM. “We didn’t directly look at the rate of treatment response or seizure freedom on levetiracetam,” which is something that will be addressed in a follow-up study, Barnard added.
The difference could be due to the study including only focal epilepsy patients, “who usually have a different treatment regime,” or it could be related to using updated definitions in this study, she said.
Results also showed that patients are at high risk during the first year of treatment, with two thirds experiencing ongoing or worsening seizures during this period. “People have ongoing seizures for the first year, even if they go on to become seizure-free,” Barnard noted.
Experiencing ongoing seizures has potential implications for driving and for employment, she added.
A self-reported history of a psychological disorder was a risk factor for increased treatment resistance. Upon enrollment, each participant completed the Mini International Neuropsychiatric Interview, which Barnard said is a diagnostic, rather than a screening, tool.
One of the team’s next research steps is to look more closely at the role of depression, anxiety, bipolar disorder, and suicidality on treatment response in this patient population, said Barnard.
Important for Patient Counseling
Commenting on the research, Patrick Kwan, MD, PhD, professor, Department of Neuroscience, Monash University, said the research is “very important” in terms of patient counseling.
“For someone newly diagnosed with epilepsy, starting the first medication can be both daunting and confusing, with many uncertainties,” said Kwan. “That’s why it’s valuable to know that nearly a third of patients may not respond to initial treatment.”
He noted that the patients in the study were recruited from major centers, which could attract a specific subset of individuals. “It’s possible that this patient population might represent more severe cases,” he explained.
Kwan also emphasized that the study did not examine the “patterns” of prescription drug choices, adding that he agreed this should be addressed in future analyses.
The researchers and Kwan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
LOS ANGELES — Only about 27% of patients newly diagnosed with focal epilepsy are seizure-free on initial anti-seizure medications (ASMs), new research suggested.
This is sobering information to pass on to patients with focal epilepsy who may have high expectations based on prior data. “Patients tend to expect things to happen quickly, said study investigator Sarah Barnard, MD, a research fellow at the School of Translational Medicine, Monash University, Melbourne, Australia.
The study was presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
An International Collaboration
The study is part of the International Human Epilepsy Project (HEP), which focuses on new-onset focal epilepsy, one of the most common forms of the disorder. The researchers are aiming to identify factors that influence treatment response in this population.
For example, they will investigate how specific medications and coexisting conditions affect treatment outcomes. Ultimately, the goal is to enable the development of individualized treatment plans for patients, leading to faster and more effective improvements or potential cures for the condition.
“The investigators wanted to focus in on focal epilepsy and exclude patients with more severe phenotypes, such as those with developmental delays or significant brain injury,” said Barnard. Individuals with focal epilepsy are generally healthy, she added.
In addition, previous studies may have used differing definitions of seizure freedom, said Barnard.
The study included 448 patients, median age about 33 years and 60% women, with focal epilepsy who were enrolled at 34 tertiary epilepsy centers in the United States, Europe, and Australia within 4 months of initiating ASM treatment.
Participants were followed for up to 6 years (the median was 3.13 years). The median age at seizure onset was 29 years, and the median age of treatment initiation was 32 years. The most common first-line ASMs were levetiracetam (56.9%) and lamotrigine (16.5%).
Researchers used updated International League Against Epilepsy definitions. Seizure freedom is defined as no seizures for 12 months or three times the longest pretreatment seizure-free interval, whichever is longer.
Results showed that only 27% of patients were seizure-free in the first year after diagnosis even accounting for a 2-month “medication adjustment” period.
Managing Expectations
Although the study excluded individuals with more severe types of epilepsy, “we still identified a substantial proportion of treatment-resistant cases, suggesting that much more complex factors are at play,” said Jacqueline French, MD, a study coinvestigator and professor at the NYU Langone’s Comprehensive Epilepsy Center in New York City.
“I don’t think we adequately prepare our patients for the challenges of the first year, which can be quite turbulent,” French said.
However, the seizure freedom rate in this study is lower than previous estimates. “It’s much less than what was predicted in other studies, some of which quote around 50%-55% seizure freedom on the first ASM,” said Barnard.
It’s not clear why there’s such a difference, although it may be related to a predominance in the HEP study of patients taking levetiracetam as the first-line ASM. “We didn’t directly look at the rate of treatment response or seizure freedom on levetiracetam,” which is something that will be addressed in a follow-up study, Barnard added.
The difference could be due to the study including only focal epilepsy patients, “who usually have a different treatment regime,” or it could be related to using updated definitions in this study, she said.
Results also showed that patients are at high risk during the first year of treatment, with two thirds experiencing ongoing or worsening seizures during this period. “People have ongoing seizures for the first year, even if they go on to become seizure-free,” Barnard noted.
Experiencing ongoing seizures has potential implications for driving and for employment, she added.
A self-reported history of a psychological disorder was a risk factor for increased treatment resistance. Upon enrollment, each participant completed the Mini International Neuropsychiatric Interview, which Barnard said is a diagnostic, rather than a screening, tool.
One of the team’s next research steps is to look more closely at the role of depression, anxiety, bipolar disorder, and suicidality on treatment response in this patient population, said Barnard.
Important for Patient Counseling
Commenting on the research, Patrick Kwan, MD, PhD, professor, Department of Neuroscience, Monash University, said the research is “very important” in terms of patient counseling.
“For someone newly diagnosed with epilepsy, starting the first medication can be both daunting and confusing, with many uncertainties,” said Kwan. “That’s why it’s valuable to know that nearly a third of patients may not respond to initial treatment.”
He noted that the patients in the study were recruited from major centers, which could attract a specific subset of individuals. “It’s possible that this patient population might represent more severe cases,” he explained.
Kwan also emphasized that the study did not examine the “patterns” of prescription drug choices, adding that he agreed this should be addressed in future analyses.
The researchers and Kwan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
LOS ANGELES — Only about 27% of patients newly diagnosed with focal epilepsy are seizure-free on initial anti-seizure medications (ASMs), new research suggested.
This is sobering information to pass on to patients with focal epilepsy who may have high expectations based on prior data. “Patients tend to expect things to happen quickly, said study investigator Sarah Barnard, MD, a research fellow at the School of Translational Medicine, Monash University, Melbourne, Australia.
The study was presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
An International Collaboration
The study is part of the International Human Epilepsy Project (HEP), which focuses on new-onset focal epilepsy, one of the most common forms of the disorder. The researchers are aiming to identify factors that influence treatment response in this population.
For example, they will investigate how specific medications and coexisting conditions affect treatment outcomes. Ultimately, the goal is to enable the development of individualized treatment plans for patients, leading to faster and more effective improvements or potential cures for the condition.
“The investigators wanted to focus in on focal epilepsy and exclude patients with more severe phenotypes, such as those with developmental delays or significant brain injury,” said Barnard. Individuals with focal epilepsy are generally healthy, she added.
In addition, previous studies may have used differing definitions of seizure freedom, said Barnard.
The study included 448 patients, median age about 33 years and 60% women, with focal epilepsy who were enrolled at 34 tertiary epilepsy centers in the United States, Europe, and Australia within 4 months of initiating ASM treatment.
Participants were followed for up to 6 years (the median was 3.13 years). The median age at seizure onset was 29 years, and the median age of treatment initiation was 32 years. The most common first-line ASMs were levetiracetam (56.9%) and lamotrigine (16.5%).
Researchers used updated International League Against Epilepsy definitions. Seizure freedom is defined as no seizures for 12 months or three times the longest pretreatment seizure-free interval, whichever is longer.
Results showed that only 27% of patients were seizure-free in the first year after diagnosis even accounting for a 2-month “medication adjustment” period.
Managing Expectations
Although the study excluded individuals with more severe types of epilepsy, “we still identified a substantial proportion of treatment-resistant cases, suggesting that much more complex factors are at play,” said Jacqueline French, MD, a study coinvestigator and professor at the NYU Langone’s Comprehensive Epilepsy Center in New York City.
“I don’t think we adequately prepare our patients for the challenges of the first year, which can be quite turbulent,” French said.
However, the seizure freedom rate in this study is lower than previous estimates. “It’s much less than what was predicted in other studies, some of which quote around 50%-55% seizure freedom on the first ASM,” said Barnard.
It’s not clear why there’s such a difference, although it may be related to a predominance in the HEP study of patients taking levetiracetam as the first-line ASM. “We didn’t directly look at the rate of treatment response or seizure freedom on levetiracetam,” which is something that will be addressed in a follow-up study, Barnard added.
The difference could be due to the study including only focal epilepsy patients, “who usually have a different treatment regime,” or it could be related to using updated definitions in this study, she said.
Results also showed that patients are at high risk during the first year of treatment, with two thirds experiencing ongoing or worsening seizures during this period. “People have ongoing seizures for the first year, even if they go on to become seizure-free,” Barnard noted.
Experiencing ongoing seizures has potential implications for driving and for employment, she added.
A self-reported history of a psychological disorder was a risk factor for increased treatment resistance. Upon enrollment, each participant completed the Mini International Neuropsychiatric Interview, which Barnard said is a diagnostic, rather than a screening, tool.
One of the team’s next research steps is to look more closely at the role of depression, anxiety, bipolar disorder, and suicidality on treatment response in this patient population, said Barnard.
Important for Patient Counseling
Commenting on the research, Patrick Kwan, MD, PhD, professor, Department of Neuroscience, Monash University, said the research is “very important” in terms of patient counseling.
“For someone newly diagnosed with epilepsy, starting the first medication can be both daunting and confusing, with many uncertainties,” said Kwan. “That’s why it’s valuable to know that nearly a third of patients may not respond to initial treatment.”
He noted that the patients in the study were recruited from major centers, which could attract a specific subset of individuals. “It’s possible that this patient population might represent more severe cases,” he explained.
Kwan also emphasized that the study did not examine the “patterns” of prescription drug choices, adding that he agreed this should be addressed in future analyses.
The researchers and Kwan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AES 2024
Smart Mattress to Reduce SUDEP?
LOS ANGELES — says one of the experts involved in its development.
When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.
In addition, early results from an observational study are backing this up, he said.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Most SUDEP Cases Found Face Down
SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.
About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.
“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.
Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.
“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.
However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”
Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”
There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.
Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.
The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.
If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.
Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.
Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.
The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.
Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.
Big Step Forward
Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”
The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.
However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”
Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”
However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”
He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”
The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
LOS ANGELES — says one of the experts involved in its development.
When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.
In addition, early results from an observational study are backing this up, he said.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Most SUDEP Cases Found Face Down
SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.
About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.
“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.
Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.
“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.
However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”
Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”
There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.
Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.
The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.
If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.
Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.
Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.
The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.
Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.
Big Step Forward
Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”
The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.
However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”
Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”
However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”
He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”
The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
LOS ANGELES — says one of the experts involved in its development.
When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.
In addition, early results from an observational study are backing this up, he said.
The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.
Most SUDEP Cases Found Face Down
SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.
About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.
“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.
Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.
“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.
However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”
Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”
There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.
Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.
The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.
If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.
Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.
Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.
The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.
Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.
Big Step Forward
Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”
The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.
However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”
Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”
However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”
He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”
The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM AES 2024
Experts Challenge New Diagnostic Criteria for Alzheimer’s disease
In a paper published online in JAMA Neurology, the International Working Group (IWG), which includes 46 experts from 17 countries, is recommending that the diagnosis of Alzheimer’s disease be limited to individuals with mild cognitive impairment or dementia and not be applied to cognitively normal individuals with Alzheimer’s disease biomarkers such as amyloid-beta 42/40 or p-tau.
Clinicians should be “very careful” about using the “A” word (Alzheimer’s) for cognitively unimpaired people with Alzheimer’s disease biomarkers, said the paper’s first author Bruno Dubois, MD, professor of neurology, Sorbonne University and Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
Providing an Alzheimer’s disease diagnosis to those who have a high chance of never developing cognitive impairment can be psychologically harmful, said Dubois.
“It’s not something small like telling someone they have a fever. Just imagine you’re 65 years old and are amyloid positive, and you’re told you have Alzheimer’s disease. It affects the decisions you make for the rest of your life and changes your vision of your future, even though you may never develop the disease,” he added.
Divergent View
The IWG’s perspective on Alzheimer’s disease contrasts with a recent proposal from the Alzheimer’s Association. The Alzheimer’s Association criteria suggest that Alzheimer’s disease should be regarded solely as a biological entity, which could include cognitively normal individuals with one core Alzheimer’s disease biomarker.
The IWG noted that its concerns regarding the application of a purely biological definition of Alzheimer’s disease in clinical practice prompted the group to consider updating its guidelines, potentially offering “an alternative definitional view of Alzheimer’s disease as a clinical-biological construct for clinical use.”
The group conducted a PubMed search for relevant Alzheimer’s disease articles, and included references, published between July 2020 and March 2024. The research showed the majority of biomarker-positive, cognitively normal individuals will not become symptomatic during their lifetime.
The risk of a 55-year-old who is amyloid positive developing Alzheimer’s disease is not that much higher than that for an individual of a similar age who is amyloid negative, Dubois noted. “There’s an 83% chance that person will never develop Alzheimer’s disease.”
Disclosing a diagnosis of Alzheimer’s disease to cognitively normal people with only one core Alzheimer’s disease biomarker represents “the most problematic implication of a purely biological definition of the disease,” the authors noted.
“A biomarker is a marker of pathology, not a biomarker of disease,” said Dubois, adding that a person may have markers for several different brain diseases.
The IWG recommends the following nomenclature: At risk for Alzheimer’s disease for those with Alzheimer’s disease biomarkers but low lifetime risk and presymptomatic Alzheimer’s disease for those with Alzheimer’s disease biomarkers with a very high lifetime risk for progression such as individuals with autosomal dominant genetic mutations and other distinct biomarker profiles that put them at extremely high lifetime risk of developing the disease.
Dubois emphasized the difference between those showing typical Alzheimer’s disease symptoms with positive biomarkers who should be considered to have the disease and those with positive biomarkers but no typical Alzheimer’s disease symptoms who should be considered at risk.
This is an important distinction as it affects research approaches and assessment of risks, he said.
For low-risk asymptomatic individuals, the IWG does not recommend routine diagnostic testing outside of the research setting. “There’s no reason to send a 65-year-old cognitively normal subject off to collect biomarker information,” said Dubois.
He reiterated the importance of clinicians using appropriate and sensitive language surrounding Alzheimer’s disease when face to face with patients. This issue “is not purely semantic; this is real life.”
For these patients in the clinical setting, “we have to be very careful about proposing treatments that may have side effects,” he said.
However, this does not mean asymptomatic at-risk people should not be studied to determine what pharmacological interventions might prevent or delay the onset of clinical disease, he noted.
Presymptomatic individuals who are at a high risk of developing Alzheimer’s disease “should be the target for clinical trials in the future” to determine best ways to delay the conversion to Alzheimer’s disease, he said.
The main focus of such research should be to better understand the “biomarker pattern profile” that is associated with a high risk of developing Alzheimer’s disease, said Dubois.
Plea for Unity
In an accompanying editorial, Ronald C. Petersen, PhD, MD, director, Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging, Rochester, Minnesota, and colleagues outline the difference between the IWG and Alzheimer’s Association positions.
As the IWG uses Alzheimer’s disease to define those with cognitive impairment and the Alzheimer’s Association group uses Alzheimer’s disease to define those with the pathology of the disease, the field is now at a crossroads. “Do we name the disease before clinical symptoms?” they asked.
They note that Alzheimer’s Association criteria distinguish between a disease and an illness, whereas the IWG does not. “As such, although the primary disagreement between the groups is semantic, the ramifications of the labeling can be significant.”
It is “incumbent” that the field “come together” on an Alzheimer’s disease definition, the editorial concluded. “Neither the Alzheimer’s Association or IWG documents are appropriate to serve as a guide for how to apply biomarkers in a clinical setting. Appropriate-use criteria are needed to form a bridge between biological frameworks and real-world clinical practice so we can all maximally help all of our patients with this disorder.”
In a comment, Reisa Sperling, MD, professor of neurology, Harvard Medical School, and director, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital and Massachusetts General Hospital, all in Boston, who is part of the Alzheimer’s Association work group that published the revised criteria for diagnosis and staging of Alzheimer’s disease, likened Alzheimer’s disease, which begins in the brain many years before dementia onset, to cardiovascular disease in that it involves multiple processes. She noted the World Health Organization classifies cardiovascular disease as a “disease” prior to clinical manifestations such as stroke and myocardial infarction.
“If someone has Alzheimer’s disease pathology in their brain, they are at risk for dementia or clinical manifestations of the disease — just like vascular disease quantifies the risk of stroke or heart attack, not risk of developing ‘vascular disease’ if the underlying vascular disease is already present,” said Sperling.
A large part of the controversy is related to terminology and the “stigma” of the “A” word in the same way there used to be fear around using the “C” word — cancer, said Sperling.
“Once people began talking about cancer publicly as a potentially treatable disease and began getting screened and diagnosed before symptoms of cancer were manifest, this has had a tremendous impact on public health.”
She clarified that her work group does not recommend screening asymptomatic people with Alzheimer’s disease biomarkers. “We actually need to prove that treating at the preclinical stage of the disease is able to prevent clinical impairment and dementia,” she said, adding “hopefully, we are getting closer to this.”
Dubois reported no relevant disclosures. Petersen reported receiving personal fees from Roche, Genentech, Eli Lilly and Company, Eisai, and Novo Nordisk outside the submitted work and royalties from Oxford University Press, UpToDate, and Medscape educational activities.
A version of this article appeared on Medscape.com.
In a paper published online in JAMA Neurology, the International Working Group (IWG), which includes 46 experts from 17 countries, is recommending that the diagnosis of Alzheimer’s disease be limited to individuals with mild cognitive impairment or dementia and not be applied to cognitively normal individuals with Alzheimer’s disease biomarkers such as amyloid-beta 42/40 or p-tau.
Clinicians should be “very careful” about using the “A” word (Alzheimer’s) for cognitively unimpaired people with Alzheimer’s disease biomarkers, said the paper’s first author Bruno Dubois, MD, professor of neurology, Sorbonne University and Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
Providing an Alzheimer’s disease diagnosis to those who have a high chance of never developing cognitive impairment can be psychologically harmful, said Dubois.
“It’s not something small like telling someone they have a fever. Just imagine you’re 65 years old and are amyloid positive, and you’re told you have Alzheimer’s disease. It affects the decisions you make for the rest of your life and changes your vision of your future, even though you may never develop the disease,” he added.
Divergent View
The IWG’s perspective on Alzheimer’s disease contrasts with a recent proposal from the Alzheimer’s Association. The Alzheimer’s Association criteria suggest that Alzheimer’s disease should be regarded solely as a biological entity, which could include cognitively normal individuals with one core Alzheimer’s disease biomarker.
The IWG noted that its concerns regarding the application of a purely biological definition of Alzheimer’s disease in clinical practice prompted the group to consider updating its guidelines, potentially offering “an alternative definitional view of Alzheimer’s disease as a clinical-biological construct for clinical use.”
The group conducted a PubMed search for relevant Alzheimer’s disease articles, and included references, published between July 2020 and March 2024. The research showed the majority of biomarker-positive, cognitively normal individuals will not become symptomatic during their lifetime.
The risk of a 55-year-old who is amyloid positive developing Alzheimer’s disease is not that much higher than that for an individual of a similar age who is amyloid negative, Dubois noted. “There’s an 83% chance that person will never develop Alzheimer’s disease.”
Disclosing a diagnosis of Alzheimer’s disease to cognitively normal people with only one core Alzheimer’s disease biomarker represents “the most problematic implication of a purely biological definition of the disease,” the authors noted.
“A biomarker is a marker of pathology, not a biomarker of disease,” said Dubois, adding that a person may have markers for several different brain diseases.
The IWG recommends the following nomenclature: At risk for Alzheimer’s disease for those with Alzheimer’s disease biomarkers but low lifetime risk and presymptomatic Alzheimer’s disease for those with Alzheimer’s disease biomarkers with a very high lifetime risk for progression such as individuals with autosomal dominant genetic mutations and other distinct biomarker profiles that put them at extremely high lifetime risk of developing the disease.
Dubois emphasized the difference between those showing typical Alzheimer’s disease symptoms with positive biomarkers who should be considered to have the disease and those with positive biomarkers but no typical Alzheimer’s disease symptoms who should be considered at risk.
This is an important distinction as it affects research approaches and assessment of risks, he said.
For low-risk asymptomatic individuals, the IWG does not recommend routine diagnostic testing outside of the research setting. “There’s no reason to send a 65-year-old cognitively normal subject off to collect biomarker information,” said Dubois.
He reiterated the importance of clinicians using appropriate and sensitive language surrounding Alzheimer’s disease when face to face with patients. This issue “is not purely semantic; this is real life.”
For these patients in the clinical setting, “we have to be very careful about proposing treatments that may have side effects,” he said.
However, this does not mean asymptomatic at-risk people should not be studied to determine what pharmacological interventions might prevent or delay the onset of clinical disease, he noted.
Presymptomatic individuals who are at a high risk of developing Alzheimer’s disease “should be the target for clinical trials in the future” to determine best ways to delay the conversion to Alzheimer’s disease, he said.
The main focus of such research should be to better understand the “biomarker pattern profile” that is associated with a high risk of developing Alzheimer’s disease, said Dubois.
Plea for Unity
In an accompanying editorial, Ronald C. Petersen, PhD, MD, director, Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging, Rochester, Minnesota, and colleagues outline the difference between the IWG and Alzheimer’s Association positions.
As the IWG uses Alzheimer’s disease to define those with cognitive impairment and the Alzheimer’s Association group uses Alzheimer’s disease to define those with the pathology of the disease, the field is now at a crossroads. “Do we name the disease before clinical symptoms?” they asked.
They note that Alzheimer’s Association criteria distinguish between a disease and an illness, whereas the IWG does not. “As such, although the primary disagreement between the groups is semantic, the ramifications of the labeling can be significant.”
It is “incumbent” that the field “come together” on an Alzheimer’s disease definition, the editorial concluded. “Neither the Alzheimer’s Association or IWG documents are appropriate to serve as a guide for how to apply biomarkers in a clinical setting. Appropriate-use criteria are needed to form a bridge between biological frameworks and real-world clinical practice so we can all maximally help all of our patients with this disorder.”
In a comment, Reisa Sperling, MD, professor of neurology, Harvard Medical School, and director, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital and Massachusetts General Hospital, all in Boston, who is part of the Alzheimer’s Association work group that published the revised criteria for diagnosis and staging of Alzheimer’s disease, likened Alzheimer’s disease, which begins in the brain many years before dementia onset, to cardiovascular disease in that it involves multiple processes. She noted the World Health Organization classifies cardiovascular disease as a “disease” prior to clinical manifestations such as stroke and myocardial infarction.
“If someone has Alzheimer’s disease pathology in their brain, they are at risk for dementia or clinical manifestations of the disease — just like vascular disease quantifies the risk of stroke or heart attack, not risk of developing ‘vascular disease’ if the underlying vascular disease is already present,” said Sperling.
A large part of the controversy is related to terminology and the “stigma” of the “A” word in the same way there used to be fear around using the “C” word — cancer, said Sperling.
“Once people began talking about cancer publicly as a potentially treatable disease and began getting screened and diagnosed before symptoms of cancer were manifest, this has had a tremendous impact on public health.”
She clarified that her work group does not recommend screening asymptomatic people with Alzheimer’s disease biomarkers. “We actually need to prove that treating at the preclinical stage of the disease is able to prevent clinical impairment and dementia,” she said, adding “hopefully, we are getting closer to this.”
Dubois reported no relevant disclosures. Petersen reported receiving personal fees from Roche, Genentech, Eli Lilly and Company, Eisai, and Novo Nordisk outside the submitted work and royalties from Oxford University Press, UpToDate, and Medscape educational activities.
A version of this article appeared on Medscape.com.
In a paper published online in JAMA Neurology, the International Working Group (IWG), which includes 46 experts from 17 countries, is recommending that the diagnosis of Alzheimer’s disease be limited to individuals with mild cognitive impairment or dementia and not be applied to cognitively normal individuals with Alzheimer’s disease biomarkers such as amyloid-beta 42/40 or p-tau.
Clinicians should be “very careful” about using the “A” word (Alzheimer’s) for cognitively unimpaired people with Alzheimer’s disease biomarkers, said the paper’s first author Bruno Dubois, MD, professor of neurology, Sorbonne University and Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
Providing an Alzheimer’s disease diagnosis to those who have a high chance of never developing cognitive impairment can be psychologically harmful, said Dubois.
“It’s not something small like telling someone they have a fever. Just imagine you’re 65 years old and are amyloid positive, and you’re told you have Alzheimer’s disease. It affects the decisions you make for the rest of your life and changes your vision of your future, even though you may never develop the disease,” he added.
Divergent View
The IWG’s perspective on Alzheimer’s disease contrasts with a recent proposal from the Alzheimer’s Association. The Alzheimer’s Association criteria suggest that Alzheimer’s disease should be regarded solely as a biological entity, which could include cognitively normal individuals with one core Alzheimer’s disease biomarker.
The IWG noted that its concerns regarding the application of a purely biological definition of Alzheimer’s disease in clinical practice prompted the group to consider updating its guidelines, potentially offering “an alternative definitional view of Alzheimer’s disease as a clinical-biological construct for clinical use.”
The group conducted a PubMed search for relevant Alzheimer’s disease articles, and included references, published between July 2020 and March 2024. The research showed the majority of biomarker-positive, cognitively normal individuals will not become symptomatic during their lifetime.
The risk of a 55-year-old who is amyloid positive developing Alzheimer’s disease is not that much higher than that for an individual of a similar age who is amyloid negative, Dubois noted. “There’s an 83% chance that person will never develop Alzheimer’s disease.”
Disclosing a diagnosis of Alzheimer’s disease to cognitively normal people with only one core Alzheimer’s disease biomarker represents “the most problematic implication of a purely biological definition of the disease,” the authors noted.
“A biomarker is a marker of pathology, not a biomarker of disease,” said Dubois, adding that a person may have markers for several different brain diseases.
The IWG recommends the following nomenclature: At risk for Alzheimer’s disease for those with Alzheimer’s disease biomarkers but low lifetime risk and presymptomatic Alzheimer’s disease for those with Alzheimer’s disease biomarkers with a very high lifetime risk for progression such as individuals with autosomal dominant genetic mutations and other distinct biomarker profiles that put them at extremely high lifetime risk of developing the disease.
Dubois emphasized the difference between those showing typical Alzheimer’s disease symptoms with positive biomarkers who should be considered to have the disease and those with positive biomarkers but no typical Alzheimer’s disease symptoms who should be considered at risk.
This is an important distinction as it affects research approaches and assessment of risks, he said.
For low-risk asymptomatic individuals, the IWG does not recommend routine diagnostic testing outside of the research setting. “There’s no reason to send a 65-year-old cognitively normal subject off to collect biomarker information,” said Dubois.
He reiterated the importance of clinicians using appropriate and sensitive language surrounding Alzheimer’s disease when face to face with patients. This issue “is not purely semantic; this is real life.”
For these patients in the clinical setting, “we have to be very careful about proposing treatments that may have side effects,” he said.
However, this does not mean asymptomatic at-risk people should not be studied to determine what pharmacological interventions might prevent or delay the onset of clinical disease, he noted.
Presymptomatic individuals who are at a high risk of developing Alzheimer’s disease “should be the target for clinical trials in the future” to determine best ways to delay the conversion to Alzheimer’s disease, he said.
The main focus of such research should be to better understand the “biomarker pattern profile” that is associated with a high risk of developing Alzheimer’s disease, said Dubois.
Plea for Unity
In an accompanying editorial, Ronald C. Petersen, PhD, MD, director, Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging, Rochester, Minnesota, and colleagues outline the difference between the IWG and Alzheimer’s Association positions.
As the IWG uses Alzheimer’s disease to define those with cognitive impairment and the Alzheimer’s Association group uses Alzheimer’s disease to define those with the pathology of the disease, the field is now at a crossroads. “Do we name the disease before clinical symptoms?” they asked.
They note that Alzheimer’s Association criteria distinguish between a disease and an illness, whereas the IWG does not. “As such, although the primary disagreement between the groups is semantic, the ramifications of the labeling can be significant.”
It is “incumbent” that the field “come together” on an Alzheimer’s disease definition, the editorial concluded. “Neither the Alzheimer’s Association or IWG documents are appropriate to serve as a guide for how to apply biomarkers in a clinical setting. Appropriate-use criteria are needed to form a bridge between biological frameworks and real-world clinical practice so we can all maximally help all of our patients with this disorder.”
In a comment, Reisa Sperling, MD, professor of neurology, Harvard Medical School, and director, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital and Massachusetts General Hospital, all in Boston, who is part of the Alzheimer’s Association work group that published the revised criteria for diagnosis and staging of Alzheimer’s disease, likened Alzheimer’s disease, which begins in the brain many years before dementia onset, to cardiovascular disease in that it involves multiple processes. She noted the World Health Organization classifies cardiovascular disease as a “disease” prior to clinical manifestations such as stroke and myocardial infarction.
“If someone has Alzheimer’s disease pathology in their brain, they are at risk for dementia or clinical manifestations of the disease — just like vascular disease quantifies the risk of stroke or heart attack, not risk of developing ‘vascular disease’ if the underlying vascular disease is already present,” said Sperling.
A large part of the controversy is related to terminology and the “stigma” of the “A” word in the same way there used to be fear around using the “C” word — cancer, said Sperling.
“Once people began talking about cancer publicly as a potentially treatable disease and began getting screened and diagnosed before symptoms of cancer were manifest, this has had a tremendous impact on public health.”
She clarified that her work group does not recommend screening asymptomatic people with Alzheimer’s disease biomarkers. “We actually need to prove that treating at the preclinical stage of the disease is able to prevent clinical impairment and dementia,” she said, adding “hopefully, we are getting closer to this.”
Dubois reported no relevant disclosures. Petersen reported receiving personal fees from Roche, Genentech, Eli Lilly and Company, Eisai, and Novo Nordisk outside the submitted work and royalties from Oxford University Press, UpToDate, and Medscape educational activities.
A version of this article appeared on Medscape.com.
From JAMA Neurology