Neurology Reviews

Older adults who participate in even light physical activity (LPA) may have a lower risk of developing dementia, new research suggests.

In a retrospective analysis of more than 62,000 individuals aged 65 or older without preexisting dementia, 6% developed dementia.

Compared with inactive individuals, “insufficiently active,” “active,” and “highly active” individuals all had a 10%, 20%, and 28% lower risk for dementia, respectively. And this association was consistent regardless of age, sex, other comorbidities, or after the researchers censored for stroke.

Even the lowest amount of LPA was associated with reduced dementia risk, investigators noted.

“In older adults, an increased physical activity level, including a low amount of LPA, was associated with a reduced risk of dementia,” Minjae Yoon, MD, division of cardiology, Severance Cardiovascular Hospital, Yonsei University, Seoul, South Korea, and colleagues wrote.

“Promotion of LPA might reduce the risk of dementia in older adults,” they added.

The findings were published online in JAMA Network Open.
 

Reverse causation?

Physical activity has been shown previously to be associated with reduced dementia risk. Current World Health Organization guidelines recommend that adults with normal cognition should engage in PA to reduce their risk for cognitive decline.

However, some studies have not yielded this result, “suggesting that previous findings showing a lower risk of dementia in physically active people could be attributed to reverse causation,” the investigators noted. Additionally, previous research regarding exercise intensity has been “inconsistent” concerning the role of LPA in reducing dementia risk.

Many older adults with frailty and comorbidity cannot perform intense or even moderate PA, therefore “these adults would have to gain the benefits of physical activity from LPA,” the researchers noted.

To clarify the potential association between PA and new-onset dementia, they focused specifically on the “dose-response association” between PA and dementia – especially LPA.

Between 2009 and 2012, the investigators enrolled 62,286 older individuals (60.4% women; mean age, 73.2 years) with available health checkup data from the National Health Insurance Service–Senior Database of Korea. All had no history of dementia.

Leisure-time PA was assessed with self-report questionnaires that used a 7-day recall method and included three questions regarding usual frequency (in days per week):

• Vigorous PA (VPA) for at least 20 minutes
• Moderate-intensity PA (MPA) for at least 30 minutes 
• LPA for at least 30 minutes

VPA was defined as “intense exercise that caused severe shortness of breath, MPA was defined as activity causing mild shortness of breath, and LPA was defined as “walking at a slow or leisurely pace.”

PA-related energy expenditure was also calculated in metabolic equivalent (MET) minutes per week by “summing the product of frequency, intensity, and duration,” the investigators noted.

Participants were stratified on the basis of their weekly total PA levels into the following groups:

• Inactive (no LPA beyond basic movements)
• Insufficiently active (less than the recommended target range of 1-499 MET-min/wk)
• Active (meeting the recommended target range of 500-999 MET-min/wk)
• Highly active (exceeding the recommended target range of at least 1,000 MET-min/wk)

Of all participants, 35% were categorized as inactive, 25% were insufficiently active, 24.4% were active, and 15.2% were highly active.
 

Controversy remains

During the total median follow-up of 42 months, 6% of participants had all-cause dementia. After the researchers excluded the first 2 years, incidence of dementia was 21.6 per 1000 person-years during follow-up. 

“The cumulative incidence of dementia was associated with a progressively decreasing trend with increasing physical activity” (P = .001 for trend), the investigators reported.

When using a competing-risk multivariable regression model, they found that higher levels of PA were associated with lower risk for dementia, compared with the inactive group.

Similar findings were obtained after censoring for stroke, and were consistent for all follow-up periods. In subgroup analysis, the association between PA level and dementia risk remained consistent, regardless of age, sex, and comorbidities.

Even a low amount of LPA (1-299 MET-min/wk) was linked to reduced risk for dementia versus total sedentary behavior (adjusted HR, 0.86; 95% CI, 0.74-0.99).

The investigators noted that some “controversy” remains regarding the possibility of reverse causation and, because their study was observational in nature, “it cannot be used to establish causal relationship.”

Nevertheless, the study had important strengths, including the large number of older adults with available data, the assessment of dose-response association between PA and dementia, and the sensitivity analyses they performed, the researchers added.
 

Piece of important evidence

Commenting on the findings, Takashi Tarumi, PhD, senior research investigator, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan, said previous studies have suggested “an inverse association between physical activity and dementia risk, such that older adults performing a higher dose of exercise may have a greater benefit for reducing the dementia risk.”

Dr. Tarumi, an associate editor at the Journal of Alzheimer’s Disease, added the current study “significantly extends our knowledge by showing that dementia risk can also be reduced by light physical activities when they are performed for longer hours.”

This provides “another piece of important evidence” to support clinicians recommending regular physical activity for the prevention of dementia in later life, said Dr. Tarumi, who was not involved with the research.

Also commenting, Martin Underwood, MD, Warwick Medical School, Coventry, England, described the association between reduced physical inactivity and dementia as well established – and noted the current study “appears to confirm earlier observational data showing this relationship.” 

The current results have “still not been able to fully exclude the possibility of reverse causation,” said Dr. Underwood, who was also not associated with the study.

However, the finding that more physically active individuals are less likely to develop dementia “only becomes of real interest if we can show that increased physical activity prevents the onset, or slows the progression, of dementia,” he noted.

“To my knowledge this has not yet been established” in randomized clinical trials, Dr. Underwood added.

The study was supported by grants from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health & Welfare, Republic of Korea; and by a research grant from Yonsei University. One coauthor reported serving as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, and Daiichi-Sankyo, and receiving research funds from Medtronic and Abbott. No other author disclosures were reported. Dr. Tarumi and Dr. Underwood have disclosed no relevant financial relationships.

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

Older adults who participate in even light physical activity (LPA) may have a lower risk of developing dementia, new research suggests.

In a retrospective analysis of more than 62,000 individuals aged 65 or older without preexisting dementia, 6% developed dementia.

Compared with inactive individuals, “insufficiently active,” “active,” and “highly active” individuals all had a 10%, 20%, and 28% lower risk for dementia, respectively. And this association was consistent regardless of age, sex, other comorbidities, or after the researchers censored for stroke.

Even the lowest amount of LPA was associated with reduced dementia risk, investigators noted.

“In older adults, an increased physical activity level, including a low amount of LPA, was associated with a reduced risk of dementia,” Minjae Yoon, MD, division of cardiology, Severance Cardiovascular Hospital, Yonsei University, Seoul, South Korea, and colleagues wrote.

“Promotion of LPA might reduce the risk of dementia in older adults,” they added.

The findings were published online in JAMA Network Open.
 

Reverse causation?

Physical activity has been shown previously to be associated with reduced dementia risk. Current World Health Organization guidelines recommend that adults with normal cognition should engage in PA to reduce their risk for cognitive decline.

However, some studies have not yielded this result, “suggesting that previous findings showing a lower risk of dementia in physically active people could be attributed to reverse causation,” the investigators noted. Additionally, previous research regarding exercise intensity has been “inconsistent” concerning the role of LPA in reducing dementia risk.

Many older adults with frailty and comorbidity cannot perform intense or even moderate PA, therefore “these adults would have to gain the benefits of physical activity from LPA,” the researchers noted.

To clarify the potential association between PA and new-onset dementia, they focused specifically on the “dose-response association” between PA and dementia – especially LPA.

Between 2009 and 2012, the investigators enrolled 62,286 older individuals (60.4% women; mean age, 73.2 years) with available health checkup data from the National Health Insurance Service–Senior Database of Korea. All had no history of dementia.

Leisure-time PA was assessed with self-report questionnaires that used a 7-day recall method and included three questions regarding usual frequency (in days per week):

• Vigorous PA (VPA) for at least 20 minutes
• Moderate-intensity PA (MPA) for at least 30 minutes 
• LPA for at least 30 minutes

VPA was defined as “intense exercise that caused severe shortness of breath, MPA was defined as activity causing mild shortness of breath, and LPA was defined as “walking at a slow or leisurely pace.”

PA-related energy expenditure was also calculated in metabolic equivalent (MET) minutes per week by “summing the product of frequency, intensity, and duration,” the investigators noted.

Participants were stratified on the basis of their weekly total PA levels into the following groups:

• Inactive (no LPA beyond basic movements)
• Insufficiently active (less than the recommended target range of 1-499 MET-min/wk)
• Active (meeting the recommended target range of 500-999 MET-min/wk)
• Highly active (exceeding the recommended target range of at least 1,000 MET-min/wk)

Of all participants, 35% were categorized as inactive, 25% were insufficiently active, 24.4% were active, and 15.2% were highly active.
 

Controversy remains

During the total median follow-up of 42 months, 6% of participants had all-cause dementia. After the researchers excluded the first 2 years, incidence of dementia was 21.6 per 1000 person-years during follow-up. 

“The cumulative incidence of dementia was associated with a progressively decreasing trend with increasing physical activity” (P = .001 for trend), the investigators reported.

When using a competing-risk multivariable regression model, they found that higher levels of PA were associated with lower risk for dementia, compared with the inactive group.

Similar findings were obtained after censoring for stroke, and were consistent for all follow-up periods. In subgroup analysis, the association between PA level and dementia risk remained consistent, regardless of age, sex, and comorbidities.

Even a low amount of LPA (1-299 MET-min/wk) was linked to reduced risk for dementia versus total sedentary behavior (adjusted HR, 0.86; 95% CI, 0.74-0.99).

The investigators noted that some “controversy” remains regarding the possibility of reverse causation and, because their study was observational in nature, “it cannot be used to establish causal relationship.”

Nevertheless, the study had important strengths, including the large number of older adults with available data, the assessment of dose-response association between PA and dementia, and the sensitivity analyses they performed, the researchers added.
 

Piece of important evidence

Commenting on the findings, Takashi Tarumi, PhD, senior research investigator, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan, said previous studies have suggested “an inverse association between physical activity and dementia risk, such that older adults performing a higher dose of exercise may have a greater benefit for reducing the dementia risk.”

Dr. Tarumi, an associate editor at the Journal of Alzheimer’s Disease, added the current study “significantly extends our knowledge by showing that dementia risk can also be reduced by light physical activities when they are performed for longer hours.”

This provides “another piece of important evidence” to support clinicians recommending regular physical activity for the prevention of dementia in later life, said Dr. Tarumi, who was not involved with the research.

Also commenting, Martin Underwood, MD, Warwick Medical School, Coventry, England, described the association between reduced physical inactivity and dementia as well established – and noted the current study “appears to confirm earlier observational data showing this relationship.” 

The current results have “still not been able to fully exclude the possibility of reverse causation,” said Dr. Underwood, who was also not associated with the study.

However, the finding that more physically active individuals are less likely to develop dementia “only becomes of real interest if we can show that increased physical activity prevents the onset, or slows the progression, of dementia,” he noted.

“To my knowledge this has not yet been established” in randomized clinical trials, Dr. Underwood added.

The study was supported by grants from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health & Welfare, Republic of Korea; and by a research grant from Yonsei University. One coauthor reported serving as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, and Daiichi-Sankyo, and receiving research funds from Medtronic and Abbott. No other author disclosures were reported. Dr. Tarumi and Dr. Underwood have disclosed no relevant financial relationships.

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

Older adults who participate in even light physical activity (LPA) may have a lower risk of developing dementia, new research suggests.

In a retrospective analysis of more than 62,000 individuals aged 65 or older without preexisting dementia, 6% developed dementia.

Compared with inactive individuals, “insufficiently active,” “active,” and “highly active” individuals all had a 10%, 20%, and 28% lower risk for dementia, respectively. And this association was consistent regardless of age, sex, other comorbidities, or after the researchers censored for stroke.

Even the lowest amount of LPA was associated with reduced dementia risk, investigators noted.

“In older adults, an increased physical activity level, including a low amount of LPA, was associated with a reduced risk of dementia,” Minjae Yoon, MD, division of cardiology, Severance Cardiovascular Hospital, Yonsei University, Seoul, South Korea, and colleagues wrote.

“Promotion of LPA might reduce the risk of dementia in older adults,” they added.

The findings were published online in JAMA Network Open.
 

Reverse causation?

Physical activity has been shown previously to be associated with reduced dementia risk. Current World Health Organization guidelines recommend that adults with normal cognition should engage in PA to reduce their risk for cognitive decline.

However, some studies have not yielded this result, “suggesting that previous findings showing a lower risk of dementia in physically active people could be attributed to reverse causation,” the investigators noted. Additionally, previous research regarding exercise intensity has been “inconsistent” concerning the role of LPA in reducing dementia risk.

Many older adults with frailty and comorbidity cannot perform intense or even moderate PA, therefore “these adults would have to gain the benefits of physical activity from LPA,” the researchers noted.

To clarify the potential association between PA and new-onset dementia, they focused specifically on the “dose-response association” between PA and dementia – especially LPA.

Between 2009 and 2012, the investigators enrolled 62,286 older individuals (60.4% women; mean age, 73.2 years) with available health checkup data from the National Health Insurance Service–Senior Database of Korea. All had no history of dementia.

Leisure-time PA was assessed with self-report questionnaires that used a 7-day recall method and included three questions regarding usual frequency (in days per week):

• Vigorous PA (VPA) for at least 20 minutes
• Moderate-intensity PA (MPA) for at least 30 minutes 
• LPA for at least 30 minutes

VPA was defined as “intense exercise that caused severe shortness of breath, MPA was defined as activity causing mild shortness of breath, and LPA was defined as “walking at a slow or leisurely pace.”

PA-related energy expenditure was also calculated in metabolic equivalent (MET) minutes per week by “summing the product of frequency, intensity, and duration,” the investigators noted.

Participants were stratified on the basis of their weekly total PA levels into the following groups:

• Inactive (no LPA beyond basic movements)
• Insufficiently active (less than the recommended target range of 1-499 MET-min/wk)
• Active (meeting the recommended target range of 500-999 MET-min/wk)
• Highly active (exceeding the recommended target range of at least 1,000 MET-min/wk)

Of all participants, 35% were categorized as inactive, 25% were insufficiently active, 24.4% were active, and 15.2% were highly active.
 

Controversy remains

During the total median follow-up of 42 months, 6% of participants had all-cause dementia. After the researchers excluded the first 2 years, incidence of dementia was 21.6 per 1000 person-years during follow-up. 

“The cumulative incidence of dementia was associated with a progressively decreasing trend with increasing physical activity” (P = .001 for trend), the investigators reported.

When using a competing-risk multivariable regression model, they found that higher levels of PA were associated with lower risk for dementia, compared with the inactive group.

Similar findings were obtained after censoring for stroke, and were consistent for all follow-up periods. In subgroup analysis, the association between PA level and dementia risk remained consistent, regardless of age, sex, and comorbidities.

Even a low amount of LPA (1-299 MET-min/wk) was linked to reduced risk for dementia versus total sedentary behavior (adjusted HR, 0.86; 95% CI, 0.74-0.99).

The investigators noted that some “controversy” remains regarding the possibility of reverse causation and, because their study was observational in nature, “it cannot be used to establish causal relationship.”

Nevertheless, the study had important strengths, including the large number of older adults with available data, the assessment of dose-response association between PA and dementia, and the sensitivity analyses they performed, the researchers added.
 

Piece of important evidence

Commenting on the findings, Takashi Tarumi, PhD, senior research investigator, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan, said previous studies have suggested “an inverse association between physical activity and dementia risk, such that older adults performing a higher dose of exercise may have a greater benefit for reducing the dementia risk.”

Dr. Tarumi, an associate editor at the Journal of Alzheimer’s Disease, added the current study “significantly extends our knowledge by showing that dementia risk can also be reduced by light physical activities when they are performed for longer hours.”

This provides “another piece of important evidence” to support clinicians recommending regular physical activity for the prevention of dementia in later life, said Dr. Tarumi, who was not involved with the research.

Also commenting, Martin Underwood, MD, Warwick Medical School, Coventry, England, described the association between reduced physical inactivity and dementia as well established – and noted the current study “appears to confirm earlier observational data showing this relationship.” 

The current results have “still not been able to fully exclude the possibility of reverse causation,” said Dr. Underwood, who was also not associated with the study.

However, the finding that more physically active individuals are less likely to develop dementia “only becomes of real interest if we can show that increased physical activity prevents the onset, or slows the progression, of dementia,” he noted.

“To my knowledge this has not yet been established” in randomized clinical trials, Dr. Underwood added.

The study was supported by grants from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health & Welfare, Republic of Korea; and by a research grant from Yonsei University. One coauthor reported serving as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, and Daiichi-Sankyo, and receiving research funds from Medtronic and Abbott. No other author disclosures were reported. Dr. Tarumi and Dr. Underwood have disclosed no relevant financial relationships.

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

Phoenix has only a few months each year to use my hot tub, so winter is when I catch up on a lot of my reading. Recently I was reading the November Lancet, which had some interesting statistics about migraine.

• It’s the second leading cause (behind back pain) of years lived with disability.
• There are 10 million people with migraines in the United Kingdom (population roughly 70 million).
• In the last 5 years, migraine use of emergency rooms has increased 14%.
• According to the U.K. National Health Service, over 16,000 ER visits for migraine could be avoided.

These are compelling statistics, and probably (taking into account population differences) similar to numbers here in the United States or Canada.

Like all neurologists, I see my share of migraine.

Like many neurologists, I also get migraines. Not many, maybe 2-3 per month, effectively treated with a triptan. So I have a decent understanding that they aren’t pleasant.

Fortunately, migraine advances have been impressive, with seven new CGRP drugs in the last 3 years, bringing successful treatment closer for many.

But the problem is far from solved, a point that was driven home yesterday.

I awoke early yesterday morning with a migraine, and took an Imitrex. But instead of feeling better in an hour, it kept worsening until I was literally disabled by it. I took some Excedrin Migraine. The last time I had a migraine this bad was in 1998, during my fellowship, and my attending had to drive me home (thanks, Joe).

It was showing no signs of letting up. I thought about going to emergency department. After all, aren’t we trained for that when we hear “worst headache of my life?” but figured it was more likely just a migraine, and didn’t want to bog down my ED colleagues in the midst of another COVID-19 wave.

I took another Imitrex. I found a sample of Ubrelvy that I’d brought home out of curiosity, and took that, too. I think I have an old, nearly empty, bottle of Norco, somewhere, from a 2014 dental surgery, but was too photophobic to go looking for it (if I still have it at all).

I lay down in bed under the ceiling fan, and somehow fell asleep.

When I woke about 90 minutes later it was gone, like a switch had been flipped. Maybe it was all, or just one of, the meds I’d taken. I’ll never know. I could now resume my regularly scheduled program.

The migraine had cost me 7 hours. Like most small business owners, I’m trying to get all the year-end paperwork wrapped up, in addition to reviewing cases, writing up reports, and spending time with my family. So none of that happened that Saturday morning. If I’d had to see patients that morning there’s no way I could have done it.

Fortunately, as I said, that’s only the second time that’s happened to me, and it’s been 25 years since the last one.

But I’m lucky. There are those who have them far more frequently, limiting their ability to work, raise families, spend time with friends. … Have a life.

Migraine is far from a deadly disease. In neurology we treat far worse conditions. But in sheer numbers migraine affects far more people, and (indirectly) an even larger group of coworkers, parents, friends, and children who have to cover unpredictably when the other person is out with one.

For all of them, improved migraine treatment approaches can’t come soon enough.

Phoenix has only a few months each year to use my hot tub, so winter is when I catch up on a lot of my reading. Recently I was reading the November Lancet, which had some interesting statistics about migraine.

• It’s the second leading cause (behind back pain) of years lived with disability.
• There are 10 million people with migraines in the United Kingdom (population roughly 70 million).
• In the last 5 years, migraine use of emergency rooms has increased 14%.
• According to the U.K. National Health Service, over 16,000 ER visits for migraine could be avoided.

These are compelling statistics, and probably (taking into account population differences) similar to numbers here in the United States or Canada.

Like all neurologists, I see my share of migraine.

Like many neurologists, I also get migraines. Not many, maybe 2-3 per month, effectively treated with a triptan. So I have a decent understanding that they aren’t pleasant.

Fortunately, migraine advances have been impressive, with seven new CGRP drugs in the last 3 years, bringing successful treatment closer for many.

But the problem is far from solved, a point that was driven home yesterday.

I awoke early yesterday morning with a migraine, and took an Imitrex. But instead of feeling better in an hour, it kept worsening until I was literally disabled by it. I took some Excedrin Migraine. The last time I had a migraine this bad was in 1998, during my fellowship, and my attending had to drive me home (thanks, Joe).

It was showing no signs of letting up. I thought about going to emergency department. After all, aren’t we trained for that when we hear “worst headache of my life?” but figured it was more likely just a migraine, and didn’t want to bog down my ED colleagues in the midst of another COVID-19 wave.

I took another Imitrex. I found a sample of Ubrelvy that I’d brought home out of curiosity, and took that, too. I think I have an old, nearly empty, bottle of Norco, somewhere, from a 2014 dental surgery, but was too photophobic to go looking for it (if I still have it at all).

I lay down in bed under the ceiling fan, and somehow fell asleep.

When I woke about 90 minutes later it was gone, like a switch had been flipped. Maybe it was all, or just one of, the meds I’d taken. I’ll never know. I could now resume my regularly scheduled program.

The migraine had cost me 7 hours. Like most small business owners, I’m trying to get all the year-end paperwork wrapped up, in addition to reviewing cases, writing up reports, and spending time with my family. So none of that happened that Saturday morning. If I’d had to see patients that morning there’s no way I could have done it.

Fortunately, as I said, that’s only the second time that’s happened to me, and it’s been 25 years since the last one.

But I’m lucky. There are those who have them far more frequently, limiting their ability to work, raise families, spend time with friends. … Have a life.

Migraine is far from a deadly disease. In neurology we treat far worse conditions. But in sheer numbers migraine affects far more people, and (indirectly) an even larger group of coworkers, parents, friends, and children who have to cover unpredictably when the other person is out with one.

For all of them, improved migraine treatment approaches can’t come soon enough.

Phoenix has only a few months each year to use my hot tub, so winter is when I catch up on a lot of my reading. Recently I was reading the November Lancet, which had some interesting statistics about migraine.

• It’s the second leading cause (behind back pain) of years lived with disability.
• There are 10 million people with migraines in the United Kingdom (population roughly 70 million).
• In the last 5 years, migraine use of emergency rooms has increased 14%.
• According to the U.K. National Health Service, over 16,000 ER visits for migraine could be avoided.

These are compelling statistics, and probably (taking into account population differences) similar to numbers here in the United States or Canada.

Like all neurologists, I see my share of migraine.

Like many neurologists, I also get migraines. Not many, maybe 2-3 per month, effectively treated with a triptan. So I have a decent understanding that they aren’t pleasant.

Fortunately, migraine advances have been impressive, with seven new CGRP drugs in the last 3 years, bringing successful treatment closer for many.

But the problem is far from solved, a point that was driven home yesterday.

I awoke early yesterday morning with a migraine, and took an Imitrex. But instead of feeling better in an hour, it kept worsening until I was literally disabled by it. I took some Excedrin Migraine. The last time I had a migraine this bad was in 1998, during my fellowship, and my attending had to drive me home (thanks, Joe).

It was showing no signs of letting up. I thought about going to emergency department. After all, aren’t we trained for that when we hear “worst headache of my life?” but figured it was more likely just a migraine, and didn’t want to bog down my ED colleagues in the midst of another COVID-19 wave.

I took another Imitrex. I found a sample of Ubrelvy that I’d brought home out of curiosity, and took that, too. I think I have an old, nearly empty, bottle of Norco, somewhere, from a 2014 dental surgery, but was too photophobic to go looking for it (if I still have it at all).

I lay down in bed under the ceiling fan, and somehow fell asleep.

When I woke about 90 minutes later it was gone, like a switch had been flipped. Maybe it was all, or just one of, the meds I’d taken. I’ll never know. I could now resume my regularly scheduled program.

The migraine had cost me 7 hours. Like most small business owners, I’m trying to get all the year-end paperwork wrapped up, in addition to reviewing cases, writing up reports, and spending time with my family. So none of that happened that Saturday morning. If I’d had to see patients that morning there’s no way I could have done it.

Fortunately, as I said, that’s only the second time that’s happened to me, and it’s been 25 years since the last one.

But I’m lucky. There are those who have them far more frequently, limiting their ability to work, raise families, spend time with friends. … Have a life.

Migraine is far from a deadly disease. In neurology we treat far worse conditions. But in sheer numbers migraine affects far more people, and (indirectly) an even larger group of coworkers, parents, friends, and children who have to cover unpredictably when the other person is out with one.

For all of them, improved migraine treatment approaches can’t come soon enough.

The ophthalmologist credited with developing botulinum toxin (Botox) for medical use has died at the age of 89, his family confirmed to National Public Radio.

Four decades ago, Alan Brown Scott, MD, a native of Berkeley, Calif., turned the drug, once a deadly poison, into a revolutionary treatment for obscure eye diseases. It later became a well-known blockbuster treatment for reducing the appearance of wrinkles and treating hyperhidrosis (excessive sweating). Other approved medical uses include treatment of overactive bladder and urinary incontinence.

According to the American Society of Plastic Surgeons, its popularity for cosmetic use was boosted further during the pandemic and it was the No. 1 minimally invasive cosmetic procedure performed in 2020. Among the 13.3 million procedures, 4.4 million involved Botox.

According to Bloomberg Businessweek, Ed Schantz, who was working in the military’s biological weapons program, was the one to first send the toxin to Dr. Scott, who wanted to explore its properties for medical use.

The same Bloomberg article also noted that the original botulinum toxin itself “is so powerful that a tiny amount can suffocate a person by paralyzing the muscles used for breathing.”

Dr. Scott was looking for a way to help his patients avoid extensive surgeries.

“Specifically, he was aiming to treat people with strabismus, or cross-eyes, and blepharospasm, which is an uncontrollable closure of eyes. Today, it’s also used as a treatment to help with migraines, hair loss, and drooling,” NPR reported.

The New York Times once described Botox as “medicine’s answer to duct tape.”

Dr. Scott was the executive director of the Smith-Kettlewell Eye Research Institute in San Francisco when he did his pioneering research with botulinum toxin in the 1970s and 1980s, according to a 2002 article in SFGate.

In 1991, Dr. Scott sold the drug to Allergan, when it was called Oculinum. The next year, the name was officially changed to Botox.

In 2002, Dr. Scott told SFGate, when asked about the more popular use for the drug, “I think that’s a charming, slightly frivolous use,” adding, “but it’s not along the lines of what I was into, applications for serious disorders.”

According to Scientific American in 2016, Dr. Scott, then age 83, kept working on the noncosmetic benefits of botulism-toxin injections for eye-related disorders at the Strabismus Research Foundation,

He told Scientific American he was proud that his efforts “are directly helpful to people.”

“There are interesting and difficult problems still to be solved, and I’m a practicing physician and I see them every day,” he said.

Dr. Scott’s daughter, Ann Scott, told NPR: “He definitely loved his work and he was also a really great father.” She said her dad involved his children in his research and work.

She added, “He was a really calm, more of a quiet reserved person,” and said he was committed to teaching his students, many of them international students.

“That was what he really loved,” she said.

Dr. Scott, who died Dec. 16, was in intensive care for the last 10 days from an unspecified illness, his daughter told NPR.

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

The ophthalmologist credited with developing botulinum toxin (Botox) for medical use has died at the age of 89, his family confirmed to National Public Radio.

Four decades ago, Alan Brown Scott, MD, a native of Berkeley, Calif., turned the drug, once a deadly poison, into a revolutionary treatment for obscure eye diseases. It later became a well-known blockbuster treatment for reducing the appearance of wrinkles and treating hyperhidrosis (excessive sweating). Other approved medical uses include treatment of overactive bladder and urinary incontinence.

According to the American Society of Plastic Surgeons, its popularity for cosmetic use was boosted further during the pandemic and it was the No. 1 minimally invasive cosmetic procedure performed in 2020. Among the 13.3 million procedures, 4.4 million involved Botox.

According to Bloomberg Businessweek, Ed Schantz, who was working in the military’s biological weapons program, was the one to first send the toxin to Dr. Scott, who wanted to explore its properties for medical use.

The same Bloomberg article also noted that the original botulinum toxin itself “is so powerful that a tiny amount can suffocate a person by paralyzing the muscles used for breathing.”

Dr. Scott was looking for a way to help his patients avoid extensive surgeries.

“Specifically, he was aiming to treat people with strabismus, or cross-eyes, and blepharospasm, which is an uncontrollable closure of eyes. Today, it’s also used as a treatment to help with migraines, hair loss, and drooling,” NPR reported.

The New York Times once described Botox as “medicine’s answer to duct tape.”

Dr. Scott was the executive director of the Smith-Kettlewell Eye Research Institute in San Francisco when he did his pioneering research with botulinum toxin in the 1970s and 1980s, according to a 2002 article in SFGate.

In 1991, Dr. Scott sold the drug to Allergan, when it was called Oculinum. The next year, the name was officially changed to Botox.

In 2002, Dr. Scott told SFGate, when asked about the more popular use for the drug, “I think that’s a charming, slightly frivolous use,” adding, “but it’s not along the lines of what I was into, applications for serious disorders.”

According to Scientific American in 2016, Dr. Scott, then age 83, kept working on the noncosmetic benefits of botulism-toxin injections for eye-related disorders at the Strabismus Research Foundation,

He told Scientific American he was proud that his efforts “are directly helpful to people.”

“There are interesting and difficult problems still to be solved, and I’m a practicing physician and I see them every day,” he said.

Dr. Scott’s daughter, Ann Scott, told NPR: “He definitely loved his work and he was also a really great father.” She said her dad involved his children in his research and work.

She added, “He was a really calm, more of a quiet reserved person,” and said he was committed to teaching his students, many of them international students.

“That was what he really loved,” she said.

Dr. Scott, who died Dec. 16, was in intensive care for the last 10 days from an unspecified illness, his daughter told NPR.

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

The ophthalmologist credited with developing botulinum toxin (Botox) for medical use has died at the age of 89, his family confirmed to National Public Radio.

Four decades ago, Alan Brown Scott, MD, a native of Berkeley, Calif., turned the drug, once a deadly poison, into a revolutionary treatment for obscure eye diseases. It later became a well-known blockbuster treatment for reducing the appearance of wrinkles and treating hyperhidrosis (excessive sweating). Other approved medical uses include treatment of overactive bladder and urinary incontinence.

According to the American Society of Plastic Surgeons, its popularity for cosmetic use was boosted further during the pandemic and it was the No. 1 minimally invasive cosmetic procedure performed in 2020. Among the 13.3 million procedures, 4.4 million involved Botox.

According to Bloomberg Businessweek, Ed Schantz, who was working in the military’s biological weapons program, was the one to first send the toxin to Dr. Scott, who wanted to explore its properties for medical use.

The same Bloomberg article also noted that the original botulinum toxin itself “is so powerful that a tiny amount can suffocate a person by paralyzing the muscles used for breathing.”

Dr. Scott was looking for a way to help his patients avoid extensive surgeries.

“Specifically, he was aiming to treat people with strabismus, or cross-eyes, and blepharospasm, which is an uncontrollable closure of eyes. Today, it’s also used as a treatment to help with migraines, hair loss, and drooling,” NPR reported.

The New York Times once described Botox as “medicine’s answer to duct tape.”

Dr. Scott was the executive director of the Smith-Kettlewell Eye Research Institute in San Francisco when he did his pioneering research with botulinum toxin in the 1970s and 1980s, according to a 2002 article in SFGate.

In 1991, Dr. Scott sold the drug to Allergan, when it was called Oculinum. The next year, the name was officially changed to Botox.

In 2002, Dr. Scott told SFGate, when asked about the more popular use for the drug, “I think that’s a charming, slightly frivolous use,” adding, “but it’s not along the lines of what I was into, applications for serious disorders.”

According to Scientific American in 2016, Dr. Scott, then age 83, kept working on the noncosmetic benefits of botulism-toxin injections for eye-related disorders at the Strabismus Research Foundation,

He told Scientific American he was proud that his efforts “are directly helpful to people.”

“There are interesting and difficult problems still to be solved, and I’m a practicing physician and I see them every day,” he said.

Dr. Scott’s daughter, Ann Scott, told NPR: “He definitely loved his work and he was also a really great father.” She said her dad involved his children in his research and work.

She added, “He was a really calm, more of a quiet reserved person,” and said he was committed to teaching his students, many of them international students.

“That was what he really loved,” she said.

Dr. Scott, who died Dec. 16, was in intensive care for the last 10 days from an unspecified illness, his daughter told NPR.

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

Editors at the BMJ have released an urgent request to Facebook’s Mark Zuckerberg and parent company Meta regarding a recent “fact-check” on the medical trade journal’s article about questionable Pfizer vaccine trial practices.

According to an open letter written by outgoing BMJ editor-in-chief Fiona Godlee, MD, and incoming editor-in-chief Kamran Abbasi, MD, Facebook hired a third-party contractor to evaluate the article’s findings. This resulted in “inaccurate, incompetent, and irresponsible” conclusions that “should be of concern to anyone who values and relies on sources such as the BMJ for reliable medical information.”

The article in question investigated data integrity concerns at Pfizer vaccine clinical trial sites. In September 2020, the letter states, a former employee of the research group involved in Pfizer’s main vaccine trials, Ventavia, reached out to the BMJ and “began providing ... dozens of internal company documents, photos, audio recordings, and emails.” According to the company’s website, Ventavia “played a significant part in [COVID-19 clinical trial] recruitment” and “has received recognition by Pfizer for their contribution to vaccine trials.”

It was previously reported that the whistle-blower is a former regional director who was involved in Pfizer’s vaccine trials in Texas during the fall of 2020. She alleges “the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase 3 trial.”

The images provided to the BMJ “showed needles discarded in a plastic biohazard bag instead of a sharps container box” and another displayed “vaccine packaging materials with trial participants’ identification numbers written on them left out in the open, potentially unblinding participants.”

Despite informing Ventavia, the director’s concerns went unaddressed. She then filed a complaint with the Food and Drug Administration and was subsequently fired the same day. The FDA did not investigate the director’s allegations, said Dr. Godlee and Dr. Abbasi, even though the evidence “revealed a host of poor clinical trial research practices occurring at Ventavia that could impact data integrity and patient safety.”
 

Article labeled as ‘hoax,’ without pointing out errors

The BMJ hired an investigative reporter to follow up on the clinical trial claims. The findings were published in an article on Nov. 2, 2021, after the article “went through ... the usual high-level legal and editorial oversight and peer review,” according to the journal.

However, by Nov. 10, the journal began receiving complaints from readers unable to share the article on social media. Others had their posts flagged with warnings, such as “missing context ... independent fact-checkers say this information could mislead people.” Administrators of various Facebook groups were notified that posts containing the article were “partly false.”

Readers were informed that Facebook contractor Lead Stories performed the article’s “fact check.” Lead Stories is “an award-winning innovative fact checking and debunking website” and “an active part of Facebook’s partnership with third-party fact checkers” – with the latter granting them “access to listings of content that has been flagged as potentially false by Facebook’s systems or its users.” The company said they “decide independently if we want to fact check it or not.”

Lead Stories stated that they “can enter our fact checks into a tool provided by Facebook and Facebook then uses our data to help slow down the spread of false information on its platform.” Although the contractor is compensated, Lead Stories claims they have “no say or influence over what we fact check or what our conclusions are.”

Both editors question the validity of the fact check performed by Lead Stories, as it failed to provide any “assertions of fact” as to what the BMJ got wrong. Moreover, the editors take issue with Lead Stories referring to the journal as a “news blog” and using the phrase “hoax-alert” in the URL when publishing the story on its site.

The BMJ has reached out to Lead Stories and Facebook, said the letter, but Lead Stories refuses to “change anything about their article or actions that have led to Facebook flagging our article.” Requests for Facebook to remove the “fact-checking” label and allow “readers to freely share the article on [Facebook’s] platform” have been unfruitful.

Dr. Godlee and Dr. Abbasi expressed concern that other “high quality information provider[s] have been affected by the incompetence of Meta’s fact checking regime.” In November, Instagram censored Cochrane, an international provider of independent systematic medical reviews. Instagram, also owned by Meta, prohibited users from tagging Cochrane because the organization “repeatedly posted ... false content about COVID-19 or vaccines.” Cochrane refuted the allegations.

While “fact checking has been a staple of good journalism for decades,” said the editors, Meta has “apparently delegated responsibility to people incompetent in carrying out this crucial task.” They urged the company to reconsider its fact-checking strategy and review the issues that contributed to the error.

This news organization reached out to Meta for comment but did not receive a response at press time.

Lead Stories has posted a reply (Lead Stories’ Response To BMJ Open Letter Objecting To A Lead Stories Fact Check) to the BMJ’s complaint on its website.

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

Editors at the BMJ have released an urgent request to Facebook’s Mark Zuckerberg and parent company Meta regarding a recent “fact-check” on the medical trade journal’s article about questionable Pfizer vaccine trial practices.

According to an open letter written by outgoing BMJ editor-in-chief Fiona Godlee, MD, and incoming editor-in-chief Kamran Abbasi, MD, Facebook hired a third-party contractor to evaluate the article’s findings. This resulted in “inaccurate, incompetent, and irresponsible” conclusions that “should be of concern to anyone who values and relies on sources such as the BMJ for reliable medical information.”

The article in question investigated data integrity concerns at Pfizer vaccine clinical trial sites. In September 2020, the letter states, a former employee of the research group involved in Pfizer’s main vaccine trials, Ventavia, reached out to the BMJ and “began providing ... dozens of internal company documents, photos, audio recordings, and emails.” According to the company’s website, Ventavia “played a significant part in [COVID-19 clinical trial] recruitment” and “has received recognition by Pfizer for their contribution to vaccine trials.”

It was previously reported that the whistle-blower is a former regional director who was involved in Pfizer’s vaccine trials in Texas during the fall of 2020. She alleges “the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase 3 trial.”

The images provided to the BMJ “showed needles discarded in a plastic biohazard bag instead of a sharps container box” and another displayed “vaccine packaging materials with trial participants’ identification numbers written on them left out in the open, potentially unblinding participants.”

Despite informing Ventavia, the director’s concerns went unaddressed. She then filed a complaint with the Food and Drug Administration and was subsequently fired the same day. The FDA did not investigate the director’s allegations, said Dr. Godlee and Dr. Abbasi, even though the evidence “revealed a host of poor clinical trial research practices occurring at Ventavia that could impact data integrity and patient safety.”
 

Article labeled as ‘hoax,’ without pointing out errors

The BMJ hired an investigative reporter to follow up on the clinical trial claims. The findings were published in an article on Nov. 2, 2021, after the article “went through ... the usual high-level legal and editorial oversight and peer review,” according to the journal.

However, by Nov. 10, the journal began receiving complaints from readers unable to share the article on social media. Others had their posts flagged with warnings, such as “missing context ... independent fact-checkers say this information could mislead people.” Administrators of various Facebook groups were notified that posts containing the article were “partly false.”

Readers were informed that Facebook contractor Lead Stories performed the article’s “fact check.” Lead Stories is “an award-winning innovative fact checking and debunking website” and “an active part of Facebook’s partnership with third-party fact checkers” – with the latter granting them “access to listings of content that has been flagged as potentially false by Facebook’s systems or its users.” The company said they “decide independently if we want to fact check it or not.”

Lead Stories stated that they “can enter our fact checks into a tool provided by Facebook and Facebook then uses our data to help slow down the spread of false information on its platform.” Although the contractor is compensated, Lead Stories claims they have “no say or influence over what we fact check or what our conclusions are.”

Both editors question the validity of the fact check performed by Lead Stories, as it failed to provide any “assertions of fact” as to what the BMJ got wrong. Moreover, the editors take issue with Lead Stories referring to the journal as a “news blog” and using the phrase “hoax-alert” in the URL when publishing the story on its site.

The BMJ has reached out to Lead Stories and Facebook, said the letter, but Lead Stories refuses to “change anything about their article or actions that have led to Facebook flagging our article.” Requests for Facebook to remove the “fact-checking” label and allow “readers to freely share the article on [Facebook’s] platform” have been unfruitful.

Dr. Godlee and Dr. Abbasi expressed concern that other “high quality information provider[s] have been affected by the incompetence of Meta’s fact checking regime.” In November, Instagram censored Cochrane, an international provider of independent systematic medical reviews. Instagram, also owned by Meta, prohibited users from tagging Cochrane because the organization “repeatedly posted ... false content about COVID-19 or vaccines.” Cochrane refuted the allegations.

While “fact checking has been a staple of good journalism for decades,” said the editors, Meta has “apparently delegated responsibility to people incompetent in carrying out this crucial task.” They urged the company to reconsider its fact-checking strategy and review the issues that contributed to the error.

This news organization reached out to Meta for comment but did not receive a response at press time.

Lead Stories has posted a reply (Lead Stories’ Response To BMJ Open Letter Objecting To A Lead Stories Fact Check) to the BMJ’s complaint on its website.

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

Editors at the BMJ have released an urgent request to Facebook’s Mark Zuckerberg and parent company Meta regarding a recent “fact-check” on the medical trade journal’s article about questionable Pfizer vaccine trial practices.

According to an open letter written by outgoing BMJ editor-in-chief Fiona Godlee, MD, and incoming editor-in-chief Kamran Abbasi, MD, Facebook hired a third-party contractor to evaluate the article’s findings. This resulted in “inaccurate, incompetent, and irresponsible” conclusions that “should be of concern to anyone who values and relies on sources such as the BMJ for reliable medical information.”

The article in question investigated data integrity concerns at Pfizer vaccine clinical trial sites. In September 2020, the letter states, a former employee of the research group involved in Pfizer’s main vaccine trials, Ventavia, reached out to the BMJ and “began providing ... dozens of internal company documents, photos, audio recordings, and emails.” According to the company’s website, Ventavia “played a significant part in [COVID-19 clinical trial] recruitment” and “has received recognition by Pfizer for their contribution to vaccine trials.”

It was previously reported that the whistle-blower is a former regional director who was involved in Pfizer’s vaccine trials in Texas during the fall of 2020. She alleges “the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase 3 trial.”

The images provided to the BMJ “showed needles discarded in a plastic biohazard bag instead of a sharps container box” and another displayed “vaccine packaging materials with trial participants’ identification numbers written on them left out in the open, potentially unblinding participants.”

Despite informing Ventavia, the director’s concerns went unaddressed. She then filed a complaint with the Food and Drug Administration and was subsequently fired the same day. The FDA did not investigate the director’s allegations, said Dr. Godlee and Dr. Abbasi, even though the evidence “revealed a host of poor clinical trial research practices occurring at Ventavia that could impact data integrity and patient safety.”
 

Article labeled as ‘hoax,’ without pointing out errors

The BMJ hired an investigative reporter to follow up on the clinical trial claims. The findings were published in an article on Nov. 2, 2021, after the article “went through ... the usual high-level legal and editorial oversight and peer review,” according to the journal.

However, by Nov. 10, the journal began receiving complaints from readers unable to share the article on social media. Others had their posts flagged with warnings, such as “missing context ... independent fact-checkers say this information could mislead people.” Administrators of various Facebook groups were notified that posts containing the article were “partly false.”

Readers were informed that Facebook contractor Lead Stories performed the article’s “fact check.” Lead Stories is “an award-winning innovative fact checking and debunking website” and “an active part of Facebook’s partnership with third-party fact checkers” – with the latter granting them “access to listings of content that has been flagged as potentially false by Facebook’s systems or its users.” The company said they “decide independently if we want to fact check it or not.”

Lead Stories stated that they “can enter our fact checks into a tool provided by Facebook and Facebook then uses our data to help slow down the spread of false information on its platform.” Although the contractor is compensated, Lead Stories claims they have “no say or influence over what we fact check or what our conclusions are.”

Both editors question the validity of the fact check performed by Lead Stories, as it failed to provide any “assertions of fact” as to what the BMJ got wrong. Moreover, the editors take issue with Lead Stories referring to the journal as a “news blog” and using the phrase “hoax-alert” in the URL when publishing the story on its site.

The BMJ has reached out to Lead Stories and Facebook, said the letter, but Lead Stories refuses to “change anything about their article or actions that have led to Facebook flagging our article.” Requests for Facebook to remove the “fact-checking” label and allow “readers to freely share the article on [Facebook’s] platform” have been unfruitful.

Dr. Godlee and Dr. Abbasi expressed concern that other “high quality information provider[s] have been affected by the incompetence of Meta’s fact checking regime.” In November, Instagram censored Cochrane, an international provider of independent systematic medical reviews. Instagram, also owned by Meta, prohibited users from tagging Cochrane because the organization “repeatedly posted ... false content about COVID-19 or vaccines.” Cochrane refuted the allegations.

While “fact checking has been a staple of good journalism for decades,” said the editors, Meta has “apparently delegated responsibility to people incompetent in carrying out this crucial task.” They urged the company to reconsider its fact-checking strategy and review the issues that contributed to the error.

This news organization reached out to Meta for comment but did not receive a response at press time.

Lead Stories has posted a reply (Lead Stories’ Response To BMJ Open Letter Objecting To A Lead Stories Fact Check) to the BMJ’s complaint on its website.

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

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

It has been well established that device closure has, on average, prevented stroke recurrence in people who’ve had patent foramen ovale–associated stroke, but a meta-analysis has drilled down into clinical trials to advance a potentially practice-changing principle: that, while device closure shows an overall benefit, not all patients derive a benefit and some may actually be harmed by the procedure.

What’s more, the researchers developed a scoring system that helps determine which patients are likely to benefit from device closure.

“What was unknown was how to treat individual patients because the decision to close the patent foramen ovale (PFO) is still preference sensitive because the risk of a recurrent stroke is low, and most of the strokes that recur are not terribly severe,” lead study author David M. Kent, MD, MS, said in an interview.

“On top of this,” he said, “it was still suspected that some of the PFOs, even in trials of well-selected patients, may not be causally related to stroke; the stroke may still have another occult cause, such as paroxysmal atrial fibrillation or aortic arch atheroma.” Dr. Kent is a professor of medicine at Tufts University in Boston and director of the Predictive Analytics and Comparative Effectiveness Center there.

The meta-analysis, conducted by the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium, analyzed data from six randomized clinical trials that compared device closure and medical therapy to medical therapy alone in 3,740 patients who had PFO-associated stroke from 2000 to 2017. It was published in JAMA.

Overall, the rate of recurrent ischemic stroke was less than half that in patients who had device closure, compared with those who were on medical therapy: 0.47% (n = 39 of 1,889) vs. 1.09% (n = 82 of 1,851).

The researchers also applied two tools designed to calculate the probability of recurrent stroke in individual patients: Risk of Paradoxical Embolism (RoPE), an index that assigns a score of 0-10 to stratify cryptogenic stroke patients with PFO by the likelihood that the stroke was associated with their PFO; and the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system, which integrates the RoPE score with physiological and anatomical features – namely, the size of the PFO shunt and the presence of an atrial septal aneurysm.

“We came up with a way to more accurately identify those patients who are likely to get the most benefit from PFO closure based on mathematic modeling that estimates an individual’s probability that the PFO is causally related to the stroke,” Dr. Kent said.
 

Multivariate analysis determines risk

The study used a multivariate classification system that Dr. Kent had been developing to perform subgroup analyses of the clinical trials. It assigned patients to three different risk groups based on the likelihood that the PFO was causally related to their stroke: PASCAL categories of unlikely, possible, and probable.

The PASCAL unlikely group had a risk of stroke recurrence in the first 2 years of 3.4% (95% confidence interval, 1.1%-5.7%) if they were on medical therapy, and 4.1% (95% CI, 1.7%-6.4%) if they had device closure. In the PASCAL possible group, those risks were 3.6% (95% CI, 2.4%-4.9%) and 1.5% (95% CI, 0.7-2.3%), respectively. For the probable group, device closure represents “a near perfect therapy” with a 90% risk reduction, Dr. Kent said. “Moreover,” he said, “adverse events of device closure, such as atrial fibrillation, appear to be concentrated in those patients who fall into the unlikely classification, who appear to get no benefit.”

The ideal patient for device closure is age 60 years or younger and without vascular risk factors such as hypertension, diabetes, a history of smoking, or a prior stroke, but has high-risk PFO features such as a large shunt or atrial septal aneurysm, Dr. Kent said.

“We think these findings should be practice changing now,” Dr. Kent said.

Top infectious disease officials expect a surge of COVID-19 cases after the holidays and say Omicron will soon take over as the dominant strain in the United States.

The best way to stay protected is by getting vaccinated and boosted, they said.

“For the unvaccinated, you’re looking at a winter of severe illness and death – for yourselves, families, and the hospitals who may soon overwhelm,” White House COVID-19 Response Coordinator Jeff Zients said at a news briefing Dec. 17. “We need the American people to do their part.”

The Omicron variant has been detected in at least 39 states and 75 countries, according to CDC director Rochelle Walensky, MD.

The strain is more transmissible than the already highly infectious Delta variant, and although there was early evidence that it caused more mild disease, she said that is likely because many of those infected have been vaccinated and boosted.

“Although Delta continues to circulate widely in the United States, Omicron is increasing rapidly and we expect it to become the dominant strain in the United States, as it has in other countries, in the coming weeks,” Dr. Walensky said.

The United States is averaging close to 1,300 deaths from COVID-19 each day. New cases, deaths, and hospitalizations are higher now than in the previous winter – before vaccines were so widely available. The New York Times reported on Dec. 17 that new infections in Connecticut and Maine have grown 150% in the past 2 weeks, and Ohio and Indiana are seeing hospitalization rates nearing the worst of 2020-2021’s winter surge.

Dueling reports released recently gave cause for relief and concern about Omicron.

A study from South Africa released on Dec. 14 shows lower hospitalizations during the first 3 weeks of the Omicron wave than during earlier waves from other variants. That’s the good news.

The concerning news is out of the United Kingdom, where Imperial College London reported Dec. 17 that the risk of reinfection with COVID-19 from Omicron is more than 5 times as high and that cases of Omicron-based COVID-19 are doubling every 2 days.

What’s more, the study “finds no evidence of Omicron having lower severity than Delta, judged by either the proportion of people testing positive who report symptoms, or by the proportion of cases seeking hospital care after infection. However, hospitalization data remains very limited at this time,” the researchers said.

“We have no evidence that the virus itself is more mild,” Eric Topol, MD, executive vice president of Scripps Research and editor-in-chief of Medscape, told PBS NewsHour. “Until we have that, we have to assume that people who don’t have any protection are highly vulnerable to getting very ill.”

The White House COVID-19 team continues to urge parents and guardians to get their children vaccinated, especially in anticipation of a post-holiday spike. Dr. Walensky said the CDC’s vaccine advisory board met on Dec. 16 to continue the safety discussion about COVID-19 vaccinations in children.

So far, 20 million children under 17 and 5 million under 11 have received their shots.

“Looking specifically at vaccine safety data from over 50,000 children 5-11 years old, we found no evidence of serious safety concerns,” Dr. Walensky said.

Top infectious disease expert Anthony S. Fauci, MD, highlighted the importance of getting vaccinated and boosted to avoid serious disease from Delta and Omicron.

“We’re in a situation where we are now facing a very important Delta surge and we are looking over our shoulder at an oncoming Omicron surge,” he said. “The optimum protection is fully vaccinated plus a boost.”

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

Top infectious disease officials expect a surge of COVID-19 cases after the holidays and say Omicron will soon take over as the dominant strain in the United States.

The best way to stay protected is by getting vaccinated and boosted, they said.

“For the unvaccinated, you’re looking at a winter of severe illness and death – for yourselves, families, and the hospitals who may soon overwhelm,” White House COVID-19 Response Coordinator Jeff Zients said at a news briefing Dec. 17. “We need the American people to do their part.”

The Omicron variant has been detected in at least 39 states and 75 countries, according to CDC director Rochelle Walensky, MD.

The strain is more transmissible than the already highly infectious Delta variant, and although there was early evidence that it caused more mild disease, she said that is likely because many of those infected have been vaccinated and boosted.

“Although Delta continues to circulate widely in the United States, Omicron is increasing rapidly and we expect it to become the dominant strain in the United States, as it has in other countries, in the coming weeks,” Dr. Walensky said.

The United States is averaging close to 1,300 deaths from COVID-19 each day. New cases, deaths, and hospitalizations are higher now than in the previous winter – before vaccines were so widely available. The New York Times reported on Dec. 17 that new infections in Connecticut and Maine have grown 150% in the past 2 weeks, and Ohio and Indiana are seeing hospitalization rates nearing the worst of 2020-2021’s winter surge.

Dueling reports released recently gave cause for relief and concern about Omicron.

A study from South Africa released on Dec. 14 shows lower hospitalizations during the first 3 weeks of the Omicron wave than during earlier waves from other variants. That’s the good news.

The concerning news is out of the United Kingdom, where Imperial College London reported Dec. 17 that the risk of reinfection with COVID-19 from Omicron is more than 5 times as high and that cases of Omicron-based COVID-19 are doubling every 2 days.

What’s more, the study “finds no evidence of Omicron having lower severity than Delta, judged by either the proportion of people testing positive who report symptoms, or by the proportion of cases seeking hospital care after infection. However, hospitalization data remains very limited at this time,” the researchers said.

“We have no evidence that the virus itself is more mild,” Eric Topol, MD, executive vice president of Scripps Research and editor-in-chief of Medscape, told PBS NewsHour. “Until we have that, we have to assume that people who don’t have any protection are highly vulnerable to getting very ill.”

The White House COVID-19 team continues to urge parents and guardians to get their children vaccinated, especially in anticipation of a post-holiday spike. Dr. Walensky said the CDC’s vaccine advisory board met on Dec. 16 to continue the safety discussion about COVID-19 vaccinations in children.

So far, 20 million children under 17 and 5 million under 11 have received their shots.

“Looking specifically at vaccine safety data from over 50,000 children 5-11 years old, we found no evidence of serious safety concerns,” Dr. Walensky said.

Top infectious disease expert Anthony S. Fauci, MD, highlighted the importance of getting vaccinated and boosted to avoid serious disease from Delta and Omicron.

“We’re in a situation where we are now facing a very important Delta surge and we are looking over our shoulder at an oncoming Omicron surge,” he said. “The optimum protection is fully vaccinated plus a boost.”

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

Top infectious disease officials expect a surge of COVID-19 cases after the holidays and say Omicron will soon take over as the dominant strain in the United States.

The best way to stay protected is by getting vaccinated and boosted, they said.

“For the unvaccinated, you’re looking at a winter of severe illness and death – for yourselves, families, and the hospitals who may soon overwhelm,” White House COVID-19 Response Coordinator Jeff Zients said at a news briefing Dec. 17. “We need the American people to do their part.”

The Omicron variant has been detected in at least 39 states and 75 countries, according to CDC director Rochelle Walensky, MD.

The strain is more transmissible than the already highly infectious Delta variant, and although there was early evidence that it caused more mild disease, she said that is likely because many of those infected have been vaccinated and boosted.

“Although Delta continues to circulate widely in the United States, Omicron is increasing rapidly and we expect it to become the dominant strain in the United States, as it has in other countries, in the coming weeks,” Dr. Walensky said.

The United States is averaging close to 1,300 deaths from COVID-19 each day. New cases, deaths, and hospitalizations are higher now than in the previous winter – before vaccines were so widely available. The New York Times reported on Dec. 17 that new infections in Connecticut and Maine have grown 150% in the past 2 weeks, and Ohio and Indiana are seeing hospitalization rates nearing the worst of 2020-2021’s winter surge.

Dueling reports released recently gave cause for relief and concern about Omicron.

A study from South Africa released on Dec. 14 shows lower hospitalizations during the first 3 weeks of the Omicron wave than during earlier waves from other variants. That’s the good news.

The concerning news is out of the United Kingdom, where Imperial College London reported Dec. 17 that the risk of reinfection with COVID-19 from Omicron is more than 5 times as high and that cases of Omicron-based COVID-19 are doubling every 2 days.

What’s more, the study “finds no evidence of Omicron having lower severity than Delta, judged by either the proportion of people testing positive who report symptoms, or by the proportion of cases seeking hospital care after infection. However, hospitalization data remains very limited at this time,” the researchers said.

“We have no evidence that the virus itself is more mild,” Eric Topol, MD, executive vice president of Scripps Research and editor-in-chief of Medscape, told PBS NewsHour. “Until we have that, we have to assume that people who don’t have any protection are highly vulnerable to getting very ill.”

The White House COVID-19 team continues to urge parents and guardians to get their children vaccinated, especially in anticipation of a post-holiday spike. Dr. Walensky said the CDC’s vaccine advisory board met on Dec. 16 to continue the safety discussion about COVID-19 vaccinations in children.

So far, 20 million children under 17 and 5 million under 11 have received their shots.

“Looking specifically at vaccine safety data from over 50,000 children 5-11 years old, we found no evidence of serious safety concerns,” Dr. Walensky said.

Top infectious disease expert Anthony S. Fauci, MD, highlighted the importance of getting vaccinated and boosted to avoid serious disease from Delta and Omicron.

“We’re in a situation where we are now facing a very important Delta surge and we are looking over our shoulder at an oncoming Omicron surge,” he said. “The optimum protection is fully vaccinated plus a boost.”

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

The Food and Drug Administration has approved efgartigimod (Vyvgart, argenx), a first-in-class, targeted therapy for adults with generalized myasthenia gravis (gMG) who test positive for the antiacetylcholine receptor (AChR) antibody.

“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.

This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
 

Effective, well tolerated

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.

The results were published in Lancet Neurology.
 

‘Important new advance’

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.

The FDA granted efgartigimod fast track and orphan drug designation.

“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.

This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.

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

The Food and Drug Administration has approved efgartigimod (Vyvgart, argenx), a first-in-class, targeted therapy for adults with generalized myasthenia gravis (gMG) who test positive for the antiacetylcholine receptor (AChR) antibody.

“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.

This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
 

Effective, well tolerated

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.

The results were published in Lancet Neurology.
 

‘Important new advance’

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.

The FDA granted efgartigimod fast track and orphan drug designation.

“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.

This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.

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

The Food and Drug Administration has approved efgartigimod (Vyvgart, argenx), a first-in-class, targeted therapy for adults with generalized myasthenia gravis (gMG) who test positive for the antiacetylcholine receptor (AChR) antibody.

“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.

This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
 

Effective, well tolerated

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.

The results were published in Lancet Neurology.
 

‘Important new advance’

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.

The FDA granted efgartigimod fast track and orphan drug designation.

“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.

This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.

Ivan Pantic/Getty Images

The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.

The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.

“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.

“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.

To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.

As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.

Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.

“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”

The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.

“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.

It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.

“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”

James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.

“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
 

Large-scale data

The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.

The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.

There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).

In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.

Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.  

“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.

“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
 

Analyses by sex and age

A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.

“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.

Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).

“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.

The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.

Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).

“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”

Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.

“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”

Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.

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

Despite a flurry of publicity about its newfound cardiac risk profile, the antiseizure medication lamotrigine (Lamictal) is “still a good drug” in epilepsy and an excellent treatment for certain groups, New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.

“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”

In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”

The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”

Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”

As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.

But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
 

Special precautions

So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.

• Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
• “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
• Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
• “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
• “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”

Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”

For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.

Dr. French reported no disclosures.

Despite a flurry of publicity about its newfound cardiac risk profile, the antiseizure medication lamotrigine (Lamictal) is “still a good drug” in epilepsy and an excellent treatment for certain groups, New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.

“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”

In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”

The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”

Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”

As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.

But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
 

Special precautions

So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.

• Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
• “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
• Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
• “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
• “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”

Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”

For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.

Dr. French reported no disclosures.

Despite a flurry of publicity about its newfound cardiac risk profile, the antiseizure medication lamotrigine (Lamictal) is “still a good drug” in epilepsy and an excellent treatment for certain groups, New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.

“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”

In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”

The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”

Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”

As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.

But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
 

Special precautions

So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.

• Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
• “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
• Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
• “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
• “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”

Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”

For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.

Dr. French reported no disclosures.

Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.

“Genetic testing is significantly impacting medical care in a population of individuals with infantile- or childhood-onset epilepsy. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.

According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”

Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.

“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”

As examples, she mentioned three cases:

• Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
• A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
• Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”

In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.

As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”

No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.

Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.

“Genetic testing is significantly impacting medical care in a population of individuals with infantile- or childhood-onset epilepsy. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.

According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”

Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.

“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”

As examples, she mentioned three cases:

• Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
• A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
• Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”

In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.

As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”

No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.

Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.

“Genetic testing is significantly impacting medical care in a population of individuals with infantile- or childhood-onset epilepsy. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.

According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”

Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.

“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”

As examples, she mentioned three cases:

• Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
• A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
• Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”

In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.

As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”

No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.