Neurology Reviews

SAVANNAH, GEORGIA — Heart problems are common in the vast majority of neuromuscular disorders, and cardiac monitoring of patients is crucial, even at younger ages, a neurologist told an audience of nerve/muscle specialists.

The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
 

Protein Alterations May Disrupt Heart Muscles

In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.

In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.

Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”

Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
 

ECGs and Echos Are Recommended

Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”

The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”

Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
 

Worse Outcomes in Becker Muscular Dystrophy (BMD)

Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.

Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.

Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.

“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
 

Pacemakers May Be Considered in Type 1 Myotonic Dystrophy

In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.

Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.

“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”

Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Heart problems are common in the vast majority of neuromuscular disorders, and cardiac monitoring of patients is crucial, even at younger ages, a neurologist told an audience of nerve/muscle specialists.

The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
 

Protein Alterations May Disrupt Heart Muscles

In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.

In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.

Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”

Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
 

ECGs and Echos Are Recommended

Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”

The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”

Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
 

Worse Outcomes in Becker Muscular Dystrophy (BMD)

Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.

Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.

Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.

“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
 

Pacemakers May Be Considered in Type 1 Myotonic Dystrophy

In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.

Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.

“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”

Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Heart problems are common in the vast majority of neuromuscular disorders, and cardiac monitoring of patients is crucial, even at younger ages, a neurologist told an audience of nerve/muscle specialists.

The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
 

Protein Alterations May Disrupt Heart Muscles

In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.

In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.

Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”

Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
 

ECGs and Echos Are Recommended

Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”

The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”

Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
 

Worse Outcomes in Becker Muscular Dystrophy (BMD)

Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.

Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.

Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.

“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
 

Pacemakers May Be Considered in Type 1 Myotonic Dystrophy

In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.

Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.

“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”

Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Current disease-modifying therapies for amyotrophic lateral sclerosis (ALS) don’t extend lifespans by much, but several drug options are available, nerve specialists learned.

The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
 

Earlier Treatment Could Pay Dividends

A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.

Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).

There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.” 

He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
 

Edaravone Could Lack Relevant Benefit

No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.

The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.

That’s a “substantial delay,” Weiss said.

The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*

Other Options

As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.

In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”

Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.

Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.

*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Current disease-modifying therapies for amyotrophic lateral sclerosis (ALS) don’t extend lifespans by much, but several drug options are available, nerve specialists learned.

The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
 

Earlier Treatment Could Pay Dividends

A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.

Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).

There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.” 

He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
 

Edaravone Could Lack Relevant Benefit

No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.

The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.

That’s a “substantial delay,” Weiss said.

The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*

Other Options

As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.

In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”

Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.

Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.

*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Current disease-modifying therapies for amyotrophic lateral sclerosis (ALS) don’t extend lifespans by much, but several drug options are available, nerve specialists learned.

The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
 

Earlier Treatment Could Pay Dividends

A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.

Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).

There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.” 

He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
 

Edaravone Could Lack Relevant Benefit

No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.

The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.

That’s a “substantial delay,” Weiss said.

The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*

Other Options

As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.

In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”

Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.

Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.

*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”

A version of this article appeared on Medscape.com.

Like millions of other modern humans, my daughter and I stood in the backyard recently and watched comet C/2023 A3 (Tsuchinshan–ATLAS) with binoculars. It took a few minutes to locate, but once you see it is unmistakable.

It’s got a long (at least in human terms) orbit, roughly 80,000 years. So what was going on here, on our pale blue dot, the last time it graced our skies?

Well, here in Phoenix, the people were ... not here. Nor were they in Arizona, or North America, or pretty much the entire Western Hemisphere.

In fact, Homo sapiens were confined to Africa. The hardier Neanderthals had successfully moved into Eurasia, but our lineage was just starting to migrate there. There’s some evidence that we numbered maybe 10,000-15,000 at that point. Far more people saw the comet that night in the United States than our entire population count last time it swung by.

But we were moving up in the world. Our ancestors at the time had developed the first forms of jewelry, using seashells. There’s evidence that we’d learned to trade with other, distant, communities. We were using spears to put dinner on the table with less risk to ourselves than clubs posed.

And, in what’s now Kenya, in the same time frame, a pair of grieving parents carefully buried their 3-year-old child, wrapped in a covering and gently placed on a pillow.

Sadly, this isn’t a scene we’re unfamiliar with. Possibly the most famous painting of a physician is “The Doctor” (1891) by Luke Fildes, showing a physician trying to treat a seriously ill child while the parents look on helplessly.

Tate, London 2017

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Like millions of other modern humans, my daughter and I stood in the backyard recently and watched comet C/2023 A3 (Tsuchinshan–ATLAS) with binoculars. It took a few minutes to locate, but once you see it is unmistakable.

It’s got a long (at least in human terms) orbit, roughly 80,000 years. So what was going on here, on our pale blue dot, the last time it graced our skies?

Well, here in Phoenix, the people were ... not here. Nor were they in Arizona, or North America, or pretty much the entire Western Hemisphere.

In fact, Homo sapiens were confined to Africa. The hardier Neanderthals had successfully moved into Eurasia, but our lineage was just starting to migrate there. There’s some evidence that we numbered maybe 10,000-15,000 at that point. Far more people saw the comet that night in the United States than our entire population count last time it swung by.

But we were moving up in the world. Our ancestors at the time had developed the first forms of jewelry, using seashells. There’s evidence that we’d learned to trade with other, distant, communities. We were using spears to put dinner on the table with less risk to ourselves than clubs posed.

And, in what’s now Kenya, in the same time frame, a pair of grieving parents carefully buried their 3-year-old child, wrapped in a covering and gently placed on a pillow.

Sadly, this isn’t a scene we’re unfamiliar with. Possibly the most famous painting of a physician is “The Doctor” (1891) by Luke Fildes, showing a physician trying to treat a seriously ill child while the parents look on helplessly.

Tate, London 2017

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Like millions of other modern humans, my daughter and I stood in the backyard recently and watched comet C/2023 A3 (Tsuchinshan–ATLAS) with binoculars. It took a few minutes to locate, but once you see it is unmistakable.

It’s got a long (at least in human terms) orbit, roughly 80,000 years. So what was going on here, on our pale blue dot, the last time it graced our skies?

Well, here in Phoenix, the people were ... not here. Nor were they in Arizona, or North America, or pretty much the entire Western Hemisphere.

In fact, Homo sapiens were confined to Africa. The hardier Neanderthals had successfully moved into Eurasia, but our lineage was just starting to migrate there. There’s some evidence that we numbered maybe 10,000-15,000 at that point. Far more people saw the comet that night in the United States than our entire population count last time it swung by.

But we were moving up in the world. Our ancestors at the time had developed the first forms of jewelry, using seashells. There’s evidence that we’d learned to trade with other, distant, communities. We were using spears to put dinner on the table with less risk to ourselves than clubs posed.

And, in what’s now Kenya, in the same time frame, a pair of grieving parents carefully buried their 3-year-old child, wrapped in a covering and gently placed on a pillow.

Sadly, this isn’t a scene we’re unfamiliar with. Possibly the most famous painting of a physician is “The Doctor” (1891) by Luke Fildes, showing a physician trying to treat a seriously ill child while the parents look on helplessly.

Tate, London 2017

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

This transcript has been edited for clarity. 

What do we do if we don’t like patients? We take the Hippocratic Oath as young students in Glasgow. We do that just before our graduation ceremony; we hold our hands up and repeat the Hippocratic Oath: “First, do no harm,” and so on.

What happens if we intensely dislike a patient? Is it possible to offer them the very best care? I was thinking back over a long career. I’ve been a cancer doctor for 40 years and I quite like saying that.

I can only think genuinely over a couple of times in which I’ve acted reflexively when a patient has done something awful. The couple of times it happened, it was just terrible racist comments to junior doctors who were with me. Extraordinarily dreadful things such as, “I don’t want to be touched by ...” or something of that sort.

Without really thinking about it, you react as a normal citizen and say, “That’s absolutely awful. Apologize immediately or leave the consultation room, and never ever come back again.” 

I remember that it happened once in Glasgow and once when I was a young professor in Birmingham, and it’s just an automatic gut reaction. The patient got a fright, and I immediately apologized and groveled around. In that relationship, we hold all the power, don’t we? Rather than being gentle about it, I was genuinely angry because of these ridiculous comments. 

Otherwise, I think most of the doctor-patient relationships are predicated on nonromantic love. I think patients want us to love them as one would a son, mother, father, or daughter, because if we do, then we will do better for them and we’ll pull out all the stops. “Placebo” means “I will please.” I think in the vast majority of cases, at least in our National Health Service (NHS), patients come with trust and a sense of wanting to build that relationship. That may be changing, but not for me. 

What about putting the boot on the other foot? What if the patients don’t like us rather than vice versa? As part of our accreditation appraisal process, from time to time we have to take patient surveys as to whether the patients felt that, after they had been seen in a consultation, they were treated with dignity, the quality of information given was appropriate, and they were treated with kindness. 

It’s an excellent exercise. Without bragging about it, patients objectively, according to these measures, appreciate the service that I give. It’s like getting five-star reviews on Trustpilot, or whatever these things are, that allow you to review car salesmen and so on. I have always had five-star reviews across the board. 

That, again, I thought was just a feature of that relationship, of patients wanting to please. These are patients who had been treated, who were in the outpatient department, who were in the midst of battle. Still, the scores are very high. I speak to my colleagues and that’s not uniformly the case. Patients actually do use these feedback forms, I think in a positive rather than negative way, reflecting back on the way that they were treated.

It has caused some of my colleagues to think quite hard about their personal style and approach to patients. That sense of feedback is important. 

What about losing trust? If that’s at the heart of everything that we do, then what would be an objective measure of losing trust? Again, in our healthcare system, it has been exceedingly unusual for a patient to request a second opinion. Now, that’s changing. The government is trying to change it. Leaders of the NHS are trying to change it so that patients feel assured that they can seek second opinions.

Again, in all the years I’ve been a cancer doctor, it has been incredibly infrequent that somebody has sought a second opinion after I’ve said something. That may be a measure of trust. Again, I’ve lived through an NHS in which seeking second opinions was something of a rarity. 

I’d be really interested to see what you think. In your own sphere of healthcare practice, is it possible for us to look after patients that we don’t like, or should we be honest and say, “I don’t like you. Our relationship has broken down. I want you to be seen by a colleague,” or “I want you to be nursed by somebody else”?

Has that happened? Is that something that you think is common or may become more common? What about when trust breaks down the other way? Can you think of instances in which the relationship, for whatever reason, just didn’t work and the patient had to move on because of that loss of trust and what underpinned it? I’d be really interested to know. 

I seek to be informed rather than the other way around. Can we truly look after patients that we don’t like or can we rise above it as Hippocrates might have done? 

Thanks for listening, as always. For the time being, over and out.

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, disclosed ties with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, and Roche.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

What do we do if we don’t like patients? We take the Hippocratic Oath as young students in Glasgow. We do that just before our graduation ceremony; we hold our hands up and repeat the Hippocratic Oath: “First, do no harm,” and so on.

What happens if we intensely dislike a patient? Is it possible to offer them the very best care? I was thinking back over a long career. I’ve been a cancer doctor for 40 years and I quite like saying that.

I can only think genuinely over a couple of times in which I’ve acted reflexively when a patient has done something awful. The couple of times it happened, it was just terrible racist comments to junior doctors who were with me. Extraordinarily dreadful things such as, “I don’t want to be touched by ...” or something of that sort.

Without really thinking about it, you react as a normal citizen and say, “That’s absolutely awful. Apologize immediately or leave the consultation room, and never ever come back again.” 

I remember that it happened once in Glasgow and once when I was a young professor in Birmingham, and it’s just an automatic gut reaction. The patient got a fright, and I immediately apologized and groveled around. In that relationship, we hold all the power, don’t we? Rather than being gentle about it, I was genuinely angry because of these ridiculous comments. 

Otherwise, I think most of the doctor-patient relationships are predicated on nonromantic love. I think patients want us to love them as one would a son, mother, father, or daughter, because if we do, then we will do better for them and we’ll pull out all the stops. “Placebo” means “I will please.” I think in the vast majority of cases, at least in our National Health Service (NHS), patients come with trust and a sense of wanting to build that relationship. That may be changing, but not for me. 

What about putting the boot on the other foot? What if the patients don’t like us rather than vice versa? As part of our accreditation appraisal process, from time to time we have to take patient surveys as to whether the patients felt that, after they had been seen in a consultation, they were treated with dignity, the quality of information given was appropriate, and they were treated with kindness. 

It’s an excellent exercise. Without bragging about it, patients objectively, according to these measures, appreciate the service that I give. It’s like getting five-star reviews on Trustpilot, or whatever these things are, that allow you to review car salesmen and so on. I have always had five-star reviews across the board. 

That, again, I thought was just a feature of that relationship, of patients wanting to please. These are patients who had been treated, who were in the outpatient department, who were in the midst of battle. Still, the scores are very high. I speak to my colleagues and that’s not uniformly the case. Patients actually do use these feedback forms, I think in a positive rather than negative way, reflecting back on the way that they were treated.

It has caused some of my colleagues to think quite hard about their personal style and approach to patients. That sense of feedback is important. 

What about losing trust? If that’s at the heart of everything that we do, then what would be an objective measure of losing trust? Again, in our healthcare system, it has been exceedingly unusual for a patient to request a second opinion. Now, that’s changing. The government is trying to change it. Leaders of the NHS are trying to change it so that patients feel assured that they can seek second opinions.

Again, in all the years I’ve been a cancer doctor, it has been incredibly infrequent that somebody has sought a second opinion after I’ve said something. That may be a measure of trust. Again, I’ve lived through an NHS in which seeking second opinions was something of a rarity. 

I’d be really interested to see what you think. In your own sphere of healthcare practice, is it possible for us to look after patients that we don’t like, or should we be honest and say, “I don’t like you. Our relationship has broken down. I want you to be seen by a colleague,” or “I want you to be nursed by somebody else”?

Has that happened? Is that something that you think is common or may become more common? What about when trust breaks down the other way? Can you think of instances in which the relationship, for whatever reason, just didn’t work and the patient had to move on because of that loss of trust and what underpinned it? I’d be really interested to know. 

I seek to be informed rather than the other way around. Can we truly look after patients that we don’t like or can we rise above it as Hippocrates might have done? 

Thanks for listening, as always. For the time being, over and out.

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, disclosed ties with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, and Roche.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

What do we do if we don’t like patients? We take the Hippocratic Oath as young students in Glasgow. We do that just before our graduation ceremony; we hold our hands up and repeat the Hippocratic Oath: “First, do no harm,” and so on.

What happens if we intensely dislike a patient? Is it possible to offer them the very best care? I was thinking back over a long career. I’ve been a cancer doctor for 40 years and I quite like saying that.

I can only think genuinely over a couple of times in which I’ve acted reflexively when a patient has done something awful. The couple of times it happened, it was just terrible racist comments to junior doctors who were with me. Extraordinarily dreadful things such as, “I don’t want to be touched by ...” or something of that sort.

Without really thinking about it, you react as a normal citizen and say, “That’s absolutely awful. Apologize immediately or leave the consultation room, and never ever come back again.” 

I remember that it happened once in Glasgow and once when I was a young professor in Birmingham, and it’s just an automatic gut reaction. The patient got a fright, and I immediately apologized and groveled around. In that relationship, we hold all the power, don’t we? Rather than being gentle about it, I was genuinely angry because of these ridiculous comments. 

Otherwise, I think most of the doctor-patient relationships are predicated on nonromantic love. I think patients want us to love them as one would a son, mother, father, or daughter, because if we do, then we will do better for them and we’ll pull out all the stops. “Placebo” means “I will please.” I think in the vast majority of cases, at least in our National Health Service (NHS), patients come with trust and a sense of wanting to build that relationship. That may be changing, but not for me. 

What about putting the boot on the other foot? What if the patients don’t like us rather than vice versa? As part of our accreditation appraisal process, from time to time we have to take patient surveys as to whether the patients felt that, after they had been seen in a consultation, they were treated with dignity, the quality of information given was appropriate, and they were treated with kindness. 

It’s an excellent exercise. Without bragging about it, patients objectively, according to these measures, appreciate the service that I give. It’s like getting five-star reviews on Trustpilot, or whatever these things are, that allow you to review car salesmen and so on. I have always had five-star reviews across the board. 

That, again, I thought was just a feature of that relationship, of patients wanting to please. These are patients who had been treated, who were in the outpatient department, who were in the midst of battle. Still, the scores are very high. I speak to my colleagues and that’s not uniformly the case. Patients actually do use these feedback forms, I think in a positive rather than negative way, reflecting back on the way that they were treated.

It has caused some of my colleagues to think quite hard about their personal style and approach to patients. That sense of feedback is important. 

What about losing trust? If that’s at the heart of everything that we do, then what would be an objective measure of losing trust? Again, in our healthcare system, it has been exceedingly unusual for a patient to request a second opinion. Now, that’s changing. The government is trying to change it. Leaders of the NHS are trying to change it so that patients feel assured that they can seek second opinions.

Again, in all the years I’ve been a cancer doctor, it has been incredibly infrequent that somebody has sought a second opinion after I’ve said something. That may be a measure of trust. Again, I’ve lived through an NHS in which seeking second opinions was something of a rarity. 

I’d be really interested to see what you think. In your own sphere of healthcare practice, is it possible for us to look after patients that we don’t like, or should we be honest and say, “I don’t like you. Our relationship has broken down. I want you to be seen by a colleague,” or “I want you to be nursed by somebody else”?

Has that happened? Is that something that you think is common or may become more common? What about when trust breaks down the other way? Can you think of instances in which the relationship, for whatever reason, just didn’t work and the patient had to move on because of that loss of trust and what underpinned it? I’d be really interested to know. 

I seek to be informed rather than the other way around. Can we truly look after patients that we don’t like or can we rise above it as Hippocrates might have done? 

Thanks for listening, as always. For the time being, over and out.

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, disclosed ties with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, and Roche.

A version of this article appeared on Medscape.com.

The American Stroke Association (ASA) has issued a new updated guideline for primary stroke prevention.

The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.

“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

It was published online on October 21 in Stroke.
 

Up to 80% of Strokes Preventable

Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.

This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.

The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.

Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.

“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell. 

She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
 

At Least Two Meds Needed to Reduce BP

Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.

Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.

In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
 

Emphasis on Women’s Health

Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.

They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.

Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”

Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
 

Challenges Lie Ahead

Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.

Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added. 

Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs. 

“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.

“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell. 
 

A version of this article appeared on Medscape.com.

The American Stroke Association (ASA) has issued a new updated guideline for primary stroke prevention.

The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.

“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

It was published online on October 21 in Stroke.
 

Up to 80% of Strokes Preventable

Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.

This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.

The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.

Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.

“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell. 

She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
 

At Least Two Meds Needed to Reduce BP

Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.

Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.

In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
 

Emphasis on Women’s Health

Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.

They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.

Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”

Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
 

Challenges Lie Ahead

Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.

Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added. 

Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs. 

“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.

“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell. 
 

A version of this article appeared on Medscape.com.

The American Stroke Association (ASA) has issued a new updated guideline for primary stroke prevention.

The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.

“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

It was published online on October 21 in Stroke.
 

Up to 80% of Strokes Preventable

Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.

This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.

The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.

Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.

“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell. 

She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
 

At Least Two Meds Needed to Reduce BP

Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.

Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.

In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
 

Emphasis on Women’s Health

Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.

They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.

Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”

Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
 

Challenges Lie Ahead

Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.

Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added. 

Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs. 

“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.

“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Fetuses exposed in utero to SARS-CoV-2 are not at an increased risk for neurodevelopmental problems in early childhood.

METHODOLOGY:

• This prospective study aimed to assess whether in utero exposure to SARS-CoV-2, which causes COVID-19, is associated with abnormal neurodevelopment among children at ages 12, 18, and 24 months.
• It included 2003 pregnant individuals (mean age, 33.3 years) from the ASPIRE cohort who were enrolled before 10 weeks’ gestation and followed through 24 months post partum; 10.8% of them were exposed to SARS-CoV-2 during pregnancy, as determined via self-reported data or dried blood spot cards.
• The birth mothers were required to complete the Ages & Stages Questionnaires, Third Edition (ASQ-3), a validated screening tool for neurodevelopmental delays, at 12, 18, and 24 months postpartum.
• Neurodevelopmental outcomes were available for 1757, 1522, and 1523 children at ages 12, 18, and 24 months, respectively.
• The primary outcome was a score below the cutoff on the ASQ-3 across any of the following developmental domains: Communication, gross motor, fine motor, problem-solving, and social skills.

TAKEAWAY:

• The prevalence of abnormal ASQ-3 scores did not differ between children who were exposed to SARS-CoV-2 in utero and those who were not, at ages 12 (P = .39), 18 (P = .58), and 24 (P = .45) months.
• No association was observed between in utero exposure to SARS-CoV-2 and abnormal ASQ-3 scores among children in any of the age groups.
• The lack of an association between exposure to SARS-CoV-2 during pregnancy and abnormal neurodevelopment remained unchanged even when factors such as preterm delivery and the sex of the infant were considered.
• Supplemental analyses found no difference in risk based on the trimester of infection, presence of fever, or incidence of breakthrough infection following vaccination.

IN PRACTICE:

“In this prospective cohort study of pregnant individuals and offspring, in utero exposure to maternal SARS-CoV-2 infection was not associated with abnormal neurodevelopmental screening scores of children through age 24 months. These findings are critical considering the novelty of the SARS-CoV-2 virus to the human species, the global scale of the initial COVID-19 outbreak, the now-endemic nature of the virus indicating ongoing relevance for pregnant individuals,” the authors of the study wrote. 

“While the scientific consensus resists a link between in utero COVID-19 exposure and impaired offspring neurodevelopment, the question remains whether societal responses to the pandemic impacted developmental trajectories,” the researchers added. “Certain studies comparing infants from a pandemic cohort with historic controls have raised concerns about lower ASQ-3 scores among children living during the pandemic. Critically, socioeconomic factors influence vulnerability, not only to infection itself but also regarding the ability to deploy resources in times of stress (eg, school closures) to mitigate sources of developmental harm. Our data support this theory, with the observed independent protective association of increasing household income with childhood ASQ-3 scores. Additional research is warranted to clarify the potential impact of societal measures on early development and the differential impact of these measures on different communities.”
 

SOURCE:

The study was led by Eleni G. Jaswa, MD, MSc, of the Department of Obstetrics, Gynecology & Reproductive Sciences at the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS: 

Limitations of the research included the use of self-reported data and dried blood spot cards for determining exposure to SARS-CoV-2, which may have led to misclassification. The ASQ-3 is a modestly sensitive tool for detecting developmental delays that may have affected the study’s power to detect associations. The sample size of this study, while larger than many, may still have been underpowered to detect small differences in neurodevelopmental outcomes.

DISCLOSURES:

The ASPIRE cohort was supported by research grants provided to the University of California, San Francisco, and by the Start Small Foundation, the California Breast Cancer Research Program, the COVID Catalyst Award, and other sources. Some authors reported receiving grants, royalties, and personal fees, serving on medical advisory boards, and having other ties with several institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Fetuses exposed in utero to SARS-CoV-2 are not at an increased risk for neurodevelopmental problems in early childhood.

METHODOLOGY:

• This prospective study aimed to assess whether in utero exposure to SARS-CoV-2, which causes COVID-19, is associated with abnormal neurodevelopment among children at ages 12, 18, and 24 months.
• It included 2003 pregnant individuals (mean age, 33.3 years) from the ASPIRE cohort who were enrolled before 10 weeks’ gestation and followed through 24 months post partum; 10.8% of them were exposed to SARS-CoV-2 during pregnancy, as determined via self-reported data or dried blood spot cards.
• The birth mothers were required to complete the Ages & Stages Questionnaires, Third Edition (ASQ-3), a validated screening tool for neurodevelopmental delays, at 12, 18, and 24 months postpartum.
• Neurodevelopmental outcomes were available for 1757, 1522, and 1523 children at ages 12, 18, and 24 months, respectively.
• The primary outcome was a score below the cutoff on the ASQ-3 across any of the following developmental domains: Communication, gross motor, fine motor, problem-solving, and social skills.

TAKEAWAY:

• The prevalence of abnormal ASQ-3 scores did not differ between children who were exposed to SARS-CoV-2 in utero and those who were not, at ages 12 (P = .39), 18 (P = .58), and 24 (P = .45) months.
• No association was observed between in utero exposure to SARS-CoV-2 and abnormal ASQ-3 scores among children in any of the age groups.
• The lack of an association between exposure to SARS-CoV-2 during pregnancy and abnormal neurodevelopment remained unchanged even when factors such as preterm delivery and the sex of the infant were considered.
• Supplemental analyses found no difference in risk based on the trimester of infection, presence of fever, or incidence of breakthrough infection following vaccination.

IN PRACTICE:

“In this prospective cohort study of pregnant individuals and offspring, in utero exposure to maternal SARS-CoV-2 infection was not associated with abnormal neurodevelopmental screening scores of children through age 24 months. These findings are critical considering the novelty of the SARS-CoV-2 virus to the human species, the global scale of the initial COVID-19 outbreak, the now-endemic nature of the virus indicating ongoing relevance for pregnant individuals,” the authors of the study wrote. 

“While the scientific consensus resists a link between in utero COVID-19 exposure and impaired offspring neurodevelopment, the question remains whether societal responses to the pandemic impacted developmental trajectories,” the researchers added. “Certain studies comparing infants from a pandemic cohort with historic controls have raised concerns about lower ASQ-3 scores among children living during the pandemic. Critically, socioeconomic factors influence vulnerability, not only to infection itself but also regarding the ability to deploy resources in times of stress (eg, school closures) to mitigate sources of developmental harm. Our data support this theory, with the observed independent protective association of increasing household income with childhood ASQ-3 scores. Additional research is warranted to clarify the potential impact of societal measures on early development and the differential impact of these measures on different communities.”
 

SOURCE:

The study was led by Eleni G. Jaswa, MD, MSc, of the Department of Obstetrics, Gynecology & Reproductive Sciences at the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS: 

Limitations of the research included the use of self-reported data and dried blood spot cards for determining exposure to SARS-CoV-2, which may have led to misclassification. The ASQ-3 is a modestly sensitive tool for detecting developmental delays that may have affected the study’s power to detect associations. The sample size of this study, while larger than many, may still have been underpowered to detect small differences in neurodevelopmental outcomes.

DISCLOSURES:

The ASPIRE cohort was supported by research grants provided to the University of California, San Francisco, and by the Start Small Foundation, the California Breast Cancer Research Program, the COVID Catalyst Award, and other sources. Some authors reported receiving grants, royalties, and personal fees, serving on medical advisory boards, and having other ties with several institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Fetuses exposed in utero to SARS-CoV-2 are not at an increased risk for neurodevelopmental problems in early childhood.

METHODOLOGY:

• This prospective study aimed to assess whether in utero exposure to SARS-CoV-2, which causes COVID-19, is associated with abnormal neurodevelopment among children at ages 12, 18, and 24 months.
• It included 2003 pregnant individuals (mean age, 33.3 years) from the ASPIRE cohort who were enrolled before 10 weeks’ gestation and followed through 24 months post partum; 10.8% of them were exposed to SARS-CoV-2 during pregnancy, as determined via self-reported data or dried blood spot cards.
• The birth mothers were required to complete the Ages & Stages Questionnaires, Third Edition (ASQ-3), a validated screening tool for neurodevelopmental delays, at 12, 18, and 24 months postpartum.
• Neurodevelopmental outcomes were available for 1757, 1522, and 1523 children at ages 12, 18, and 24 months, respectively.
• The primary outcome was a score below the cutoff on the ASQ-3 across any of the following developmental domains: Communication, gross motor, fine motor, problem-solving, and social skills.

TAKEAWAY:

• The prevalence of abnormal ASQ-3 scores did not differ between children who were exposed to SARS-CoV-2 in utero and those who were not, at ages 12 (P = .39), 18 (P = .58), and 24 (P = .45) months.
• No association was observed between in utero exposure to SARS-CoV-2 and abnormal ASQ-3 scores among children in any of the age groups.
• The lack of an association between exposure to SARS-CoV-2 during pregnancy and abnormal neurodevelopment remained unchanged even when factors such as preterm delivery and the sex of the infant were considered.
• Supplemental analyses found no difference in risk based on the trimester of infection, presence of fever, or incidence of breakthrough infection following vaccination.

IN PRACTICE:

“In this prospective cohort study of pregnant individuals and offspring, in utero exposure to maternal SARS-CoV-2 infection was not associated with abnormal neurodevelopmental screening scores of children through age 24 months. These findings are critical considering the novelty of the SARS-CoV-2 virus to the human species, the global scale of the initial COVID-19 outbreak, the now-endemic nature of the virus indicating ongoing relevance for pregnant individuals,” the authors of the study wrote. 

“While the scientific consensus resists a link between in utero COVID-19 exposure and impaired offspring neurodevelopment, the question remains whether societal responses to the pandemic impacted developmental trajectories,” the researchers added. “Certain studies comparing infants from a pandemic cohort with historic controls have raised concerns about lower ASQ-3 scores among children living during the pandemic. Critically, socioeconomic factors influence vulnerability, not only to infection itself but also regarding the ability to deploy resources in times of stress (eg, school closures) to mitigate sources of developmental harm. Our data support this theory, with the observed independent protective association of increasing household income with childhood ASQ-3 scores. Additional research is warranted to clarify the potential impact of societal measures on early development and the differential impact of these measures on different communities.”
 

SOURCE:

The study was led by Eleni G. Jaswa, MD, MSc, of the Department of Obstetrics, Gynecology & Reproductive Sciences at the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS: 

Limitations of the research included the use of self-reported data and dried blood spot cards for determining exposure to SARS-CoV-2, which may have led to misclassification. The ASQ-3 is a modestly sensitive tool for detecting developmental delays that may have affected the study’s power to detect associations. The sample size of this study, while larger than many, may still have been underpowered to detect small differences in neurodevelopmental outcomes.

DISCLOSURES:

The ASPIRE cohort was supported by research grants provided to the University of California, San Francisco, and by the Start Small Foundation, the California Breast Cancer Research Program, the COVID Catalyst Award, and other sources. Some authors reported receiving grants, royalties, and personal fees, serving on medical advisory boards, and having other ties with several institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?

“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.

“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.

“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
 

Two Cases

In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.

A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.

The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.

In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.

This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.

“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
 

Genetics and Environment May Each Play a Role

Shanina called for research exploring mutations and inheritance patterns in families with MG.

“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”

Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.” 

Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.” 

While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”

While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.

Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”

Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.

There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.

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

SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?

“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.

“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.

“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
 

Two Cases

In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.

A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.

The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.

In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.

This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.

“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
 

Genetics and Environment May Each Play a Role

Shanina called for research exploring mutations and inheritance patterns in families with MG.

“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”

Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.” 

Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.” 

While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”

While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.

Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”

Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.

There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.

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

SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?

“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.

“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.

“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
 

Two Cases

In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.

A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.

The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.

In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.

This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.

“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
 

Genetics and Environment May Each Play a Role

Shanina called for research exploring mutations and inheritance patterns in families with MG.

“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”

Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.” 

Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.” 

While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”

While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.

Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”

Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.

There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.

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

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

It has been 24 years since a pharmaceutical was last approved for posttraumatic stress disorder (PTSD). The condition is notoriously difficult to treat, with up to 40% patients finding no relief from symptoms through psychotherapy or current medications.

Many clinicians, advocates, and patients had pinned their hopes on the psychedelic drug midomafetamine with assisted therapy (MDMA-AT). However, in August, the US Food and Drug Administration (FDA) rejected it. At this point, it’s unclear when the therapy will be available, if ever.

“Not getting the FDA approval of any drug at this point is a setback for the field,” Lori Davis, MD, a senior research psychiatrist at the Birmingham Veterans Affairs (VA) Health Care System in Birmingham, Alabama, told Medscape Medical News.

Having an FDA-approved product would have helped increase public awareness of PTSD and driven interest in developing new therapies, said Davis, who is also adjunct professor of psychiatry at the Heersink School of Medicine, University of Alabama at Birmingham.
 

A Treatable Condition

So with MDMA-AT off the table, where does the field go next? 

A public meeting in September hosted by the Reagan-Udall Foundation for the FDA in sought to answer that question. Agency officials joined representatives from the Department of Defense (DoD) and VA, patients, advocates, and industry representatives to discuss the current treatment landscape and what can be done to accelerate development of PTSD treatment.

Despite the common belief that PTSD is intractable, it “is a treatable condition,” Paula P. Schnurr, PhD, executive director of the VA National Center for PTSD, said at the meeting.

“There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response,” she added.

The most effective psychotherapies are “trauma-focused,” and include cognitive processing therapy, eye movement desensitization and reprocessing, and prolonged exposure, according to the VA National Center for PTSD.

Three drugs have been approved by the FDA for PTSD: Venlafaxine (Effexor) in 1993, sertraline (Zoloft) in 1999, and paroxetine (Paxil) in 2000.

However, as the September meeting demonstrated, more therapies are needed.

“It’s clear to FDA and the federal government at large that there is an unmet need for safe and effective therapies to treat PTSD,” Bernard Fischer, MD, deputy director of the Division of Psychiatry in the Office of New Drugs at FDA’s Center for Drug Evaluation and Research, said at the meeting.

There is no shortage of research, Fischer added. Nearly 500 trials focused on PTSD are listed on clinicaltrials.gov are recruiting participants now or plan to soon.

Unsurprisingly, one of the primary drivers of PTSD therapeutics research is the VA. About 14% of the 5.7 million veterans who received care through the VA in 2023 had a diagnosis of PTSD.

“The US military is currently losing thousands of service members each year to PTSD- related disability discharges,” US Army Maj. Aaron Wolfgang, MD, a psychiatrist at the Walter Reed National Military Medical Center, said at the meeting. Only about 12%-20% of patients achieve remission with conventional therapies, added Wolfgang, who also is an assistant professor at the Uniformed Services University.

“For these reasons, establishing better treatments for PTSD is not only a matter of humanitarianism but also a pressing matter of national security,” he said.

The VA has committed at least $230 million to more than 140 active research projects in PTSD, Miriam J. Smyth, PhD, acting director of the clinical science, research and development service at the VA, said at the Reagan-Udall meeting.

One of the VA projects is the PTSD psychopharmacology initiative, which began in 2017 and now has 14 active clinical trials, said Smyth, who is also acting director for brain behavior and mental health at the VA. The first study should be finished by 2025.

The Million Veteran Program, with more than 1 million enrollees, has led to the discovery of genes related to re-experiencing traumatic memories and has confirmed that both PTSD and traumatic brain injury are risk factors for dementia, Smyth said.

The DoD has created a novel platform that establishes a common infrastructure for testing multiple drugs, called M-PACT. The platform allows sharing of placebo data across treatment arms. Drugs cycle off the platform if evidence indicates probability of success or failure.

Four trials are actively recruiting veterans and current service members. One is looking at vilazodone, approved in 2011 for major depressive disorder. It is being compared with placebo and fluoxetine in a trial that is currently recruiting.

Another trial will study daridorexant (sold as Quviviq), an orexin receptor antagonist, against placebo. The FDA approved daridorexant in 2022 as an insomnia treatment. A core issue in PTSD is sleep disruption, noted Davis.
 

New Therapies on the Way

Separately, Davis and colleagues are also studying methylphenidate, the stimulant used for attention-deficit/hyperactivity disorder. It may help with neurocognitive complaints and reduce PTSD symptoms, said Davis.

Because it is generic, few pharmaceutical manufacturers are likely to test it for PTSD, she said. But eventually, their work may lead a company to test newer stimulants for PTSD, she said.

Another potential therapeutic, BNC210, received Fast Track designation for PTSD from the FDA in 2019. Bionomics Limited in Australia will soon launch phase 3 trials of the investigational oral drug, which is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. In late July, the company announced “ favorable feedback” from the agency on its phase 2 study, which led to the decision to move forward with larger trials.

Researchers at Brigham and Women’s Hospital have just reported that they may have found a target within the brain that will allow for transcranial magnetic stimulation (TMS) to ameliorate PTSD symptoms. They published results of a mapping effort in Nature Neuroscience and reported on one patient who had improved symptoms after receiving TMS for severe PTSD.

But perhaps one of the most promising treatments is a combination of sertraline and the new psychiatric medication brexpiprazole.

Brexpiprazole was developed by Otsuka Pharmaceutical and approved in the United States in 2015 as an adjunctive therapy to antidepressants for major depressive disorder and as a treatment for schizophrenia. In 2023, the FDA approved it for Alzheimer’s-related agitation. However, according to Otsuka, its mechanism of action is unknown.

Its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha-1B/2C receptors, said the company.

“It is the combination, rather than either alone, that’s going to have that broad synergistic pharmacology that is obviously potent for ameliorating the symptoms of PTSD,” said Davis, who has received consulting fees from Otsuka. “That’s an exciting development.”

Otsuka and partner Lundbeck Pharmaceuticals reported results in May from the companies’ phase 2 and 3 randomized clinical trials. The therapy achieved a statistically significant reduction (P <.05) in PTSD symptoms compared with sertraline plus placebo. This was without any supplemental psychotherapy.

The FDA accepted the companies’ new drug application in June and is expected to make a decision on approval in February 2025.
 

The Potential of Psychedelics

Though Lykos Therapeutics may have to go back to the drawing board on its MDMA-AT, psychedelics still have potential as PTSD therapies, Smyth said, who added that the VA is continuing to encourage study of MDMA and other psychedelic agents.

The VA issued a call for proposals for research on psychedelics in January, focused on MDMA or psilocybin in combination with psychotherapy. The administration received the first wave of applications early in the summer.

Scientific peer review panels made up of research experts from within and outside the VA have reviewed the applications and funding announcements are expected this fall, Smyth said.

Wolfgang, the Army psychiatrist, said, “Under the psychedelic treatment research clinical trial award, we welcome investigators to apply to what we anticipate will usher in a new era of innovation and hope for service members and their families who need it the most.”

Psychedelic studies are also proceeding without VA funding, as they have for years, when most of the trials were backed by universities or foundations or other private money. Johns Hopkins University is recruiting for a study in which patients would receive psilocybin along with trauma-focused psychotherapy, as is Ohio State University.

London-based Compass Pathways said in May that it successfully completed a phase 2 trial of Comp360, its synthetic psilocybin, in PTSD. The company has started a phase 3 study in treatment-resistant depression but has not given any further updates on PTSD.

Davis said that she believes that the FDA’s rejection of Lykos won’t lead to a shutdown of exploration of psychedelics.

“I think it informs these designs going forward, but it doesn’t eliminate that whole field of research,” she said.

Davis reported receiving consulting fees from Boehringer Ingelheim and Otsuka and research funding from Alkermes, the Patient-Centered Outcomes Research Institute, and the VA. Schnurr, Fischer, Smyth, and Wolfgang reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

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

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

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

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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