Neurology Reviews

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

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

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

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

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

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

PHOENIX – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, compared with untreated patients who showed significant decline over the same time period, new research shows.

“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.

The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
 

Severe type of DMD

Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.

SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.

In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.

The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.

For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.

All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.

At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.

The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.

Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.

No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.

Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).

Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).

Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.

Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.

The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.

Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
 

Increased function, long-term stability

Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.

“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.

“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.

A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.

In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments. 

“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”

She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”

The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.

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

PHOENIX – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, compared with untreated patients who showed significant decline over the same time period, new research shows.

“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.

The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
 

Severe type of DMD

Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.

SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.

In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.

The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.

For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.

All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.

At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.

The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.

Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.

No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.

Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).

Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).

Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.

Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.

The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.

Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
 

Increased function, long-term stability

Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.

“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.

“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.

A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.

In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments. 

“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”

She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”

The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.

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

PHOENIX – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, compared with untreated patients who showed significant decline over the same time period, new research shows.

“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.

The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
 

Severe type of DMD

Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.

SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.

In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.

The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.

For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.

All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.

At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.

The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.

Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.

No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.

Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).

Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).

Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.

Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.

The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.

Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
 

Increased function, long-term stability

Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.

“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.

“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.

A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.

In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments. 

“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”

She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”

The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.

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

People infected multiple times with COVID-19 are more likely to develop long COVID, and most never fully recover from the condition. Those are two of the most striking findings of a comprehensive new research study of 138,000 veterans.

Lead researcher Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care and clinical epidemiologist at Washington University in St. Louis, spoke with this news organization about his team’s findings, what we know – and don’t – about long COVID, and what it means for physicians treating patients with the condition.

Excerpts of the interview follow.

Your research concluded that for those infected early in the pandemic, some long COVID symptoms declined over 2 years, but some did not. You have also concluded that long COVID is a chronic disease. Why?

We’ve been in this journey a little bit more than three and a half years. Some patients do experience some recovery. But that’s not the norm. Most people do not really fully recover. The health trajectory for people with long COVID is really very heterogeneous. There is no one-size-fits-all. There’s really no one line that I could give you that could cover all your patients. But it is very, very, very clear that a bunch of them experienced long COVID for sure; that’s really happening.

It happened in the pre-Delta era and in the Delta era, and with Omicron subvariants, even now. There are people who think, “This is a nothing-burger anymore,” or “It’s not an issue anymore.” It’s still happening with the current variants. Vaccines do reduce risk for long COVID, but do not completely eliminate the risk for long COVID.

You work with patients with long COVID in the clinic and also analyze data from thousands more. If long COVID does not go away, what should doctors look for in everyday practice that will help them recognize and help patients with long COVID?

Long COVID is not uncommon. We see it in the clinic in large numbers. Whatever clinic you’re running – if you’re running a cardiology clinic, or a nephrology clinic, or diabetes, or primary care – probably some of your people have it. You may not know about it. They may not tell you about it. You may not recognize it.

Not all long COVID is the same, and that’s really what makes it complex and makes it really hard to deal with in the clinic. But that’s the reality that we’re all dealing with. And it’s multisystemic; it’s not like it affects the heart only, the brain only, or the autonomic nervous system only. It does not behave in the same way in different individuals – they may have different manifestations, various health trajectories, and different outcomes. It’s important for doctors to get up to speed on long COVID as a multisystem illness.

Management at this point is really managing the symptoms. We don’t have a treatment for it; we don’t have a cure for it.

Some patients experience what you’ve described as partial recovery. What does that look like?

Some individuals do experience some recovery over time, but for most individuals, the recovery is long and arduous. Long COVID can last with them for many years. Some people may come back to the clinic and say, “I’m doing better,” but if you really flesh it out and dig deeper, they didn’t do better; they adjusted to a new baseline. They used to walk the dog three to four blocks, and now they walk the dog only half a block. They used to do an activity with their partner every Saturday or Sunday, and now they do half of that.

If you’re a physician, a primary care provider, or any other provider who is dealing with a patient with long COVID, know that this is really happening. It can happen even in vaccinated individuals. The presentation is heterogeneous. Some people may present to you with and say. “Well, before I had COVID I was mentally sharp and now having I’m having difficulty with memory, etc.” It can sometimes present as fatigue or postexertional malaise.

In some instances, it can present as sleep problems. It can present as what we call postural orthostatic tachycardia syndrome (POTS). Those people get a significant increase in heart rate with postural changes.

What the most important thing we can we learn from the emergence of long COVID?

This whole thing taught us that infections can cause chronic disease. That’s really the No. 1 lesson that I take from this pandemic – that infections can cause chronic disease.

Looking at only acute illness from COVID is really only looking at the tip of the iceberg. Beneath that tip of the iceberg lies this hidden toll of disease that we don’t really talk about that much.

This pandemic shone a very, very good light on the idea that there is really an intimate connection between infections and chronic disease. It was really hardwired into our medical training as doctors that most infections, when people get over the hump of the acute phase of the disease, it’s all behind them. I think long COVID has humbled us in many, many ways, but chief among those is the realization – the stark realization – that infections can cause chronic disease.

That’s really going back to your [first] question: What does it mean that some people are not recovering? They actually have chronic illness. I’m hoping that we will find a treatment, that we’ll start finding things that would help them get back to baseline. But at this point in time, what we’re dealing with is people with chronic illness or chronic disease that may continue to affect them for many years to come in the absence of a treatment or a cure.

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

People infected multiple times with COVID-19 are more likely to develop long COVID, and most never fully recover from the condition. Those are two of the most striking findings of a comprehensive new research study of 138,000 veterans.

Lead researcher Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care and clinical epidemiologist at Washington University in St. Louis, spoke with this news organization about his team’s findings, what we know – and don’t – about long COVID, and what it means for physicians treating patients with the condition.

Excerpts of the interview follow.

Your research concluded that for those infected early in the pandemic, some long COVID symptoms declined over 2 years, but some did not. You have also concluded that long COVID is a chronic disease. Why?

We’ve been in this journey a little bit more than three and a half years. Some patients do experience some recovery. But that’s not the norm. Most people do not really fully recover. The health trajectory for people with long COVID is really very heterogeneous. There is no one-size-fits-all. There’s really no one line that I could give you that could cover all your patients. But it is very, very, very clear that a bunch of them experienced long COVID for sure; that’s really happening.

It happened in the pre-Delta era and in the Delta era, and with Omicron subvariants, even now. There are people who think, “This is a nothing-burger anymore,” or “It’s not an issue anymore.” It’s still happening with the current variants. Vaccines do reduce risk for long COVID, but do not completely eliminate the risk for long COVID.

You work with patients with long COVID in the clinic and also analyze data from thousands more. If long COVID does not go away, what should doctors look for in everyday practice that will help them recognize and help patients with long COVID?

Long COVID is not uncommon. We see it in the clinic in large numbers. Whatever clinic you’re running – if you’re running a cardiology clinic, or a nephrology clinic, or diabetes, or primary care – probably some of your people have it. You may not know about it. They may not tell you about it. You may not recognize it.

Not all long COVID is the same, and that’s really what makes it complex and makes it really hard to deal with in the clinic. But that’s the reality that we’re all dealing with. And it’s multisystemic; it’s not like it affects the heart only, the brain only, or the autonomic nervous system only. It does not behave in the same way in different individuals – they may have different manifestations, various health trajectories, and different outcomes. It’s important for doctors to get up to speed on long COVID as a multisystem illness.

Management at this point is really managing the symptoms. We don’t have a treatment for it; we don’t have a cure for it.

Some patients experience what you’ve described as partial recovery. What does that look like?

Some individuals do experience some recovery over time, but for most individuals, the recovery is long and arduous. Long COVID can last with them for many years. Some people may come back to the clinic and say, “I’m doing better,” but if you really flesh it out and dig deeper, they didn’t do better; they adjusted to a new baseline. They used to walk the dog three to four blocks, and now they walk the dog only half a block. They used to do an activity with their partner every Saturday or Sunday, and now they do half of that.

If you’re a physician, a primary care provider, or any other provider who is dealing with a patient with long COVID, know that this is really happening. It can happen even in vaccinated individuals. The presentation is heterogeneous. Some people may present to you with and say. “Well, before I had COVID I was mentally sharp and now having I’m having difficulty with memory, etc.” It can sometimes present as fatigue or postexertional malaise.

In some instances, it can present as sleep problems. It can present as what we call postural orthostatic tachycardia syndrome (POTS). Those people get a significant increase in heart rate with postural changes.

What the most important thing we can we learn from the emergence of long COVID?

This whole thing taught us that infections can cause chronic disease. That’s really the No. 1 lesson that I take from this pandemic – that infections can cause chronic disease.

Looking at only acute illness from COVID is really only looking at the tip of the iceberg. Beneath that tip of the iceberg lies this hidden toll of disease that we don’t really talk about that much.

This pandemic shone a very, very good light on the idea that there is really an intimate connection between infections and chronic disease. It was really hardwired into our medical training as doctors that most infections, when people get over the hump of the acute phase of the disease, it’s all behind them. I think long COVID has humbled us in many, many ways, but chief among those is the realization – the stark realization – that infections can cause chronic disease.

That’s really going back to your [first] question: What does it mean that some people are not recovering? They actually have chronic illness. I’m hoping that we will find a treatment, that we’ll start finding things that would help them get back to baseline. But at this point in time, what we’re dealing with is people with chronic illness or chronic disease that may continue to affect them for many years to come in the absence of a treatment or a cure.

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

People infected multiple times with COVID-19 are more likely to develop long COVID, and most never fully recover from the condition. Those are two of the most striking findings of a comprehensive new research study of 138,000 veterans.

Lead researcher Ziyad Al-Aly, MD, chief of research at Veterans Affairs St. Louis Health Care and clinical epidemiologist at Washington University in St. Louis, spoke with this news organization about his team’s findings, what we know – and don’t – about long COVID, and what it means for physicians treating patients with the condition.

Excerpts of the interview follow.

Your research concluded that for those infected early in the pandemic, some long COVID symptoms declined over 2 years, but some did not. You have also concluded that long COVID is a chronic disease. Why?

We’ve been in this journey a little bit more than three and a half years. Some patients do experience some recovery. But that’s not the norm. Most people do not really fully recover. The health trajectory for people with long COVID is really very heterogeneous. There is no one-size-fits-all. There’s really no one line that I could give you that could cover all your patients. But it is very, very, very clear that a bunch of them experienced long COVID for sure; that’s really happening.

It happened in the pre-Delta era and in the Delta era, and with Omicron subvariants, even now. There are people who think, “This is a nothing-burger anymore,” or “It’s not an issue anymore.” It’s still happening with the current variants. Vaccines do reduce risk for long COVID, but do not completely eliminate the risk for long COVID.

You work with patients with long COVID in the clinic and also analyze data from thousands more. If long COVID does not go away, what should doctors look for in everyday practice that will help them recognize and help patients with long COVID?

Long COVID is not uncommon. We see it in the clinic in large numbers. Whatever clinic you’re running – if you’re running a cardiology clinic, or a nephrology clinic, or diabetes, or primary care – probably some of your people have it. You may not know about it. They may not tell you about it. You may not recognize it.

Not all long COVID is the same, and that’s really what makes it complex and makes it really hard to deal with in the clinic. But that’s the reality that we’re all dealing with. And it’s multisystemic; it’s not like it affects the heart only, the brain only, or the autonomic nervous system only. It does not behave in the same way in different individuals – they may have different manifestations, various health trajectories, and different outcomes. It’s important for doctors to get up to speed on long COVID as a multisystem illness.

Management at this point is really managing the symptoms. We don’t have a treatment for it; we don’t have a cure for it.

Some patients experience what you’ve described as partial recovery. What does that look like?

Some individuals do experience some recovery over time, but for most individuals, the recovery is long and arduous. Long COVID can last with them for many years. Some people may come back to the clinic and say, “I’m doing better,” but if you really flesh it out and dig deeper, they didn’t do better; they adjusted to a new baseline. They used to walk the dog three to four blocks, and now they walk the dog only half a block. They used to do an activity with their partner every Saturday or Sunday, and now they do half of that.

If you’re a physician, a primary care provider, or any other provider who is dealing with a patient with long COVID, know that this is really happening. It can happen even in vaccinated individuals. The presentation is heterogeneous. Some people may present to you with and say. “Well, before I had COVID I was mentally sharp and now having I’m having difficulty with memory, etc.” It can sometimes present as fatigue or postexertional malaise.

In some instances, it can present as sleep problems. It can present as what we call postural orthostatic tachycardia syndrome (POTS). Those people get a significant increase in heart rate with postural changes.

What the most important thing we can we learn from the emergence of long COVID?

This whole thing taught us that infections can cause chronic disease. That’s really the No. 1 lesson that I take from this pandemic – that infections can cause chronic disease.

Looking at only acute illness from COVID is really only looking at the tip of the iceberg. Beneath that tip of the iceberg lies this hidden toll of disease that we don’t really talk about that much.

This pandemic shone a very, very good light on the idea that there is really an intimate connection between infections and chronic disease. It was really hardwired into our medical training as doctors that most infections, when people get over the hump of the acute phase of the disease, it’s all behind them. I think long COVID has humbled us in many, many ways, but chief among those is the realization – the stark realization – that infections can cause chronic disease.

That’s really going back to your [first] question: What does it mean that some people are not recovering? They actually have chronic illness. I’m hoping that we will find a treatment, that we’ll start finding things that would help them get back to baseline. But at this point in time, what we’re dealing with is people with chronic illness or chronic disease that may continue to affect them for many years to come in the absence of a treatment or a cure.

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

BOSTON – An investigational natural killer cell (NK) therapy has shown promise in the treatment of Alzheimer’s disease, in a small phase 1 proof-of-concept clinical trial.

SNK01, being developed by NKGen Biotech, is an autologous, nongenetically modified NK cell product that has enhanced cytotoxicity and activating receptor expression.

“When we give these enhanced natural killer cells intravenously, not only do they get into the brain, but we’ve shown, through CSF biomarker data, that they reduce both amyloid and tau proteins, dramatically reducing the neuroinflammation,” said Paul Song, MD, chief executive officer of NKGen Biotech.

“Remarkably,” in the first 6 months, 90% of patients with Alzheimer’s disease demonstrated improvement or maintained stable cognitive function, based on the Alzheimer’s Disease Composite Score (ADCOMS), suggesting that SNK01 may do more than simply slow disease progression, Dr. Song said.

The findings were presented at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Sound rationale

NK cells are an essential part of the innate immune system that can shape the adaptive response by eliminating activated (not resting) autologous CD4+ T cells. Weak or deficient NK cells have been found to correlate with various diseases, including autoimmune diseases, and emerging data suggest an autoimmune component to Alzheimer’s disease.

The phase 1 study evaluated the safety, tolerability, and exploratory efficacy of SNK01 given intravenously in escalating doses every 3 weeks (four treatments in total).

Participants included 10 patients with Alzheimer’s disease confirmed by imaging. Five had mild Alzheimer’s disease, three had moderate Alzheimer’s disease, and two had advanced Alzheimer’s disease, based on baseline Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Median baseline CDR-SB score was 9 (range, 4-18).

Cognitive assessments included CDR-SB, Mini-Mental State Examination (MMSE), Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and ADCOMS. CSF biomarker analyses were performed at baseline and at 1 and 12 weeks after the final dose (weeks 11 and 22, respectively).

NK cells were successfully activated and expanded in all 10 patients and no treatment-related adverse events were observed.

Based on the CSF biomarker data, SNK01 crossed the blood–brain barrier and reduced CSF amyloid-beta 42/40 and pTau181 levels and neuroinflammation, as measured by glial fibrillary acid protein (GFAP), and the effects appeared to persist 12 weeks after the final dose.

The exploratory efficacy data show that, 1 week after final dose (week 11), compared with baseline, 30% of patients showed clinical improvement on the composite ADCOMS and 60% had a stable ADCOMS score; 50%-70% of patients were stable or improved on the CDR-SB, ADAS-Cog and/or MMSE.

“One patient went from a MMSE score of 14, which is moderate dementia, to 22, which is mild cognitive impairment,” said Dr. Song.

At 12 weeks after the final dose (week 22), 44%-89% of patients remained stable or improved in all cognitive scores compared with week 11; and 50% of the patients with stable ADCOMS scores at week 11 remained stable.

Based on the positive phase 1 data, the Food and Drug Administration has approved a phase 1/2a study in patients with moderate Alzheimer’s disease. “The trial will use a much higher dose and a prolonged dosing regimen and we think we’ll see even more dramatic results with more sustained higher dosing,” Dr. Song said.

Down the road, it will be interesting to see how NK cell therapy could “complement” anti-amyloid and anti-tau therapies, he added.
 

Ideal treatment approach

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said NK cells have “natural abilities that could make them an ideal treatment approach for Alzheimer’s and similar neurodegenerative diseases.

“NK cells have properties that allow them to recognize and destroy diseased brain cells while leaving healthy cells intact, without causing excessive inflammation or autoimmune issues. It has historically been difficult to get immune cells to access the privileged immunological environment of the brain,” Dr. Lakhan explained.

“However, this line of early research shows that NK cells safely crosses the blood–brain barrier, infiltrates brain tissue, and may stave off Alzheimer’s disease as measured by biomarkers and clinical symptoms,” he noted.

“This emerging cell-based immunotherapy is highly-specific to the cells responsible for Alzheimer’s, avoids drug resistance, has long-lasting results, and has fewer side effects than drug counterparts,” Dr. Lakhan said.

The trial was sponsored by NKGen Biotech. Dr. Song and six coauthors are employees and shareholders in the company. Dr. Lakhan reports no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON – An investigational natural killer cell (NK) therapy has shown promise in the treatment of Alzheimer’s disease, in a small phase 1 proof-of-concept clinical trial.

SNK01, being developed by NKGen Biotech, is an autologous, nongenetically modified NK cell product that has enhanced cytotoxicity and activating receptor expression.

“When we give these enhanced natural killer cells intravenously, not only do they get into the brain, but we’ve shown, through CSF biomarker data, that they reduce both amyloid and tau proteins, dramatically reducing the neuroinflammation,” said Paul Song, MD, chief executive officer of NKGen Biotech.

“Remarkably,” in the first 6 months, 90% of patients with Alzheimer’s disease demonstrated improvement or maintained stable cognitive function, based on the Alzheimer’s Disease Composite Score (ADCOMS), suggesting that SNK01 may do more than simply slow disease progression, Dr. Song said.

The findings were presented at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Sound rationale

NK cells are an essential part of the innate immune system that can shape the adaptive response by eliminating activated (not resting) autologous CD4+ T cells. Weak or deficient NK cells have been found to correlate with various diseases, including autoimmune diseases, and emerging data suggest an autoimmune component to Alzheimer’s disease.

The phase 1 study evaluated the safety, tolerability, and exploratory efficacy of SNK01 given intravenously in escalating doses every 3 weeks (four treatments in total).

Participants included 10 patients with Alzheimer’s disease confirmed by imaging. Five had mild Alzheimer’s disease, three had moderate Alzheimer’s disease, and two had advanced Alzheimer’s disease, based on baseline Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Median baseline CDR-SB score was 9 (range, 4-18).

Cognitive assessments included CDR-SB, Mini-Mental State Examination (MMSE), Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and ADCOMS. CSF biomarker analyses were performed at baseline and at 1 and 12 weeks after the final dose (weeks 11 and 22, respectively).

NK cells were successfully activated and expanded in all 10 patients and no treatment-related adverse events were observed.

Based on the CSF biomarker data, SNK01 crossed the blood–brain barrier and reduced CSF amyloid-beta 42/40 and pTau181 levels and neuroinflammation, as measured by glial fibrillary acid protein (GFAP), and the effects appeared to persist 12 weeks after the final dose.

The exploratory efficacy data show that, 1 week after final dose (week 11), compared with baseline, 30% of patients showed clinical improvement on the composite ADCOMS and 60% had a stable ADCOMS score; 50%-70% of patients were stable or improved on the CDR-SB, ADAS-Cog and/or MMSE.

“One patient went from a MMSE score of 14, which is moderate dementia, to 22, which is mild cognitive impairment,” said Dr. Song.

At 12 weeks after the final dose (week 22), 44%-89% of patients remained stable or improved in all cognitive scores compared with week 11; and 50% of the patients with stable ADCOMS scores at week 11 remained stable.

Based on the positive phase 1 data, the Food and Drug Administration has approved a phase 1/2a study in patients with moderate Alzheimer’s disease. “The trial will use a much higher dose and a prolonged dosing regimen and we think we’ll see even more dramatic results with more sustained higher dosing,” Dr. Song said.

Down the road, it will be interesting to see how NK cell therapy could “complement” anti-amyloid and anti-tau therapies, he added.
 

Ideal treatment approach

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said NK cells have “natural abilities that could make them an ideal treatment approach for Alzheimer’s and similar neurodegenerative diseases.

“NK cells have properties that allow them to recognize and destroy diseased brain cells while leaving healthy cells intact, without causing excessive inflammation or autoimmune issues. It has historically been difficult to get immune cells to access the privileged immunological environment of the brain,” Dr. Lakhan explained.

“However, this line of early research shows that NK cells safely crosses the blood–brain barrier, infiltrates brain tissue, and may stave off Alzheimer’s disease as measured by biomarkers and clinical symptoms,” he noted.

“This emerging cell-based immunotherapy is highly-specific to the cells responsible for Alzheimer’s, avoids drug resistance, has long-lasting results, and has fewer side effects than drug counterparts,” Dr. Lakhan said.

The trial was sponsored by NKGen Biotech. Dr. Song and six coauthors are employees and shareholders in the company. Dr. Lakhan reports no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

BOSTON – An investigational natural killer cell (NK) therapy has shown promise in the treatment of Alzheimer’s disease, in a small phase 1 proof-of-concept clinical trial.

SNK01, being developed by NKGen Biotech, is an autologous, nongenetically modified NK cell product that has enhanced cytotoxicity and activating receptor expression.

“When we give these enhanced natural killer cells intravenously, not only do they get into the brain, but we’ve shown, through CSF biomarker data, that they reduce both amyloid and tau proteins, dramatically reducing the neuroinflammation,” said Paul Song, MD, chief executive officer of NKGen Biotech.

“Remarkably,” in the first 6 months, 90% of patients with Alzheimer’s disease demonstrated improvement or maintained stable cognitive function, based on the Alzheimer’s Disease Composite Score (ADCOMS), suggesting that SNK01 may do more than simply slow disease progression, Dr. Song said.

The findings were presented at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Sound rationale

NK cells are an essential part of the innate immune system that can shape the adaptive response by eliminating activated (not resting) autologous CD4+ T cells. Weak or deficient NK cells have been found to correlate with various diseases, including autoimmune diseases, and emerging data suggest an autoimmune component to Alzheimer’s disease.

The phase 1 study evaluated the safety, tolerability, and exploratory efficacy of SNK01 given intravenously in escalating doses every 3 weeks (four treatments in total).

Participants included 10 patients with Alzheimer’s disease confirmed by imaging. Five had mild Alzheimer’s disease, three had moderate Alzheimer’s disease, and two had advanced Alzheimer’s disease, based on baseline Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Median baseline CDR-SB score was 9 (range, 4-18).

Cognitive assessments included CDR-SB, Mini-Mental State Examination (MMSE), Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and ADCOMS. CSF biomarker analyses were performed at baseline and at 1 and 12 weeks after the final dose (weeks 11 and 22, respectively).

NK cells were successfully activated and expanded in all 10 patients and no treatment-related adverse events were observed.

Based on the CSF biomarker data, SNK01 crossed the blood–brain barrier and reduced CSF amyloid-beta 42/40 and pTau181 levels and neuroinflammation, as measured by glial fibrillary acid protein (GFAP), and the effects appeared to persist 12 weeks after the final dose.

The exploratory efficacy data show that, 1 week after final dose (week 11), compared with baseline, 30% of patients showed clinical improvement on the composite ADCOMS and 60% had a stable ADCOMS score; 50%-70% of patients were stable or improved on the CDR-SB, ADAS-Cog and/or MMSE.

“One patient went from a MMSE score of 14, which is moderate dementia, to 22, which is mild cognitive impairment,” said Dr. Song.

At 12 weeks after the final dose (week 22), 44%-89% of patients remained stable or improved in all cognitive scores compared with week 11; and 50% of the patients with stable ADCOMS scores at week 11 remained stable.

Based on the positive phase 1 data, the Food and Drug Administration has approved a phase 1/2a study in patients with moderate Alzheimer’s disease. “The trial will use a much higher dose and a prolonged dosing regimen and we think we’ll see even more dramatic results with more sustained higher dosing,” Dr. Song said.

Down the road, it will be interesting to see how NK cell therapy could “complement” anti-amyloid and anti-tau therapies, he added.
 

Ideal treatment approach

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said NK cells have “natural abilities that could make them an ideal treatment approach for Alzheimer’s and similar neurodegenerative diseases.

“NK cells have properties that allow them to recognize and destroy diseased brain cells while leaving healthy cells intact, without causing excessive inflammation or autoimmune issues. It has historically been difficult to get immune cells to access the privileged immunological environment of the brain,” Dr. Lakhan explained.

“However, this line of early research shows that NK cells safely crosses the blood–brain barrier, infiltrates brain tissue, and may stave off Alzheimer’s disease as measured by biomarkers and clinical symptoms,” he noted.

“This emerging cell-based immunotherapy is highly-specific to the cells responsible for Alzheimer’s, avoids drug resistance, has long-lasting results, and has fewer side effects than drug counterparts,” Dr. Lakhan said.

The trial was sponsored by NKGen Biotech. Dr. Song and six coauthors are employees and shareholders in the company. Dr. Lakhan reports no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

What’s in a day’s work? For doctors, it’s typically a mix of seeing patients and completing paperwork and follow-up. Often it extends well past the standard workday.

Dennis Hursh, JD, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, describes one overwhelmed ob.gyn. who recently consulted him for this problem.

“My client had accepted a position in a group practice where his contract stated he would be working during normal office hours, Monday through Friday, from 8 a.m. to 5 p.m. – in other words, a 40-hour workweek,” Mr. Hursh said.

But the distressed physician discovered that actually, he was working almost twice as many hours. “He’d get to work early to do charting, then see patients during the 40 hours, perhaps grabbing a quick sandwich for a few minutes – and then stay after 5 [p.m.] for a few more hours when he’d work on charts or other administrative tasks. Then he’d get something to eat, work on more charts, then go to bed, get up in the morning, and repeat.”

Mr. Hursh summarized the client’s life: “Eating, sleeping, practicing clinical medicine, and doing nonclinical tasks.”

It turned out that the 40-hour workweek included in the contract referred to patient-facing hours, not to all of the ancillary tasks that are part of practicing medicine in this day and age. “Unfortunately, this is far from an isolated story,” said Mr. Hursh.
 

Be aware of what’s in the contract

“The first draft of many standard physician employment contracts often omits mention of patient contact hour requirements and rather uses vague verbiage such as ‘full-time’ employment or ‘1.0 FTE’ – or full-time equivalent – without defining that term,” said Mr. Hursh. Typically, the 40 hours exclude call coverage, but most physicians understand that and, at least at first glance, it all sounds very reasonable.

But once charting, hours on the phone, arguing with managed care companies, sending in prescriptions, administrative meetings, and other tasks are thrown in, the work hours expand dramatically. Moreover, if your employer doesn’t utilize hospitalists, you may be expected to “round” outside of the 40 hours, which can be particularly burdensome if the employer admits patients to multiple hospitals.

Amanda Hill, JD, owner of Hill Health Law based in Austin, Texas, told this news organization that this predicament isn’t unique to physicians. Exempt employees who don’t clock in and out are often expected to work overtime – that is, to “work as long as it takes to get the job done.” It can affect NPs, PAs, and many others in the health care space. But the number of tasks that fall upon a doctor’s shoulders and the fact that patients’ health and lives are at stake up the ante and make the situation far more difficult for doctors than for employees in other industries.

So it’s important to nail down precise terms in the contract and, if possible, negotiate for a more humane schedule by specifying how the working hours will be used.

“It’s true that a 1.0 FTE definition is too vague,” Ms. Hill said. “I’ve negotiated a lot of contracts where we nail down in writing that the in-office schedule equals 34 hours per week, so the physician is guaranteed an additional 6 hours for administrative time.”

Mr. Hursh usually asks for 32 hours of patient contact per week, which leaves 1 full day per week to catch up on basic administrative tasks. “It’s important for employers to recognize that seeing patients isn’t the only thing a doctor does and there’s a lot of work in addition to face-to-face time,” he said.

But he hasn’t always been successful. One physician client was seeking a workweek consisting of 36 patient contact hours, “which is 90% of the usual FTE of a 40-hour week,” said Mr. Hursh. “But the employer called it ‘part-time,’ as if the doctor were planning to be lying in the sun for the other 4 hours.”

The client decided to accept a 10% pay cut and 10% less vacation to guarantee that she had those extra hours for administrative tasks. “She’s probably working way more than 36 hours a week, but maybe closer to 50 or 60 instead of 70 or more,” he said.
 

Clarify call coverage

Call coverage is typically not included in the hours a physician is contracted to work on a weekly basis. “Most contracts have call, and it’s usually evenly distributed among parties in a practice, but call can expand if another doctor is out sick, for example,” said Ms. Hill.

Sometimes the language in the contract is vague regarding call coverage. “I ask, how many shifts per year is the doctor is expected to work? Then, I try to negotiate extra pay if more shifts arise,” she said. “The hospital or practice may not demand extra call because they don’t want to pay extra money to the physician.”

On the other hand, some physicians may be eager to take extra call if it means extra income.

Ms. Hill stated that one of her clients was being paid as a “part-time, 2-day-a-week provider” but was asked to be on call and take night and weekend work. When you added it all up, she was putting in almost 30 hours a week.

“This is abusive to a provider that works so hard for patients,” Ms. Hill said. “We have to protect them through the contract language, so they have something hard and fast to point to when their administrator pushes them too hard. Doctors should get value for their time.”

Ms. Hill and her client pushed for more money, and the employer gave in. “All we had to do was to point out how many hours she was actually working. She didn’t mind all the extra call, but she wanted to be compensated.” The doctor’s salary was hiked by $25,000.
 

Differences in specialties and settings

There are some specialties where it might be easier to have more defined hours, while other specialties are more challenging. Anu Murthy, Esq., an attorney and associate contract review specialist at Contract Diagnostics (a national firm that reviews physician contracts) told this news organization that the work of hospitalists, intensivists, and emergency department physicians, for example, is done in shifts, which tend to be fixed hours.

“They need to get their charting completed so that whoever takes over on the next shift has access to the most recent notes about the patient,” she said. By contrast, surgeons can’t always account for how long a given surgery will take. “It could be as long as 9 hours,” she said. Notes need to be written immediately for the sake of the patient’s postsurgical care.

Dermatologists tend to deal with fewer emergencies, compared with other specialists, and it’s easier for their patients to be slotted into an organized schedule. On the other hand, primary care doctors – internists, family practice physicians, and pediatricians – may be seeing 40-50 patients a day, one every 15 minutes.

Practice setting also makes a difference, said Ms. Murthy. Veterans Administration (VA) hospitals or government-run clinics tend to have more rigidly defined hours, compared with other settings, so if you’re in a VA hospital or government-run clinic, work-life balance tends to be better.

Physicians who work remotely via telehealth also tend to have a better work-life balance, compared with those who see patients in person, Ms. Murthy said. But the difference may be in not having to spend extra time commuting to work or interacting with others in the work environment, since some research has suggested that telehealth physicians may actually spend more time engaged in charting after hours, compared with their in-person counterparts.
 

Using scribes to maximize your time

Elliott Trotter, MD, is an emergency medicine physician, associate clinical professor of emergency medicine at Texas Christian University Medical Schools, and founder of the ScribeNest, a Texas-based company that trains health care scribes. He told this news organization that there are ways to maximize one’s time during shifts so that much of the charting can be accomplished during working hours.

“About 28 years ago, I realized that the documentation load for physicians was enormous and at that time I developed the Modern Scribe, using premed students for ‘elbow support’ to help with the workload by documenting the ED encounters in real time during the encounter so I wouldn’t have to do so later.”

Over the years, as EHRs have become more ubiquitous and onerous, the role of the scribe has “evolved from a luxury to a necessity,” said Dr. Trotter. The scribes can actually record the encounter directly into the EHR so that the physician doesn’t have to do so later and doesn’t have to look at a computer screen but can look at the patient during the encounter.

“This enhances communication and has been shown to improve patient care,” he said.

Dr. Trotter said he rarely, if ever, needs to do documentation after hours. “But one of my physician colleagues had over 500 charts in his in-basket on a regular basis, which was overwhelming and untenable.”

The use of AI in health care is rapidly growing. Tools to help hasten the process of taking notes through use of AI-generated summaries is something appealing to many doctors. Ms. Hill warned physicians to “be careful not to rely so heavily on AI that you trust it over your own words.” She noted that it can make mistakes, and the liability always remains with the clinician.
 

Creating time-efficient strategies

Wilfrid Noel Raby, PhD, MD, a psychiatrist in private practice in Teaneck, N.J., was formerly a psychiatrist in the substance abuse unit at Montefiore Hospital, New York. He told this news organization that he developed a system whereby he rarely had to take work home with him. “I was working only 20 hours a week, but I was usually able to do my charting during those hours, as well as seeing patients,” he said. “I scheduled my appointments and structured a little ‘buffer time’ between them so that I had time to document the first appointment before moving on to the next one.”

There were days when this wasn’t possible because there were too many patients who needed to be seen back-to-back. “So I developed my own template where I could take rapid, very standardized notes that fit into the format of the EHR and met those expectations.” Then, when he had finished seeing patients, he could quickly enter the content of his notes into the EHR. If necessary, he completed his charting on a different day.

Viwek Bisen, DO, assistant professor of psychiatry, Hackensack (N.J.) University Medical Center, is a psychiatrist in the emergency department. “My contract is based on a traditional 40-hour workweek, with 80% of my time allotted to seeing patients and 20% of my time allotted to administration.”

But the way his time actually plays out is that he’s seeing patients during about half of the 32 hours. “The rest of the time, I’m charting, speaking to family members of patients, writing notes, engaging in team meetings, and dealing with insurance companies.” Dr. Bisen has developed his own system of completing his notes while still in the hospital. “I’ve learned to be efficient and manage my time better, so I no longer have to take work home with me.”

“At the end of the day, doctors are people,” Ms. Hill said. “They are not machines. Maybe in residency and fellowship they may grind out impossible shifts with little sleep, but this pace isn’t tenable for an entire career.”

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

What’s in a day’s work? For doctors, it’s typically a mix of seeing patients and completing paperwork and follow-up. Often it extends well past the standard workday.

Dennis Hursh, JD, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, describes one overwhelmed ob.gyn. who recently consulted him for this problem.

“My client had accepted a position in a group practice where his contract stated he would be working during normal office hours, Monday through Friday, from 8 a.m. to 5 p.m. – in other words, a 40-hour workweek,” Mr. Hursh said.

But the distressed physician discovered that actually, he was working almost twice as many hours. “He’d get to work early to do charting, then see patients during the 40 hours, perhaps grabbing a quick sandwich for a few minutes – and then stay after 5 [p.m.] for a few more hours when he’d work on charts or other administrative tasks. Then he’d get something to eat, work on more charts, then go to bed, get up in the morning, and repeat.”

Mr. Hursh summarized the client’s life: “Eating, sleeping, practicing clinical medicine, and doing nonclinical tasks.”

It turned out that the 40-hour workweek included in the contract referred to patient-facing hours, not to all of the ancillary tasks that are part of practicing medicine in this day and age. “Unfortunately, this is far from an isolated story,” said Mr. Hursh.
 

Be aware of what’s in the contract

“The first draft of many standard physician employment contracts often omits mention of patient contact hour requirements and rather uses vague verbiage such as ‘full-time’ employment or ‘1.0 FTE’ – or full-time equivalent – without defining that term,” said Mr. Hursh. Typically, the 40 hours exclude call coverage, but most physicians understand that and, at least at first glance, it all sounds very reasonable.

But once charting, hours on the phone, arguing with managed care companies, sending in prescriptions, administrative meetings, and other tasks are thrown in, the work hours expand dramatically. Moreover, if your employer doesn’t utilize hospitalists, you may be expected to “round” outside of the 40 hours, which can be particularly burdensome if the employer admits patients to multiple hospitals.

Amanda Hill, JD, owner of Hill Health Law based in Austin, Texas, told this news organization that this predicament isn’t unique to physicians. Exempt employees who don’t clock in and out are often expected to work overtime – that is, to “work as long as it takes to get the job done.” It can affect NPs, PAs, and many others in the health care space. But the number of tasks that fall upon a doctor’s shoulders and the fact that patients’ health and lives are at stake up the ante and make the situation far more difficult for doctors than for employees in other industries.

So it’s important to nail down precise terms in the contract and, if possible, negotiate for a more humane schedule by specifying how the working hours will be used.

“It’s true that a 1.0 FTE definition is too vague,” Ms. Hill said. “I’ve negotiated a lot of contracts where we nail down in writing that the in-office schedule equals 34 hours per week, so the physician is guaranteed an additional 6 hours for administrative time.”

Mr. Hursh usually asks for 32 hours of patient contact per week, which leaves 1 full day per week to catch up on basic administrative tasks. “It’s important for employers to recognize that seeing patients isn’t the only thing a doctor does and there’s a lot of work in addition to face-to-face time,” he said.

But he hasn’t always been successful. One physician client was seeking a workweek consisting of 36 patient contact hours, “which is 90% of the usual FTE of a 40-hour week,” said Mr. Hursh. “But the employer called it ‘part-time,’ as if the doctor were planning to be lying in the sun for the other 4 hours.”

The client decided to accept a 10% pay cut and 10% less vacation to guarantee that she had those extra hours for administrative tasks. “She’s probably working way more than 36 hours a week, but maybe closer to 50 or 60 instead of 70 or more,” he said.
 

Clarify call coverage

Call coverage is typically not included in the hours a physician is contracted to work on a weekly basis. “Most contracts have call, and it’s usually evenly distributed among parties in a practice, but call can expand if another doctor is out sick, for example,” said Ms. Hill.

Sometimes the language in the contract is vague regarding call coverage. “I ask, how many shifts per year is the doctor is expected to work? Then, I try to negotiate extra pay if more shifts arise,” she said. “The hospital or practice may not demand extra call because they don’t want to pay extra money to the physician.”

On the other hand, some physicians may be eager to take extra call if it means extra income.

Ms. Hill stated that one of her clients was being paid as a “part-time, 2-day-a-week provider” but was asked to be on call and take night and weekend work. When you added it all up, she was putting in almost 30 hours a week.

“This is abusive to a provider that works so hard for patients,” Ms. Hill said. “We have to protect them through the contract language, so they have something hard and fast to point to when their administrator pushes them too hard. Doctors should get value for their time.”

Ms. Hill and her client pushed for more money, and the employer gave in. “All we had to do was to point out how many hours she was actually working. She didn’t mind all the extra call, but she wanted to be compensated.” The doctor’s salary was hiked by $25,000.
 

Differences in specialties and settings

There are some specialties where it might be easier to have more defined hours, while other specialties are more challenging. Anu Murthy, Esq., an attorney and associate contract review specialist at Contract Diagnostics (a national firm that reviews physician contracts) told this news organization that the work of hospitalists, intensivists, and emergency department physicians, for example, is done in shifts, which tend to be fixed hours.

“They need to get their charting completed so that whoever takes over on the next shift has access to the most recent notes about the patient,” she said. By contrast, surgeons can’t always account for how long a given surgery will take. “It could be as long as 9 hours,” she said. Notes need to be written immediately for the sake of the patient’s postsurgical care.

Dermatologists tend to deal with fewer emergencies, compared with other specialists, and it’s easier for their patients to be slotted into an organized schedule. On the other hand, primary care doctors – internists, family practice physicians, and pediatricians – may be seeing 40-50 patients a day, one every 15 minutes.

Practice setting also makes a difference, said Ms. Murthy. Veterans Administration (VA) hospitals or government-run clinics tend to have more rigidly defined hours, compared with other settings, so if you’re in a VA hospital or government-run clinic, work-life balance tends to be better.

Physicians who work remotely via telehealth also tend to have a better work-life balance, compared with those who see patients in person, Ms. Murthy said. But the difference may be in not having to spend extra time commuting to work or interacting with others in the work environment, since some research has suggested that telehealth physicians may actually spend more time engaged in charting after hours, compared with their in-person counterparts.
 

Using scribes to maximize your time

Elliott Trotter, MD, is an emergency medicine physician, associate clinical professor of emergency medicine at Texas Christian University Medical Schools, and founder of the ScribeNest, a Texas-based company that trains health care scribes. He told this news organization that there are ways to maximize one’s time during shifts so that much of the charting can be accomplished during working hours.

“About 28 years ago, I realized that the documentation load for physicians was enormous and at that time I developed the Modern Scribe, using premed students for ‘elbow support’ to help with the workload by documenting the ED encounters in real time during the encounter so I wouldn’t have to do so later.”

Over the years, as EHRs have become more ubiquitous and onerous, the role of the scribe has “evolved from a luxury to a necessity,” said Dr. Trotter. The scribes can actually record the encounter directly into the EHR so that the physician doesn’t have to do so later and doesn’t have to look at a computer screen but can look at the patient during the encounter.

“This enhances communication and has been shown to improve patient care,” he said.

Dr. Trotter said he rarely, if ever, needs to do documentation after hours. “But one of my physician colleagues had over 500 charts in his in-basket on a regular basis, which was overwhelming and untenable.”

The use of AI in health care is rapidly growing. Tools to help hasten the process of taking notes through use of AI-generated summaries is something appealing to many doctors. Ms. Hill warned physicians to “be careful not to rely so heavily on AI that you trust it over your own words.” She noted that it can make mistakes, and the liability always remains with the clinician.
 

Creating time-efficient strategies

Wilfrid Noel Raby, PhD, MD, a psychiatrist in private practice in Teaneck, N.J., was formerly a psychiatrist in the substance abuse unit at Montefiore Hospital, New York. He told this news organization that he developed a system whereby he rarely had to take work home with him. “I was working only 20 hours a week, but I was usually able to do my charting during those hours, as well as seeing patients,” he said. “I scheduled my appointments and structured a little ‘buffer time’ between them so that I had time to document the first appointment before moving on to the next one.”

There were days when this wasn’t possible because there were too many patients who needed to be seen back-to-back. “So I developed my own template where I could take rapid, very standardized notes that fit into the format of the EHR and met those expectations.” Then, when he had finished seeing patients, he could quickly enter the content of his notes into the EHR. If necessary, he completed his charting on a different day.

Viwek Bisen, DO, assistant professor of psychiatry, Hackensack (N.J.) University Medical Center, is a psychiatrist in the emergency department. “My contract is based on a traditional 40-hour workweek, with 80% of my time allotted to seeing patients and 20% of my time allotted to administration.”

But the way his time actually plays out is that he’s seeing patients during about half of the 32 hours. “The rest of the time, I’m charting, speaking to family members of patients, writing notes, engaging in team meetings, and dealing with insurance companies.” Dr. Bisen has developed his own system of completing his notes while still in the hospital. “I’ve learned to be efficient and manage my time better, so I no longer have to take work home with me.”

“At the end of the day, doctors are people,” Ms. Hill said. “They are not machines. Maybe in residency and fellowship they may grind out impossible shifts with little sleep, but this pace isn’t tenable for an entire career.”

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

What’s in a day’s work? For doctors, it’s typically a mix of seeing patients and completing paperwork and follow-up. Often it extends well past the standard workday.

Dennis Hursh, JD, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, describes one overwhelmed ob.gyn. who recently consulted him for this problem.

“My client had accepted a position in a group practice where his contract stated he would be working during normal office hours, Monday through Friday, from 8 a.m. to 5 p.m. – in other words, a 40-hour workweek,” Mr. Hursh said.

But the distressed physician discovered that actually, he was working almost twice as many hours. “He’d get to work early to do charting, then see patients during the 40 hours, perhaps grabbing a quick sandwich for a few minutes – and then stay after 5 [p.m.] for a few more hours when he’d work on charts or other administrative tasks. Then he’d get something to eat, work on more charts, then go to bed, get up in the morning, and repeat.”

Mr. Hursh summarized the client’s life: “Eating, sleeping, practicing clinical medicine, and doing nonclinical tasks.”

It turned out that the 40-hour workweek included in the contract referred to patient-facing hours, not to all of the ancillary tasks that are part of practicing medicine in this day and age. “Unfortunately, this is far from an isolated story,” said Mr. Hursh.
 

Be aware of what’s in the contract

“The first draft of many standard physician employment contracts often omits mention of patient contact hour requirements and rather uses vague verbiage such as ‘full-time’ employment or ‘1.0 FTE’ – or full-time equivalent – without defining that term,” said Mr. Hursh. Typically, the 40 hours exclude call coverage, but most physicians understand that and, at least at first glance, it all sounds very reasonable.

But once charting, hours on the phone, arguing with managed care companies, sending in prescriptions, administrative meetings, and other tasks are thrown in, the work hours expand dramatically. Moreover, if your employer doesn’t utilize hospitalists, you may be expected to “round” outside of the 40 hours, which can be particularly burdensome if the employer admits patients to multiple hospitals.

Amanda Hill, JD, owner of Hill Health Law based in Austin, Texas, told this news organization that this predicament isn’t unique to physicians. Exempt employees who don’t clock in and out are often expected to work overtime – that is, to “work as long as it takes to get the job done.” It can affect NPs, PAs, and many others in the health care space. But the number of tasks that fall upon a doctor’s shoulders and the fact that patients’ health and lives are at stake up the ante and make the situation far more difficult for doctors than for employees in other industries.

So it’s important to nail down precise terms in the contract and, if possible, negotiate for a more humane schedule by specifying how the working hours will be used.

“It’s true that a 1.0 FTE definition is too vague,” Ms. Hill said. “I’ve negotiated a lot of contracts where we nail down in writing that the in-office schedule equals 34 hours per week, so the physician is guaranteed an additional 6 hours for administrative time.”

Mr. Hursh usually asks for 32 hours of patient contact per week, which leaves 1 full day per week to catch up on basic administrative tasks. “It’s important for employers to recognize that seeing patients isn’t the only thing a doctor does and there’s a lot of work in addition to face-to-face time,” he said.

But he hasn’t always been successful. One physician client was seeking a workweek consisting of 36 patient contact hours, “which is 90% of the usual FTE of a 40-hour week,” said Mr. Hursh. “But the employer called it ‘part-time,’ as if the doctor were planning to be lying in the sun for the other 4 hours.”

The client decided to accept a 10% pay cut and 10% less vacation to guarantee that she had those extra hours for administrative tasks. “She’s probably working way more than 36 hours a week, but maybe closer to 50 or 60 instead of 70 or more,” he said.
 

Clarify call coverage

Call coverage is typically not included in the hours a physician is contracted to work on a weekly basis. “Most contracts have call, and it’s usually evenly distributed among parties in a practice, but call can expand if another doctor is out sick, for example,” said Ms. Hill.

Sometimes the language in the contract is vague regarding call coverage. “I ask, how many shifts per year is the doctor is expected to work? Then, I try to negotiate extra pay if more shifts arise,” she said. “The hospital or practice may not demand extra call because they don’t want to pay extra money to the physician.”

On the other hand, some physicians may be eager to take extra call if it means extra income.

Ms. Hill stated that one of her clients was being paid as a “part-time, 2-day-a-week provider” but was asked to be on call and take night and weekend work. When you added it all up, she was putting in almost 30 hours a week.

“This is abusive to a provider that works so hard for patients,” Ms. Hill said. “We have to protect them through the contract language, so they have something hard and fast to point to when their administrator pushes them too hard. Doctors should get value for their time.”

Ms. Hill and her client pushed for more money, and the employer gave in. “All we had to do was to point out how many hours she was actually working. She didn’t mind all the extra call, but she wanted to be compensated.” The doctor’s salary was hiked by $25,000.
 

Differences in specialties and settings

There are some specialties where it might be easier to have more defined hours, while other specialties are more challenging. Anu Murthy, Esq., an attorney and associate contract review specialist at Contract Diagnostics (a national firm that reviews physician contracts) told this news organization that the work of hospitalists, intensivists, and emergency department physicians, for example, is done in shifts, which tend to be fixed hours.

“They need to get their charting completed so that whoever takes over on the next shift has access to the most recent notes about the patient,” she said. By contrast, surgeons can’t always account for how long a given surgery will take. “It could be as long as 9 hours,” she said. Notes need to be written immediately for the sake of the patient’s postsurgical care.

Dermatologists tend to deal with fewer emergencies, compared with other specialists, and it’s easier for their patients to be slotted into an organized schedule. On the other hand, primary care doctors – internists, family practice physicians, and pediatricians – may be seeing 40-50 patients a day, one every 15 minutes.

Practice setting also makes a difference, said Ms. Murthy. Veterans Administration (VA) hospitals or government-run clinics tend to have more rigidly defined hours, compared with other settings, so if you’re in a VA hospital or government-run clinic, work-life balance tends to be better.

Physicians who work remotely via telehealth also tend to have a better work-life balance, compared with those who see patients in person, Ms. Murthy said. But the difference may be in not having to spend extra time commuting to work or interacting with others in the work environment, since some research has suggested that telehealth physicians may actually spend more time engaged in charting after hours, compared with their in-person counterparts.
 

Using scribes to maximize your time

Elliott Trotter, MD, is an emergency medicine physician, associate clinical professor of emergency medicine at Texas Christian University Medical Schools, and founder of the ScribeNest, a Texas-based company that trains health care scribes. He told this news organization that there are ways to maximize one’s time during shifts so that much of the charting can be accomplished during working hours.

“About 28 years ago, I realized that the documentation load for physicians was enormous and at that time I developed the Modern Scribe, using premed students for ‘elbow support’ to help with the workload by documenting the ED encounters in real time during the encounter so I wouldn’t have to do so later.”

Over the years, as EHRs have become more ubiquitous and onerous, the role of the scribe has “evolved from a luxury to a necessity,” said Dr. Trotter. The scribes can actually record the encounter directly into the EHR so that the physician doesn’t have to do so later and doesn’t have to look at a computer screen but can look at the patient during the encounter.

“This enhances communication and has been shown to improve patient care,” he said.

Dr. Trotter said he rarely, if ever, needs to do documentation after hours. “But one of my physician colleagues had over 500 charts in his in-basket on a regular basis, which was overwhelming and untenable.”

The use of AI in health care is rapidly growing. Tools to help hasten the process of taking notes through use of AI-generated summaries is something appealing to many doctors. Ms. Hill warned physicians to “be careful not to rely so heavily on AI that you trust it over your own words.” She noted that it can make mistakes, and the liability always remains with the clinician.
 

Creating time-efficient strategies

Wilfrid Noel Raby, PhD, MD, a psychiatrist in private practice in Teaneck, N.J., was formerly a psychiatrist in the substance abuse unit at Montefiore Hospital, New York. He told this news organization that he developed a system whereby he rarely had to take work home with him. “I was working only 20 hours a week, but I was usually able to do my charting during those hours, as well as seeing patients,” he said. “I scheduled my appointments and structured a little ‘buffer time’ between them so that I had time to document the first appointment before moving on to the next one.”

There were days when this wasn’t possible because there were too many patients who needed to be seen back-to-back. “So I developed my own template where I could take rapid, very standardized notes that fit into the format of the EHR and met those expectations.” Then, when he had finished seeing patients, he could quickly enter the content of his notes into the EHR. If necessary, he completed his charting on a different day.

Viwek Bisen, DO, assistant professor of psychiatry, Hackensack (N.J.) University Medical Center, is a psychiatrist in the emergency department. “My contract is based on a traditional 40-hour workweek, with 80% of my time allotted to seeing patients and 20% of my time allotted to administration.”

But the way his time actually plays out is that he’s seeing patients during about half of the 32 hours. “The rest of the time, I’m charting, speaking to family members of patients, writing notes, engaging in team meetings, and dealing with insurance companies.” Dr. Bisen has developed his own system of completing his notes while still in the hospital. “I’ve learned to be efficient and manage my time better, so I no longer have to take work home with me.”

“At the end of the day, doctors are people,” Ms. Hill said. “They are not machines. Maybe in residency and fellowship they may grind out impossible shifts with little sleep, but this pace isn’t tenable for an entire career.”

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

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

A pair of new studies published about long COVID have shed more light on the sometimes-disabling condition that affects millions of people in the United States. 

Scientists worldwide have been working to understand the wide-ranging condition, from risk factors to causes to potential treatments. 

In the first study, 31 adults underwent lumbar puncture and blood draws to look for changes in their immune systems and also to look for changes in the nerve cells that could affect transmission of signals to the brain.

Among the participants, 25 people had neurocognitive symptoms of long COVID, such as memory loss or attention problems. Six participants had fully recovered from COVID, and 17 people had never had COVID. 

Those who had COVID were diagnosed between March 2020 and May 2021. Their fluid samples were drawn at least three months after their first symptoms.

The results were published in the Journal of Infectious Diseases. Study results showed that long COVID does not appear to be linked to the SARS-CoV-2 virus invading the brain or causing active brain damage.

According to a summary of the study from the University of Gothenburg (Sweden), where the researchers work, “there were no significant differences between the groups when analyzing blood and cerebrospinal fluid for immune activation or brain injury markers. The findings thus suggest that post-COVID condition is not the result of ongoing infection, immune activation, or brain damage.”

In the second study, Norwegian researchers compared the likelihood of having 17 different long COVID symptoms based on whether a person had been infected with COVID. The analysis included 53,846 people who were diagnosed with COVID between February 2020 and February 2021, as well as more than 485,000 people who were not infected. Most people had not been vaccinated against COVID-19 during the time of the study.

The results were published in the journal BMC Infectious Diseases. Study results showed that people who had COVID were more than twice as likely to experience shortness of breath or fatigue. They were also more likely to experience memory loss or headache compared to people who never had COVID. Researchers only looked at symptoms that occurred at least three months after a COVID diagnosis.

They also found that hospitalization increased the risk for experiencing long COVID symptoms of shortness of breath, fatigue, and memory loss.

The authors noted that a limitation of their study was that, often, not all symptoms reported during a visit with a general practice medical provider are recorded in Norway, which could have affected the results.

A version of this article appeared on Medscape.com.

A pair of new studies published about long COVID have shed more light on the sometimes-disabling condition that affects millions of people in the United States. 

Scientists worldwide have been working to understand the wide-ranging condition, from risk factors to causes to potential treatments. 

In the first study, 31 adults underwent lumbar puncture and blood draws to look for changes in their immune systems and also to look for changes in the nerve cells that could affect transmission of signals to the brain.

Among the participants, 25 people had neurocognitive symptoms of long COVID, such as memory loss or attention problems. Six participants had fully recovered from COVID, and 17 people had never had COVID. 

Those who had COVID were diagnosed between March 2020 and May 2021. Their fluid samples were drawn at least three months after their first symptoms.

The results were published in the Journal of Infectious Diseases. Study results showed that long COVID does not appear to be linked to the SARS-CoV-2 virus invading the brain or causing active brain damage.

According to a summary of the study from the University of Gothenburg (Sweden), where the researchers work, “there were no significant differences between the groups when analyzing blood and cerebrospinal fluid for immune activation or brain injury markers. The findings thus suggest that post-COVID condition is not the result of ongoing infection, immune activation, or brain damage.”

In the second study, Norwegian researchers compared the likelihood of having 17 different long COVID symptoms based on whether a person had been infected with COVID. The analysis included 53,846 people who were diagnosed with COVID between February 2020 and February 2021, as well as more than 485,000 people who were not infected. Most people had not been vaccinated against COVID-19 during the time of the study.

The results were published in the journal BMC Infectious Diseases. Study results showed that people who had COVID were more than twice as likely to experience shortness of breath or fatigue. They were also more likely to experience memory loss or headache compared to people who never had COVID. Researchers only looked at symptoms that occurred at least three months after a COVID diagnosis.

They also found that hospitalization increased the risk for experiencing long COVID symptoms of shortness of breath, fatigue, and memory loss.

The authors noted that a limitation of their study was that, often, not all symptoms reported during a visit with a general practice medical provider are recorded in Norway, which could have affected the results.

A version of this article appeared on Medscape.com.

A pair of new studies published about long COVID have shed more light on the sometimes-disabling condition that affects millions of people in the United States. 

Scientists worldwide have been working to understand the wide-ranging condition, from risk factors to causes to potential treatments. 

In the first study, 31 adults underwent lumbar puncture and blood draws to look for changes in their immune systems and also to look for changes in the nerve cells that could affect transmission of signals to the brain.

Among the participants, 25 people had neurocognitive symptoms of long COVID, such as memory loss or attention problems. Six participants had fully recovered from COVID, and 17 people had never had COVID. 

Those who had COVID were diagnosed between March 2020 and May 2021. Their fluid samples were drawn at least three months after their first symptoms.

The results were published in the Journal of Infectious Diseases. Study results showed that long COVID does not appear to be linked to the SARS-CoV-2 virus invading the brain or causing active brain damage.

According to a summary of the study from the University of Gothenburg (Sweden), where the researchers work, “there were no significant differences between the groups when analyzing blood and cerebrospinal fluid for immune activation or brain injury markers. The findings thus suggest that post-COVID condition is not the result of ongoing infection, immune activation, or brain damage.”

In the second study, Norwegian researchers compared the likelihood of having 17 different long COVID symptoms based on whether a person had been infected with COVID. The analysis included 53,846 people who were diagnosed with COVID between February 2020 and February 2021, as well as more than 485,000 people who were not infected. Most people had not been vaccinated against COVID-19 during the time of the study.

The results were published in the journal BMC Infectious Diseases. Study results showed that people who had COVID were more than twice as likely to experience shortness of breath or fatigue. They were also more likely to experience memory loss or headache compared to people who never had COVID. Researchers only looked at symptoms that occurred at least three months after a COVID diagnosis.

They also found that hospitalization increased the risk for experiencing long COVID symptoms of shortness of breath, fatigue, and memory loss.

The authors noted that a limitation of their study was that, often, not all symptoms reported during a visit with a general practice medical provider are recorded in Norway, which could have affected the results.

A version of this article appeared on Medscape.com.

TOPLINE:

Atrial fibrillation (AF) is associated with a 45% increased risk of mild cognitive impairment (MCI), an outcome that’s linked to cardiovascular risk factors and multi-comorbidity, results of a new study suggest.

METHODOLOGY:

• From over 4.3 million people in the UK primary electronic health record (EHR) database, researchers identified 233,833 (5.4%) with AF (mean age, 74.2 years) and randomly selected one age- and sex-matched control person without AF for each AF case patient.
• The primary outcome was incidence of mild cognitive impairment (MCI).
• The authors adjusted for age, sex, year at study entry, socioeconomic status, smoking, and a number of comorbid conditions.
• During a median of 5.3 years of follow-up, there were 4,269 incident MCI cases among both AF and non-AF patients.

TAKEAWAY:

• Individuals with AF had a higher risk of MCI than that of those without AF (adjusted hazard ratio [aHR], 1.45; 95% confidence interval [CI], 1.35-1.56).
• Besides AF, older age (risk ratio [RR], 1.08) and history of depression (RR, 1.44) were associated with greater risk of MCI, as were female sex, greater socioeconomic deprivation, stroke, and multimorbidity, including, for example, diabetes, hypercholesterolemia, and peripheral artery disease (all P < .001).
• Individuals with AF who received oral anticoagulants or amiodarone were not at increased risk of MCI, as was the case for those treated with digoxin.
• Individuals with AF and MCI were at greater risk of dementia (aHR, 1.25; 95% CI, 1.09-1.42). Sex, smoking, chronic kidney disease, and multi-comorbidity were among factors linked to elevated dementia risk.

IN PRACTICE:

The findings emphasize the association of multi-comorbidity and cardiovascular risk factors with development of MCI and progression to dementia in AF patients, the authors wrote. They noted that the data suggest combining anticoagulation and symptom and comorbidity management may prevent cognitive deterioration.

SOURCE:

The study was conducted by Sheng-Chia Chung, PhD, Institute of Health informatics Research, University College London, and colleagues. It was published online Oct. 25, 2023, as a research letter in the Journal of the American College of Cardiology (JACC): Advances. 

LIMITATIONS:

The EHR dataset may have lacked granularity and detail, and some risk factors or comorbidities may not have been measured. While those with AF receiving digoxin or amiodarone treatment had no higher risk of MCI than their non-AF peers, the study’s observational design and very wide confidence intervals for these subgroups prevent making solid inferences about causality or a potential protective role of these drugs.

DISCLOSURES:

Dr. Chung is supported by the National Institute of Health and Care Research (NIHR) Author Rui Providencia, MD, PhD, of the Institute of Health informatics Research, University College London, is supported by the University College London British Heart Foundation and NIHR. All other authors report no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Atrial fibrillation (AF) is associated with a 45% increased risk of mild cognitive impairment (MCI), an outcome that’s linked to cardiovascular risk factors and multi-comorbidity, results of a new study suggest.

METHODOLOGY:

• From over 4.3 million people in the UK primary electronic health record (EHR) database, researchers identified 233,833 (5.4%) with AF (mean age, 74.2 years) and randomly selected one age- and sex-matched control person without AF for each AF case patient.
• The primary outcome was incidence of mild cognitive impairment (MCI).
• The authors adjusted for age, sex, year at study entry, socioeconomic status, smoking, and a number of comorbid conditions.
• During a median of 5.3 years of follow-up, there were 4,269 incident MCI cases among both AF and non-AF patients.

TAKEAWAY:

• Individuals with AF had a higher risk of MCI than that of those without AF (adjusted hazard ratio [aHR], 1.45; 95% confidence interval [CI], 1.35-1.56).
• Besides AF, older age (risk ratio [RR], 1.08) and history of depression (RR, 1.44) were associated with greater risk of MCI, as were female sex, greater socioeconomic deprivation, stroke, and multimorbidity, including, for example, diabetes, hypercholesterolemia, and peripheral artery disease (all P < .001).
• Individuals with AF who received oral anticoagulants or amiodarone were not at increased risk of MCI, as was the case for those treated with digoxin.
• Individuals with AF and MCI were at greater risk of dementia (aHR, 1.25; 95% CI, 1.09-1.42). Sex, smoking, chronic kidney disease, and multi-comorbidity were among factors linked to elevated dementia risk.

IN PRACTICE:

The findings emphasize the association of multi-comorbidity and cardiovascular risk factors with development of MCI and progression to dementia in AF patients, the authors wrote. They noted that the data suggest combining anticoagulation and symptom and comorbidity management may prevent cognitive deterioration.

SOURCE:

The study was conducted by Sheng-Chia Chung, PhD, Institute of Health informatics Research, University College London, and colleagues. It was published online Oct. 25, 2023, as a research letter in the Journal of the American College of Cardiology (JACC): Advances. 

LIMITATIONS:

The EHR dataset may have lacked granularity and detail, and some risk factors or comorbidities may not have been measured. While those with AF receiving digoxin or amiodarone treatment had no higher risk of MCI than their non-AF peers, the study’s observational design and very wide confidence intervals for these subgroups prevent making solid inferences about causality or a potential protective role of these drugs.

DISCLOSURES:

Dr. Chung is supported by the National Institute of Health and Care Research (NIHR) Author Rui Providencia, MD, PhD, of the Institute of Health informatics Research, University College London, is supported by the University College London British Heart Foundation and NIHR. All other authors report no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Atrial fibrillation (AF) is associated with a 45% increased risk of mild cognitive impairment (MCI), an outcome that’s linked to cardiovascular risk factors and multi-comorbidity, results of a new study suggest.

METHODOLOGY:

• From over 4.3 million people in the UK primary electronic health record (EHR) database, researchers identified 233,833 (5.4%) with AF (mean age, 74.2 years) and randomly selected one age- and sex-matched control person without AF for each AF case patient.
• The primary outcome was incidence of mild cognitive impairment (MCI).
• The authors adjusted for age, sex, year at study entry, socioeconomic status, smoking, and a number of comorbid conditions.
• During a median of 5.3 years of follow-up, there were 4,269 incident MCI cases among both AF and non-AF patients.

TAKEAWAY:

• Individuals with AF had a higher risk of MCI than that of those without AF (adjusted hazard ratio [aHR], 1.45; 95% confidence interval [CI], 1.35-1.56).
• Besides AF, older age (risk ratio [RR], 1.08) and history of depression (RR, 1.44) were associated with greater risk of MCI, as were female sex, greater socioeconomic deprivation, stroke, and multimorbidity, including, for example, diabetes, hypercholesterolemia, and peripheral artery disease (all P < .001).
• Individuals with AF who received oral anticoagulants or amiodarone were not at increased risk of MCI, as was the case for those treated with digoxin.
• Individuals with AF and MCI were at greater risk of dementia (aHR, 1.25; 95% CI, 1.09-1.42). Sex, smoking, chronic kidney disease, and multi-comorbidity were among factors linked to elevated dementia risk.

IN PRACTICE:

The findings emphasize the association of multi-comorbidity and cardiovascular risk factors with development of MCI and progression to dementia in AF patients, the authors wrote. They noted that the data suggest combining anticoagulation and symptom and comorbidity management may prevent cognitive deterioration.

SOURCE:

The study was conducted by Sheng-Chia Chung, PhD, Institute of Health informatics Research, University College London, and colleagues. It was published online Oct. 25, 2023, as a research letter in the Journal of the American College of Cardiology (JACC): Advances. 

LIMITATIONS:

The EHR dataset may have lacked granularity and detail, and some risk factors or comorbidities may not have been measured. While those with AF receiving digoxin or amiodarone treatment had no higher risk of MCI than their non-AF peers, the study’s observational design and very wide confidence intervals for these subgroups prevent making solid inferences about causality or a potential protective role of these drugs.

DISCLOSURES:

Dr. Chung is supported by the National Institute of Health and Care Research (NIHR) Author Rui Providencia, MD, PhD, of the Institute of Health informatics Research, University College London, is supported by the University College London British Heart Foundation and NIHR. All other authors report no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.