Neurology

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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

TOPLINE:

Addressing vision impairments could help with dementia prevention, as vision impairment is linked to 19% of dementia cases in older adults.
 

METHODOLOGY:

• Researchers conducted a cross-sectional analysis using data from the National Health and Aging Trends Study (NHATS).
• The analysis included 2767 US adults aged 71 years or older (54.7% female and 45.3% male).
• Vision impairments were defined using 2019 World Health Organization criteria. Near and distance vision impairments were defined as greater than 0.30 logMAR, and contrast sensitivity impairment was identified by scores below 1.55 logCS.
• Dementia was classified using a standardized algorithm developed in NHATS, which incorporated a series of tests measuring cognition, memory and orientation, reports of Alzheimer’s disease, or a dementia diagnosis from the patient or a proxy, and an informant questionnaire (Ascertain Dementia-8 Dementia Screening Interview).
• The study analyzed data from 2021, with the primary outcome being the population attributable fraction (PAF) of dementia from vision impairment.

TAKEAWAY:

• The PAF of dementia associated with at least one vision impairment was 19% (95% CI, 8.2-29.7).
• Impairment in contrast sensitivity had the highest PAF among all other vision issues, at 15% (95% CI, 6.6-23.6). This figure was higher than that for impairment of near acuity, at 9.7% (95% CI, 2.6-17.0), or distance acuity, at 4.9% (95% CI, 0.1-9.9).
• The highest PAFs for dementia due to vision impairment was among participants aged 71-79 years (24.3%; 95% CI, 6.6-41.8), women (26.8%; 95% CI, 12.2-39.9), and non-Hispanic White participants (22.3%; 95% CI, 9.6-34.5).

IN PRACTICE:

“While not proving a cause-and-effect relationship, these findings support inclusion of multiple objective measures of vision impairments, including contrast sensitivity and visual acuity, to capture the total potential impact of addressing vision impairment on dementia,” study authors wrote.

SOURCE:

This study was led by Jason R. Smith, ScM, of the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. It was published online in JAMA Ophthalmology.

LIMITATIONS:

The limited sample sizes for American Indian, Alaska Native, Asian, and Hispanic groups prevented researchers from calculating PAFs for these populations. The cross-sectional design prevented the researchers from examining the timing of vision impairment in relation to a diagnosis of dementia. The study did not explore links between other measures of vision and dementia. Those with early cognitive impairment may not have updated glasses, affecting visual performance. The findings from the study may not apply to institutionalized older adults.

DISCLOSURES:

Jennifer A. Deal, PhD, MHS, reported receiving personal fees from Frontiers in Epidemiology, Velux Stiftung, and Medical Education Speakers Network outside the submitted work. Nicholas S. Reed, AuD, PhD, reported receiving stock options from Neosensory outside the submitted work. No other disclosures were reported.

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

TOPLINE:

Addressing vision impairments could help with dementia prevention, as vision impairment is linked to 19% of dementia cases in older adults.
 

METHODOLOGY:

• Researchers conducted a cross-sectional analysis using data from the National Health and Aging Trends Study (NHATS).
• The analysis included 2767 US adults aged 71 years or older (54.7% female and 45.3% male).
• Vision impairments were defined using 2019 World Health Organization criteria. Near and distance vision impairments were defined as greater than 0.30 logMAR, and contrast sensitivity impairment was identified by scores below 1.55 logCS.
• Dementia was classified using a standardized algorithm developed in NHATS, which incorporated a series of tests measuring cognition, memory and orientation, reports of Alzheimer’s disease, or a dementia diagnosis from the patient or a proxy, and an informant questionnaire (Ascertain Dementia-8 Dementia Screening Interview).
• The study analyzed data from 2021, with the primary outcome being the population attributable fraction (PAF) of dementia from vision impairment.

TAKEAWAY:

• The PAF of dementia associated with at least one vision impairment was 19% (95% CI, 8.2-29.7).
• Impairment in contrast sensitivity had the highest PAF among all other vision issues, at 15% (95% CI, 6.6-23.6). This figure was higher than that for impairment of near acuity, at 9.7% (95% CI, 2.6-17.0), or distance acuity, at 4.9% (95% CI, 0.1-9.9).
• The highest PAFs for dementia due to vision impairment was among participants aged 71-79 years (24.3%; 95% CI, 6.6-41.8), women (26.8%; 95% CI, 12.2-39.9), and non-Hispanic White participants (22.3%; 95% CI, 9.6-34.5).

IN PRACTICE:

“While not proving a cause-and-effect relationship, these findings support inclusion of multiple objective measures of vision impairments, including contrast sensitivity and visual acuity, to capture the total potential impact of addressing vision impairment on dementia,” study authors wrote.

SOURCE:

This study was led by Jason R. Smith, ScM, of the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. It was published online in JAMA Ophthalmology.

LIMITATIONS:

The limited sample sizes for American Indian, Alaska Native, Asian, and Hispanic groups prevented researchers from calculating PAFs for these populations. The cross-sectional design prevented the researchers from examining the timing of vision impairment in relation to a diagnosis of dementia. The study did not explore links between other measures of vision and dementia. Those with early cognitive impairment may not have updated glasses, affecting visual performance. The findings from the study may not apply to institutionalized older adults.

DISCLOSURES:

Jennifer A. Deal, PhD, MHS, reported receiving personal fees from Frontiers in Epidemiology, Velux Stiftung, and Medical Education Speakers Network outside the submitted work. Nicholas S. Reed, AuD, PhD, reported receiving stock options from Neosensory outside the submitted work. No other disclosures were reported.

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

TOPLINE:

Addressing vision impairments could help with dementia prevention, as vision impairment is linked to 19% of dementia cases in older adults.
 

METHODOLOGY:

• Researchers conducted a cross-sectional analysis using data from the National Health and Aging Trends Study (NHATS).
• The analysis included 2767 US adults aged 71 years or older (54.7% female and 45.3% male).
• Vision impairments were defined using 2019 World Health Organization criteria. Near and distance vision impairments were defined as greater than 0.30 logMAR, and contrast sensitivity impairment was identified by scores below 1.55 logCS.
• Dementia was classified using a standardized algorithm developed in NHATS, which incorporated a series of tests measuring cognition, memory and orientation, reports of Alzheimer’s disease, or a dementia diagnosis from the patient or a proxy, and an informant questionnaire (Ascertain Dementia-8 Dementia Screening Interview).
• The study analyzed data from 2021, with the primary outcome being the population attributable fraction (PAF) of dementia from vision impairment.

TAKEAWAY:

• The PAF of dementia associated with at least one vision impairment was 19% (95% CI, 8.2-29.7).
• Impairment in contrast sensitivity had the highest PAF among all other vision issues, at 15% (95% CI, 6.6-23.6). This figure was higher than that for impairment of near acuity, at 9.7% (95% CI, 2.6-17.0), or distance acuity, at 4.9% (95% CI, 0.1-9.9).
• The highest PAFs for dementia due to vision impairment was among participants aged 71-79 years (24.3%; 95% CI, 6.6-41.8), women (26.8%; 95% CI, 12.2-39.9), and non-Hispanic White participants (22.3%; 95% CI, 9.6-34.5).

IN PRACTICE:

“While not proving a cause-and-effect relationship, these findings support inclusion of multiple objective measures of vision impairments, including contrast sensitivity and visual acuity, to capture the total potential impact of addressing vision impairment on dementia,” study authors wrote.

SOURCE:

This study was led by Jason R. Smith, ScM, of the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. It was published online in JAMA Ophthalmology.

LIMITATIONS:

The limited sample sizes for American Indian, Alaska Native, Asian, and Hispanic groups prevented researchers from calculating PAFs for these populations. The cross-sectional design prevented the researchers from examining the timing of vision impairment in relation to a diagnosis of dementia. The study did not explore links between other measures of vision and dementia. Those with early cognitive impairment may not have updated glasses, affecting visual performance. The findings from the study may not apply to institutionalized older adults.

DISCLOSURES:

Jennifer A. Deal, PhD, MHS, reported receiving personal fees from Frontiers in Epidemiology, Velux Stiftung, and Medical Education Speakers Network outside the submitted work. Nicholas S. Reed, AuD, PhD, reported receiving stock options from Neosensory outside the submitted work. No other disclosures were reported.

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

The same dye that gives Twinkies their yellowish hue could be the key to invisibility. 

Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.

“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.” 

The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue. 

A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications. 

Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.

Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said. 

“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
 

From Cake Frosting to Groundbreaking Research

Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly. 

But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish. 

The dye could also be paired with imaging techniques such as MRI or electron microscopy. 

“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”

The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary. 

Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
 

Refraction, Absorption, and The Invisible Man

The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.

The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light. 

They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque. 

With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner. 

“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
 

What’s Next

Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions. 

The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.

Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds. 

“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.

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

The same dye that gives Twinkies their yellowish hue could be the key to invisibility. 

Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.

“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.” 

The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue. 

A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications. 

Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.

Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said. 

“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
 

From Cake Frosting to Groundbreaking Research

Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly. 

But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish. 

The dye could also be paired with imaging techniques such as MRI or electron microscopy. 

“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”

The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary. 

Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
 

Refraction, Absorption, and The Invisible Man

The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.

The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light. 

They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque. 

With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner. 

“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
 

What’s Next

Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions. 

The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.

Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds. 

“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.

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

The same dye that gives Twinkies their yellowish hue could be the key to invisibility. 

Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.

“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.” 

The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue. 

A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications. 

Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.

Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said. 

“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
 

From Cake Frosting to Groundbreaking Research

Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly. 

But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish. 

The dye could also be paired with imaging techniques such as MRI or electron microscopy. 

“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”

The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary. 

Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
 

Refraction, Absorption, and The Invisible Man

The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.

The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light. 

They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque. 

With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner. 

“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
 

What’s Next

Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions. 

The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.

Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds. 

“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.

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

Researchers have discovered that a brain network involved in reward processing and attention to stimuli is markedly bigger in people with depression, remains stable over time, is unaffected by mood changes, and can be detected in children before onset of depression symptoms.

Using a novel brain-mapping technique, researchers found that the frontostriatal salience network was expanded nearly twofold in the brains of most individuals studied with depression compared with controls.

“This expansion in cortex was trait-like, meaning it was stable over time and did not change as symptoms changed over time,” said lead author Charles Lynch, PhD, assistant professor of neuroscience, Department of Psychiatry, Weill Cornell Medicine in New York.

It could also be detected in children who later developed depression, suggesting it may serve as a biomarker of depression risk. Investigators said the findings could aid in prevention and early detection of depression, as well as the development of more personalized treatment.

The study was published online in Nature.
 

Prewired for Depression?

Precision functional mapping is a relatively new approach to brain mapping in individuals that uses large amounts of fMRI data from hours of scans per person. The technique has been used to show differences in brain networks between and in healthy individuals but had not been used to study brain networks in people with depression.

“We leveraged our large longitudinal datasets — with many hours of functional MRI scanning per subject — to construct individual-specific maps of functional brain networks in each patient using precision functional mapping, instead of relying on group average,” Dr. Lynch said.

In the primary analysis of 141 adults with major depression and 37 healthy controls, the frontostriatal salience network — which is involved in reward processing and attention to internal and external stimuli — was markedly larger in these individuals with depression.

“This is one of the first times these kinds of personalized maps have been created in individuals with depression, and this is how we first observed of the salience network being larger in individuals with depression,” Dr. Lynch said.

In four of the six individuals, the salience network was expanded more than twofold, outside the range observed in all 37 healthy controls. On average, the salience network occupied 73% more of the cortical surface relative to the average in healthy controls.

The findings were replicated using independent samples of repeatedly sampled individuals with depression and in large-scale group average data.

The expansion of the salience network did not change over time and was unaffected by changes in mood state.

“These observations led us to propose that instead of driving changes in depressive symptoms over time, salience network expansion may be a stable marker of risk for developing depression,” the study team wrote.

An analysis of brain scans from 57 children who went on to develop depressive symptoms during adolescence and an equal number of children who did not develop depressive symptoms supports this theory.

On average, the salience network occupied roughly 36% more of cortex in the children with no current or previous symptoms of depression at the time of their fMRI scans but who subsequently developed clinically significant symptoms of depression, relative to children with no depressive symptoms at any study time point, the researchers found.
 

Immediate Clinical Impact?

Reached for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami, said this research “exemplifies the promising intersection of neurology and digital health, where advanced neuroimaging and data-driven approaches can transform mental health care into a more precise and individualized practice,” Dr. Lakhan said. “By identifying this brain network expansion, we’re unlocking new possibilities for precision medicine in mental health.”

Dr. Lakhan, who wasn’t involved in this research, said identifying the expansion of the frontostriatal salience network in individuals with depression opens new avenues for developing novel therapeutics.

“By targeting this network through neuromodulation techniques like deep brain stimulation, transcranial magnetic stimulation, and prescription digital therapeutics, treatments can be more precisely tailored to individual neurobiological profiles,” Dr. Lakhan said. “Additionally, this network expansion could serve as a biomarker for early detection, allowing for preventive strategies or personalized treatment plans, particularly for those at risk of developing depression.”

In addition, a greater understanding of the mechanisms driving salience network expansion offers potential for discovering new pharmacological targets, Dr. Lakhan noted.

“Drugs that modulate synaptic plasticity or network connectivity might be developed to reverse or mitigate these neural changes. The findings also support the use of longitudinal monitoring to predict and preempt symptom emergence, improving outcomes through timely intervention. This research paves the way for more personalized, precise, and proactive approaches in treating depression,” Dr. Lakhan concluded.

Also weighing in, Teddy Akiki, MD, with the Department of Psychiatry and Behavioral Sciences at Stanford Medicine in California, noted that the effect size of the frontostriatal salience network difference in depression is “remarkably larger than typically seen in neuroimaging studies of depression, which often describe subtle differences. The consistency across multiple datasets and across time at the individual level adds significant weight to these findings, suggesting that it is a trait marker rather than a state-dependent marker.”

“The observation that this expansion is present even before the onset of depressive symptoms in adolescence suggests its potential as a biomarker for depression risk,” Dr. Akiki said. “This approach could lead to earlier identification of at-risk individuals and potentially inform the development of targeted preventive interventions.”

He cautioned that it remains to be seen whether interventions targeting the salience network can effectively prevent or treat depression.

This research was supported in part by the National Institute of Mental Health, the National Institute on Drug Addiction, the Hope for Depression Research Foundation, and the Foundation for OCD Research. Dr. Lynch and a coauthor are listed as inventors for Cornell University patent applications on neuroimaging biomarkers for depression which are pending or in preparation. Dr. Liston has served as a scientific advisor or consultant to Compass Pathways PLC, Delix Therapeutics, and Brainify.AI. Dr. Lakhan and Dr. Akiki had no relevant disclosures.

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

Researchers have discovered that a brain network involved in reward processing and attention to stimuli is markedly bigger in people with depression, remains stable over time, is unaffected by mood changes, and can be detected in children before onset of depression symptoms.

Using a novel brain-mapping technique, researchers found that the frontostriatal salience network was expanded nearly twofold in the brains of most individuals studied with depression compared with controls.

“This expansion in cortex was trait-like, meaning it was stable over time and did not change as symptoms changed over time,” said lead author Charles Lynch, PhD, assistant professor of neuroscience, Department of Psychiatry, Weill Cornell Medicine in New York.

It could also be detected in children who later developed depression, suggesting it may serve as a biomarker of depression risk. Investigators said the findings could aid in prevention and early detection of depression, as well as the development of more personalized treatment.

The study was published online in Nature.
 

Prewired for Depression?

Precision functional mapping is a relatively new approach to brain mapping in individuals that uses large amounts of fMRI data from hours of scans per person. The technique has been used to show differences in brain networks between and in healthy individuals but had not been used to study brain networks in people with depression.

“We leveraged our large longitudinal datasets — with many hours of functional MRI scanning per subject — to construct individual-specific maps of functional brain networks in each patient using precision functional mapping, instead of relying on group average,” Dr. Lynch said.

In the primary analysis of 141 adults with major depression and 37 healthy controls, the frontostriatal salience network — which is involved in reward processing and attention to internal and external stimuli — was markedly larger in these individuals with depression.

“This is one of the first times these kinds of personalized maps have been created in individuals with depression, and this is how we first observed of the salience network being larger in individuals with depression,” Dr. Lynch said.

In four of the six individuals, the salience network was expanded more than twofold, outside the range observed in all 37 healthy controls. On average, the salience network occupied 73% more of the cortical surface relative to the average in healthy controls.

The findings were replicated using independent samples of repeatedly sampled individuals with depression and in large-scale group average data.

The expansion of the salience network did not change over time and was unaffected by changes in mood state.

“These observations led us to propose that instead of driving changes in depressive symptoms over time, salience network expansion may be a stable marker of risk for developing depression,” the study team wrote.

An analysis of brain scans from 57 children who went on to develop depressive symptoms during adolescence and an equal number of children who did not develop depressive symptoms supports this theory.

On average, the salience network occupied roughly 36% more of cortex in the children with no current or previous symptoms of depression at the time of their fMRI scans but who subsequently developed clinically significant symptoms of depression, relative to children with no depressive symptoms at any study time point, the researchers found.
 

Immediate Clinical Impact?

Reached for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami, said this research “exemplifies the promising intersection of neurology and digital health, where advanced neuroimaging and data-driven approaches can transform mental health care into a more precise and individualized practice,” Dr. Lakhan said. “By identifying this brain network expansion, we’re unlocking new possibilities for precision medicine in mental health.”

Dr. Lakhan, who wasn’t involved in this research, said identifying the expansion of the frontostriatal salience network in individuals with depression opens new avenues for developing novel therapeutics.

“By targeting this network through neuromodulation techniques like deep brain stimulation, transcranial magnetic stimulation, and prescription digital therapeutics, treatments can be more precisely tailored to individual neurobiological profiles,” Dr. Lakhan said. “Additionally, this network expansion could serve as a biomarker for early detection, allowing for preventive strategies or personalized treatment plans, particularly for those at risk of developing depression.”

In addition, a greater understanding of the mechanisms driving salience network expansion offers potential for discovering new pharmacological targets, Dr. Lakhan noted.

“Drugs that modulate synaptic plasticity or network connectivity might be developed to reverse or mitigate these neural changes. The findings also support the use of longitudinal monitoring to predict and preempt symptom emergence, improving outcomes through timely intervention. This research paves the way for more personalized, precise, and proactive approaches in treating depression,” Dr. Lakhan concluded.

Also weighing in, Teddy Akiki, MD, with the Department of Psychiatry and Behavioral Sciences at Stanford Medicine in California, noted that the effect size of the frontostriatal salience network difference in depression is “remarkably larger than typically seen in neuroimaging studies of depression, which often describe subtle differences. The consistency across multiple datasets and across time at the individual level adds significant weight to these findings, suggesting that it is a trait marker rather than a state-dependent marker.”

“The observation that this expansion is present even before the onset of depressive symptoms in adolescence suggests its potential as a biomarker for depression risk,” Dr. Akiki said. “This approach could lead to earlier identification of at-risk individuals and potentially inform the development of targeted preventive interventions.”

He cautioned that it remains to be seen whether interventions targeting the salience network can effectively prevent or treat depression.

This research was supported in part by the National Institute of Mental Health, the National Institute on Drug Addiction, the Hope for Depression Research Foundation, and the Foundation for OCD Research. Dr. Lynch and a coauthor are listed as inventors for Cornell University patent applications on neuroimaging biomarkers for depression which are pending or in preparation. Dr. Liston has served as a scientific advisor or consultant to Compass Pathways PLC, Delix Therapeutics, and Brainify.AI. Dr. Lakhan and Dr. Akiki had no relevant disclosures.

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

Researchers have discovered that a brain network involved in reward processing and attention to stimuli is markedly bigger in people with depression, remains stable over time, is unaffected by mood changes, and can be detected in children before onset of depression symptoms.

Using a novel brain-mapping technique, researchers found that the frontostriatal salience network was expanded nearly twofold in the brains of most individuals studied with depression compared with controls.

“This expansion in cortex was trait-like, meaning it was stable over time and did not change as symptoms changed over time,” said lead author Charles Lynch, PhD, assistant professor of neuroscience, Department of Psychiatry, Weill Cornell Medicine in New York.

It could also be detected in children who later developed depression, suggesting it may serve as a biomarker of depression risk. Investigators said the findings could aid in prevention and early detection of depression, as well as the development of more personalized treatment.

The study was published online in Nature.
 

Prewired for Depression?

Precision functional mapping is a relatively new approach to brain mapping in individuals that uses large amounts of fMRI data from hours of scans per person. The technique has been used to show differences in brain networks between and in healthy individuals but had not been used to study brain networks in people with depression.

“We leveraged our large longitudinal datasets — with many hours of functional MRI scanning per subject — to construct individual-specific maps of functional brain networks in each patient using precision functional mapping, instead of relying on group average,” Dr. Lynch said.

In the primary analysis of 141 adults with major depression and 37 healthy controls, the frontostriatal salience network — which is involved in reward processing and attention to internal and external stimuli — was markedly larger in these individuals with depression.

“This is one of the first times these kinds of personalized maps have been created in individuals with depression, and this is how we first observed of the salience network being larger in individuals with depression,” Dr. Lynch said.

In four of the six individuals, the salience network was expanded more than twofold, outside the range observed in all 37 healthy controls. On average, the salience network occupied 73% more of the cortical surface relative to the average in healthy controls.

The findings were replicated using independent samples of repeatedly sampled individuals with depression and in large-scale group average data.

The expansion of the salience network did not change over time and was unaffected by changes in mood state.

“These observations led us to propose that instead of driving changes in depressive symptoms over time, salience network expansion may be a stable marker of risk for developing depression,” the study team wrote.

An analysis of brain scans from 57 children who went on to develop depressive symptoms during adolescence and an equal number of children who did not develop depressive symptoms supports this theory.

On average, the salience network occupied roughly 36% more of cortex in the children with no current or previous symptoms of depression at the time of their fMRI scans but who subsequently developed clinically significant symptoms of depression, relative to children with no depressive symptoms at any study time point, the researchers found.
 

Immediate Clinical Impact?

Reached for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami, said this research “exemplifies the promising intersection of neurology and digital health, where advanced neuroimaging and data-driven approaches can transform mental health care into a more precise and individualized practice,” Dr. Lakhan said. “By identifying this brain network expansion, we’re unlocking new possibilities for precision medicine in mental health.”

Dr. Lakhan, who wasn’t involved in this research, said identifying the expansion of the frontostriatal salience network in individuals with depression opens new avenues for developing novel therapeutics.

“By targeting this network through neuromodulation techniques like deep brain stimulation, transcranial magnetic stimulation, and prescription digital therapeutics, treatments can be more precisely tailored to individual neurobiological profiles,” Dr. Lakhan said. “Additionally, this network expansion could serve as a biomarker for early detection, allowing for preventive strategies or personalized treatment plans, particularly for those at risk of developing depression.”

In addition, a greater understanding of the mechanisms driving salience network expansion offers potential for discovering new pharmacological targets, Dr. Lakhan noted.

“Drugs that modulate synaptic plasticity or network connectivity might be developed to reverse or mitigate these neural changes. The findings also support the use of longitudinal monitoring to predict and preempt symptom emergence, improving outcomes through timely intervention. This research paves the way for more personalized, precise, and proactive approaches in treating depression,” Dr. Lakhan concluded.

Also weighing in, Teddy Akiki, MD, with the Department of Psychiatry and Behavioral Sciences at Stanford Medicine in California, noted that the effect size of the frontostriatal salience network difference in depression is “remarkably larger than typically seen in neuroimaging studies of depression, which often describe subtle differences. The consistency across multiple datasets and across time at the individual level adds significant weight to these findings, suggesting that it is a trait marker rather than a state-dependent marker.”

“The observation that this expansion is present even before the onset of depressive symptoms in adolescence suggests its potential as a biomarker for depression risk,” Dr. Akiki said. “This approach could lead to earlier identification of at-risk individuals and potentially inform the development of targeted preventive interventions.”

He cautioned that it remains to be seen whether interventions targeting the salience network can effectively prevent or treat depression.

This research was supported in part by the National Institute of Mental Health, the National Institute on Drug Addiction, the Hope for Depression Research Foundation, and the Foundation for OCD Research. Dr. Lynch and a coauthor are listed as inventors for Cornell University patent applications on neuroimaging biomarkers for depression which are pending or in preparation. Dr. Liston has served as a scientific advisor or consultant to Compass Pathways PLC, Delix Therapeutics, and Brainify.AI. Dr. Lakhan and Dr. Akiki had no relevant disclosures.

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

Living in areas saturated with artificial outdoor light at night is associated with an increased risk for Alzheimer’s disease, a new national study suggested.

Analyses of state and county light pollution data and Medicare claims showed that areas with higher average nighttime light intensity had a greater prevalence of Alzheimer’s disease.

Among people aged 65 years or older, Alzheimer’s disease prevalence was more strongly associated with nightly light pollution exposure than with alcohol misuse, chronic kidney disease, depression, or obesity.

In those younger than 65 years, greater nighttime light intensity had a stronger association with Alzheimer’s disease prevalence than any other risk factor included in the study.

“The results are pretty striking when you do these comparisons and it’s true for people of all ages,” said Robin Voigt-Zuwala, PhD, lead author and director, Circadian Rhythm Research Laboratory, Rush University, Chicago, Illinois.

The study was published online in Frontiers of Neuroscience.
 

Shining a Light

Exposure to artificial outdoor light at night has been associated with adverse health effects such as sleep disruption, obesity, atherosclerosis, and cancer, but this is the first study to look specifically at Alzheimer’s disease, investigators noted.

Two recent studies reported higher risks for mild cognitive impairment among Chinese veterans and late-onset dementia among Italian residents living in areas with brighter outdoor light at night.

For this study, Dr. Voigt-Zuwala and colleagues examined the relationship between Alzheimer’s disease prevalence and average nighttime light intensity in the lower 48 states using data from Medicare Part A and B, the Centers for Disease Control and Prevention, and NASA satellite–acquired radiance data.

The data were averaged for the years 2012-2018 and states divided into five groups based on average nighttime light intensity.

The darkest states were Montana, Wyoming, South Dakota, Idaho, Maine, New Mexico, Vermont, Oregon, Utah, and Nevada. The brightest states were Indiana, Illinois, Florida, Ohio, Massachusetts, Connecticut, Maryland, Delaware, Rhode Island, and New Jersey.

Analysis of variance revealed a significant difference in Alzheimer’s disease prevalence between state groups (P < .0001). Multiple comparisons testing also showed that states with the lowest average nighttime light had significantly different Alzheimer’s disease prevalence than those with higher intensity.

The same positive relationship was observed when each year was assessed individually and at the county level, using data from 45 counties and the District of Columbia.
 

Strong Association

The investigators also found that state average nighttime light intensity is significantly associated with Alzheimer’s disease prevalence (P = .006). This effect was seen across all ages, sexes, and races except Asian Pacific Island, the latter possibly related to statistical power, the authors said.

When known or proposed risk factors for Alzheimer’s disease were added to the model, atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke had a stronger association with Alzheimer’s disease than average nighttime light intensity.

Nighttime light intensity, however, was more strongly associated with Alzheimer’s disease prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity.

Moreover, in people younger than 65 years, nighttime light pollution had a stronger association with Alzheimer’s disease prevalence than all other risk factors (P = .007).

The mechanism behind this increased vulnerability is unclear, but there may be an interplay between genetic susceptibility of an individual and how they respond to light, Dr. Voigt-Zuwala suggested.

“APOE4 is the genotype most highly associated with Alzheimer’s disease risk, and maybe the people who have that genotype are just more sensitive to the effects of light exposure at night, more sensitive to circadian rhythm disruption,” she said.

The authors noted that additional research is needed but suggested light pollution may also influence Alzheimer’s disease through sleep disruption, which can promote inflammation, activate microglia and astrocytes, and negatively alter the clearance of amyloid beta, and by decreasing the levels of brain-derived neurotrophic factor.
 

Are We Measuring the Right Light?

“It’s a good article and it’s got a good message, but I have some caveats to that,” said George C. Brainard, PhD, director, Light Research Program, Thomas Jefferson University in Philadelphia, Pennsylvania, and a pioneer in the study of how light affects biology including breast cancer in night-shift workers.

The biggest caveat, and one acknowledged by the authors, is that the study didn’t measure indoor light exposure and relied instead on satellite imaging.

“They’re very striking images, but they may not be particularly relevant. And here’s why: People don’t live outdoors all night,” Dr. Brainard said.

Instead, people spend much of their time at night indoors where they’re exposed to lighting in the home and from smartphones, laptops, and television screens.

“It doesn’t invalidate their work. It’s an important advancement, an important observation,” Dr. Brainard said. “But the important thing really is to find out what is the population exposed to that triggers this response, and it’s probably indoor lighting related to the amount and physical characteristics of indoor lighting. It doesn’t mean outdoor lighting can’t play a role. It certainly can.”

Reached for comment, Erik Musiek, MD, PhD, a professor of neurology whose lab at Washington University School of Medicine in St. Louis, Missouri, has extensively studied circadian clock disruption and Alzheimer’s disease pathology in the brain, said the study provides a 10,000-foot view of the issue.

For example, the study was not designed to detect whether people living in high light pollution areas are actually experiencing more outdoor light at night and if risk factors such as air pollution and low socioeconomic status may correlate with these areas.

“Most of what we worry about is do people have lights on in the house, do they have their TV on, their screens up to their face late at night? This can’t tell us about that,” Dr. Musiek said. “But on the other hand, this kind of light exposure is something that public policy can affect.”

“It’s hard to control people’s personal habits nor should we probably, but we can control what types of bulbs you put into streetlights, how bright they are, and where you put lighting in a public place,” he added. “So I do think there’s value there.”

At least 19 states, the District of Columbia, and Puerto Rico have laws in place to reduce light pollution, with the majority doing so to promote energy conservation, public safety, aesthetic interests, or astronomical research, according to the National Conference of State Legislatures.

To respond to some of the limitations in this study, Dr. Voigt-Zuwala is writing a grant application for a new project to look at both indoor and outdoor light exposure on an individual level.

“This is what I’ve been wanting to study for a long time, and this study is just sort of the stepping stone, the proof of concept that this is something we need to be investigating,” she said.

Dr. Voigt-Zuwala reported RO1 and R24 grants from the National Institutes of Health (NIH), one coauthor reported an NIH R24 grant; another reported having no conflicts of interest. Dr. Brainard reported having no relevant conflicts of interest. Dr. Musiek reported research funding from Eisai Pharmaceuticals.

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

Living in areas saturated with artificial outdoor light at night is associated with an increased risk for Alzheimer’s disease, a new national study suggested.

Analyses of state and county light pollution data and Medicare claims showed that areas with higher average nighttime light intensity had a greater prevalence of Alzheimer’s disease.

Among people aged 65 years or older, Alzheimer’s disease prevalence was more strongly associated with nightly light pollution exposure than with alcohol misuse, chronic kidney disease, depression, or obesity.

In those younger than 65 years, greater nighttime light intensity had a stronger association with Alzheimer’s disease prevalence than any other risk factor included in the study.

“The results are pretty striking when you do these comparisons and it’s true for people of all ages,” said Robin Voigt-Zuwala, PhD, lead author and director, Circadian Rhythm Research Laboratory, Rush University, Chicago, Illinois.

The study was published online in Frontiers of Neuroscience.
 

Shining a Light

Exposure to artificial outdoor light at night has been associated with adverse health effects such as sleep disruption, obesity, atherosclerosis, and cancer, but this is the first study to look specifically at Alzheimer’s disease, investigators noted.

Two recent studies reported higher risks for mild cognitive impairment among Chinese veterans and late-onset dementia among Italian residents living in areas with brighter outdoor light at night.

For this study, Dr. Voigt-Zuwala and colleagues examined the relationship between Alzheimer’s disease prevalence and average nighttime light intensity in the lower 48 states using data from Medicare Part A and B, the Centers for Disease Control and Prevention, and NASA satellite–acquired radiance data.

The data were averaged for the years 2012-2018 and states divided into five groups based on average nighttime light intensity.

The darkest states were Montana, Wyoming, South Dakota, Idaho, Maine, New Mexico, Vermont, Oregon, Utah, and Nevada. The brightest states were Indiana, Illinois, Florida, Ohio, Massachusetts, Connecticut, Maryland, Delaware, Rhode Island, and New Jersey.

Analysis of variance revealed a significant difference in Alzheimer’s disease prevalence between state groups (P < .0001). Multiple comparisons testing also showed that states with the lowest average nighttime light had significantly different Alzheimer’s disease prevalence than those with higher intensity.

The same positive relationship was observed when each year was assessed individually and at the county level, using data from 45 counties and the District of Columbia.
 

Strong Association

The investigators also found that state average nighttime light intensity is significantly associated with Alzheimer’s disease prevalence (P = .006). This effect was seen across all ages, sexes, and races except Asian Pacific Island, the latter possibly related to statistical power, the authors said.

When known or proposed risk factors for Alzheimer’s disease were added to the model, atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke had a stronger association with Alzheimer’s disease than average nighttime light intensity.

Nighttime light intensity, however, was more strongly associated with Alzheimer’s disease prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity.

Moreover, in people younger than 65 years, nighttime light pollution had a stronger association with Alzheimer’s disease prevalence than all other risk factors (P = .007).

The mechanism behind this increased vulnerability is unclear, but there may be an interplay between genetic susceptibility of an individual and how they respond to light, Dr. Voigt-Zuwala suggested.

“APOE4 is the genotype most highly associated with Alzheimer’s disease risk, and maybe the people who have that genotype are just more sensitive to the effects of light exposure at night, more sensitive to circadian rhythm disruption,” she said.

The authors noted that additional research is needed but suggested light pollution may also influence Alzheimer’s disease through sleep disruption, which can promote inflammation, activate microglia and astrocytes, and negatively alter the clearance of amyloid beta, and by decreasing the levels of brain-derived neurotrophic factor.
 

Are We Measuring the Right Light?

“It’s a good article and it’s got a good message, but I have some caveats to that,” said George C. Brainard, PhD, director, Light Research Program, Thomas Jefferson University in Philadelphia, Pennsylvania, and a pioneer in the study of how light affects biology including breast cancer in night-shift workers.

The biggest caveat, and one acknowledged by the authors, is that the study didn’t measure indoor light exposure and relied instead on satellite imaging.

“They’re very striking images, but they may not be particularly relevant. And here’s why: People don’t live outdoors all night,” Dr. Brainard said.

Instead, people spend much of their time at night indoors where they’re exposed to lighting in the home and from smartphones, laptops, and television screens.

“It doesn’t invalidate their work. It’s an important advancement, an important observation,” Dr. Brainard said. “But the important thing really is to find out what is the population exposed to that triggers this response, and it’s probably indoor lighting related to the amount and physical characteristics of indoor lighting. It doesn’t mean outdoor lighting can’t play a role. It certainly can.”

Reached for comment, Erik Musiek, MD, PhD, a professor of neurology whose lab at Washington University School of Medicine in St. Louis, Missouri, has extensively studied circadian clock disruption and Alzheimer’s disease pathology in the brain, said the study provides a 10,000-foot view of the issue.

For example, the study was not designed to detect whether people living in high light pollution areas are actually experiencing more outdoor light at night and if risk factors such as air pollution and low socioeconomic status may correlate with these areas.

“Most of what we worry about is do people have lights on in the house, do they have their TV on, their screens up to their face late at night? This can’t tell us about that,” Dr. Musiek said. “But on the other hand, this kind of light exposure is something that public policy can affect.”

“It’s hard to control people’s personal habits nor should we probably, but we can control what types of bulbs you put into streetlights, how bright they are, and where you put lighting in a public place,” he added. “So I do think there’s value there.”

At least 19 states, the District of Columbia, and Puerto Rico have laws in place to reduce light pollution, with the majority doing so to promote energy conservation, public safety, aesthetic interests, or astronomical research, according to the National Conference of State Legislatures.

To respond to some of the limitations in this study, Dr. Voigt-Zuwala is writing a grant application for a new project to look at both indoor and outdoor light exposure on an individual level.

“This is what I’ve been wanting to study for a long time, and this study is just sort of the stepping stone, the proof of concept that this is something we need to be investigating,” she said.

Dr. Voigt-Zuwala reported RO1 and R24 grants from the National Institutes of Health (NIH), one coauthor reported an NIH R24 grant; another reported having no conflicts of interest. Dr. Brainard reported having no relevant conflicts of interest. Dr. Musiek reported research funding from Eisai Pharmaceuticals.

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

Living in areas saturated with artificial outdoor light at night is associated with an increased risk for Alzheimer’s disease, a new national study suggested.

Analyses of state and county light pollution data and Medicare claims showed that areas with higher average nighttime light intensity had a greater prevalence of Alzheimer’s disease.

Among people aged 65 years or older, Alzheimer’s disease prevalence was more strongly associated with nightly light pollution exposure than with alcohol misuse, chronic kidney disease, depression, or obesity.

In those younger than 65 years, greater nighttime light intensity had a stronger association with Alzheimer’s disease prevalence than any other risk factor included in the study.

“The results are pretty striking when you do these comparisons and it’s true for people of all ages,” said Robin Voigt-Zuwala, PhD, lead author and director, Circadian Rhythm Research Laboratory, Rush University, Chicago, Illinois.

The study was published online in Frontiers of Neuroscience.
 

Shining a Light

Exposure to artificial outdoor light at night has been associated with adverse health effects such as sleep disruption, obesity, atherosclerosis, and cancer, but this is the first study to look specifically at Alzheimer’s disease, investigators noted.

Two recent studies reported higher risks for mild cognitive impairment among Chinese veterans and late-onset dementia among Italian residents living in areas with brighter outdoor light at night.

For this study, Dr. Voigt-Zuwala and colleagues examined the relationship between Alzheimer’s disease prevalence and average nighttime light intensity in the lower 48 states using data from Medicare Part A and B, the Centers for Disease Control and Prevention, and NASA satellite–acquired radiance data.

The data were averaged for the years 2012-2018 and states divided into five groups based on average nighttime light intensity.

The darkest states were Montana, Wyoming, South Dakota, Idaho, Maine, New Mexico, Vermont, Oregon, Utah, and Nevada. The brightest states were Indiana, Illinois, Florida, Ohio, Massachusetts, Connecticut, Maryland, Delaware, Rhode Island, and New Jersey.

Analysis of variance revealed a significant difference in Alzheimer’s disease prevalence between state groups (P < .0001). Multiple comparisons testing also showed that states with the lowest average nighttime light had significantly different Alzheimer’s disease prevalence than those with higher intensity.

The same positive relationship was observed when each year was assessed individually and at the county level, using data from 45 counties and the District of Columbia.
 

Strong Association

The investigators also found that state average nighttime light intensity is significantly associated with Alzheimer’s disease prevalence (P = .006). This effect was seen across all ages, sexes, and races except Asian Pacific Island, the latter possibly related to statistical power, the authors said.

When known or proposed risk factors for Alzheimer’s disease were added to the model, atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke had a stronger association with Alzheimer’s disease than average nighttime light intensity.

Nighttime light intensity, however, was more strongly associated with Alzheimer’s disease prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity.

Moreover, in people younger than 65 years, nighttime light pollution had a stronger association with Alzheimer’s disease prevalence than all other risk factors (P = .007).

The mechanism behind this increased vulnerability is unclear, but there may be an interplay between genetic susceptibility of an individual and how they respond to light, Dr. Voigt-Zuwala suggested.

“APOE4 is the genotype most highly associated with Alzheimer’s disease risk, and maybe the people who have that genotype are just more sensitive to the effects of light exposure at night, more sensitive to circadian rhythm disruption,” she said.

The authors noted that additional research is needed but suggested light pollution may also influence Alzheimer’s disease through sleep disruption, which can promote inflammation, activate microglia and astrocytes, and negatively alter the clearance of amyloid beta, and by decreasing the levels of brain-derived neurotrophic factor.
 

Are We Measuring the Right Light?

“It’s a good article and it’s got a good message, but I have some caveats to that,” said George C. Brainard, PhD, director, Light Research Program, Thomas Jefferson University in Philadelphia, Pennsylvania, and a pioneer in the study of how light affects biology including breast cancer in night-shift workers.

The biggest caveat, and one acknowledged by the authors, is that the study didn’t measure indoor light exposure and relied instead on satellite imaging.

“They’re very striking images, but they may not be particularly relevant. And here’s why: People don’t live outdoors all night,” Dr. Brainard said.

Instead, people spend much of their time at night indoors where they’re exposed to lighting in the home and from smartphones, laptops, and television screens.

“It doesn’t invalidate their work. It’s an important advancement, an important observation,” Dr. Brainard said. “But the important thing really is to find out what is the population exposed to that triggers this response, and it’s probably indoor lighting related to the amount and physical characteristics of indoor lighting. It doesn’t mean outdoor lighting can’t play a role. It certainly can.”

Reached for comment, Erik Musiek, MD, PhD, a professor of neurology whose lab at Washington University School of Medicine in St. Louis, Missouri, has extensively studied circadian clock disruption and Alzheimer’s disease pathology in the brain, said the study provides a 10,000-foot view of the issue.

For example, the study was not designed to detect whether people living in high light pollution areas are actually experiencing more outdoor light at night and if risk factors such as air pollution and low socioeconomic status may correlate with these areas.

“Most of what we worry about is do people have lights on in the house, do they have their TV on, their screens up to their face late at night? This can’t tell us about that,” Dr. Musiek said. “But on the other hand, this kind of light exposure is something that public policy can affect.”

“It’s hard to control people’s personal habits nor should we probably, but we can control what types of bulbs you put into streetlights, how bright they are, and where you put lighting in a public place,” he added. “So I do think there’s value there.”

At least 19 states, the District of Columbia, and Puerto Rico have laws in place to reduce light pollution, with the majority doing so to promote energy conservation, public safety, aesthetic interests, or astronomical research, according to the National Conference of State Legislatures.

To respond to some of the limitations in this study, Dr. Voigt-Zuwala is writing a grant application for a new project to look at both indoor and outdoor light exposure on an individual level.

“This is what I’ve been wanting to study for a long time, and this study is just sort of the stepping stone, the proof of concept that this is something we need to be investigating,” she said.

Dr. Voigt-Zuwala reported RO1 and R24 grants from the National Institutes of Health (NIH), one coauthor reported an NIH R24 grant; another reported having no conflicts of interest. Dr. Brainard reported having no relevant conflicts of interest. Dr. Musiek reported research funding from Eisai Pharmaceuticals.

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

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

Earlier in 2024 the American Headache Society issued a position statement that CGRP (calcitonin gene-related peptide) agents are a first-line option for migraine prevention.

No Shinola, Sherlock.

Any of us working frontline neurology have figured that out, including me. And I was, honestly, pretty skeptical of them when they hit the pharmacy shelves. But these days, to quote The Monkees (and Neil Diamond), “I’m a Believer.”

Unfortunately, things don’t quite work out that way. Just because a drug is clearly successful doesn’t make it practical to use first line. Most insurances won’t even let family doctors prescribe them, so they have to send patients to a neurologist (which I’m not complaining about).

Then me and my neuro-brethren have to jump through hoops because of their cost. One month of any of these drugs costs the same as a few years (or more) of generic Topamax, Nortriptyline, Nadolol, etc. Granted, I shouldn’t complain about that, either. If everyone with migraines was getting them it would drive up insurance premiums across the board — including mine.

So, after patients have tried and failed at least two to four other options (depending on their plan) I can usually get a CGRP covered. This involves filling out some forms online and submitting them ... then waiting.

Even if the drug is approved, and successful, that’s still not the end of the story. Depending on the plan I have to get them reauthorized anywhere from every 3 to 12 months. There’s also the chance that in December I’ll get a letter saying the drug won’t be covered starting January, and to try one of the recommended alternatives, like generic Topamax, Nortriptyline, Nadolol, etc. Wash, rinse, repeat.

Having celebrities like Lady Gaga pushing them doesn’t help. The commercials never mention that getting the medication isn’t as easy as “ask your doctor.” Nor does it point out that Lady Gaga won’t have an issue with a CGRP agent’s price tag of $800-$1000 per month, while most of her fans need that money for rent and groceries.

The guidelines, in essence, are useful, but only apply to a perfect world where drug cost doesn’t matter. We aren’t in one. I’m not knocking the pharmaceutical companies — research and development take A LOT of money, and every drug that comes to market has to pay not only for itself, but for several others that failed. Innovation isn’t cheap.

That doesn’t make it any easier to explain to patients, who see ads, or news blurbs on Facebook, or whatever. I just wish the advertisements would have more transparency about how the pricing works.

After all, regardless of how good an automobile may be, don’t car ads show an MSRP?

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

Earlier in 2024 the American Headache Society issued a position statement that CGRP (calcitonin gene-related peptide) agents are a first-line option for migraine prevention.

No Shinola, Sherlock.

Any of us working frontline neurology have figured that out, including me. And I was, honestly, pretty skeptical of them when they hit the pharmacy shelves. But these days, to quote The Monkees (and Neil Diamond), “I’m a Believer.”

Unfortunately, things don’t quite work out that way. Just because a drug is clearly successful doesn’t make it practical to use first line. Most insurances won’t even let family doctors prescribe them, so they have to send patients to a neurologist (which I’m not complaining about).

Then me and my neuro-brethren have to jump through hoops because of their cost. One month of any of these drugs costs the same as a few years (or more) of generic Topamax, Nortriptyline, Nadolol, etc. Granted, I shouldn’t complain about that, either. If everyone with migraines was getting them it would drive up insurance premiums across the board — including mine.

So, after patients have tried and failed at least two to four other options (depending on their plan) I can usually get a CGRP covered. This involves filling out some forms online and submitting them ... then waiting.

Even if the drug is approved, and successful, that’s still not the end of the story. Depending on the plan I have to get them reauthorized anywhere from every 3 to 12 months. There’s also the chance that in December I’ll get a letter saying the drug won’t be covered starting January, and to try one of the recommended alternatives, like generic Topamax, Nortriptyline, Nadolol, etc. Wash, rinse, repeat.

Having celebrities like Lady Gaga pushing them doesn’t help. The commercials never mention that getting the medication isn’t as easy as “ask your doctor.” Nor does it point out that Lady Gaga won’t have an issue with a CGRP agent’s price tag of $800-$1000 per month, while most of her fans need that money for rent and groceries.

The guidelines, in essence, are useful, but only apply to a perfect world where drug cost doesn’t matter. We aren’t in one. I’m not knocking the pharmaceutical companies — research and development take A LOT of money, and every drug that comes to market has to pay not only for itself, but for several others that failed. Innovation isn’t cheap.

That doesn’t make it any easier to explain to patients, who see ads, or news blurbs on Facebook, or whatever. I just wish the advertisements would have more transparency about how the pricing works.

After all, regardless of how good an automobile may be, don’t car ads show an MSRP?

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

Earlier in 2024 the American Headache Society issued a position statement that CGRP (calcitonin gene-related peptide) agents are a first-line option for migraine prevention.

No Shinola, Sherlock.

Any of us working frontline neurology have figured that out, including me. And I was, honestly, pretty skeptical of them when they hit the pharmacy shelves. But these days, to quote The Monkees (and Neil Diamond), “I’m a Believer.”

Unfortunately, things don’t quite work out that way. Just because a drug is clearly successful doesn’t make it practical to use first line. Most insurances won’t even let family doctors prescribe them, so they have to send patients to a neurologist (which I’m not complaining about).

Then me and my neuro-brethren have to jump through hoops because of their cost. One month of any of these drugs costs the same as a few years (or more) of generic Topamax, Nortriptyline, Nadolol, etc. Granted, I shouldn’t complain about that, either. If everyone with migraines was getting them it would drive up insurance premiums across the board — including mine.

So, after patients have tried and failed at least two to four other options (depending on their plan) I can usually get a CGRP covered. This involves filling out some forms online and submitting them ... then waiting.

Even if the drug is approved, and successful, that’s still not the end of the story. Depending on the plan I have to get them reauthorized anywhere from every 3 to 12 months. There’s also the chance that in December I’ll get a letter saying the drug won’t be covered starting January, and to try one of the recommended alternatives, like generic Topamax, Nortriptyline, Nadolol, etc. Wash, rinse, repeat.

Having celebrities like Lady Gaga pushing them doesn’t help. The commercials never mention that getting the medication isn’t as easy as “ask your doctor.” Nor does it point out that Lady Gaga won’t have an issue with a CGRP agent’s price tag of $800-$1000 per month, while most of her fans need that money for rent and groceries.

The guidelines, in essence, are useful, but only apply to a perfect world where drug cost doesn’t matter. We aren’t in one. I’m not knocking the pharmaceutical companies — research and development take A LOT of money, and every drug that comes to market has to pay not only for itself, but for several others that failed. Innovation isn’t cheap.

That doesn’t make it any easier to explain to patients, who see ads, or news blurbs on Facebook, or whatever. I just wish the advertisements would have more transparency about how the pricing works.

After all, regardless of how good an automobile may be, don’t car ads show an MSRP?

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

Advocacy groups for patients with neurologic disorders have become a common feature in the landscape of drug and device development and federal research funding allocation.

On Capitol Hill, advocates have racked up some impressive legislative wins that aim to set a federal agenda for developing new medications.

At the Food and Drug Administration (FDA), advocacy groups played a significant role in several recent high-profile and controversial approvals for drugs for Alzheimer’s disease, Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS).

Such gains suggest these groups are growing in power. But with these wins come questions about whether large advocacy organizations — some of which receive significant industry funding — wield too much influence.

“You need to think very carefully about how you open these processes up to greater patient involvement,” Matthew S. McCoy, PhD, assistant professor of medical ethics and health policy at the University of Pennsylvania, Philadelphia, told this news organization. It’s important not to “end up with a situation where it’s the best-connected, the most well-resourced, the most-savvy patient organizations that are able to exercise outsize influence.”

Just because a group has deep pockets does not mean that its priorities align with the disease burden. And not every patient population is represented by a professionalized patient advocacy organization, Dr. McCoy noted. “There is the potential for the rich to get richer.”
 

A Seat at the Table

Long ago, the FDA and the National Institutes of Health (NIH) began giving patients a seat at the table, in part because of the path blazed by AIDS activists in the late 1980s and early 1990s, said Dr. McCoy.

Patient advocacy is often visible during FDA advisory committee meetings. The agency usually allows an hour, sometimes more, for members of the public to express support or concerns about the product being reviewed. Patients and caregivers — often aided by advocacy organizations — also submit hundreds, sometimes thousands, of letters before a product review.

The Alzheimer’s Association spent years advocating for approval of the anti-amyloid agent aducanumab (Aduhelm, Biogen/Eisai). In 2020, the organization urged patients and caregivers to submit written and oral testimony to the FDA advisory panel that was reviewing the drug. Despite patients’ pleas, the panel ultimately declined to support the drug’s approval, citing safety concerns and limited evidence of efficacy.

As controversy swirled around the medication — which had the potential for life-threatening brain swelling — advocates continued to apply pressure. Going against the expert panel’s recommendation, in June 2021, the FDA granted accelerated approval prompting three of the panelists to resign in protest.

Aducanumab’s initial price — $56,000 a year — was seen as a major threat to the viability of Medicare. Still, the Alzheimer’s Association stood behind the decision to approve the drug. But by early 2024, Biogen/Eisai said they would stop selling aducanumab, citing other priorities.

Once again patient advocates showed up in March 2022 when the FDA advisers were reviewing Amylyx Pharmaceuticals’ ALS drug Relyvrio (sodium phenylbutyrate and taurursodiol). Trials had showed limited efficacy, but patients testified they would accept greater risk for a chance to be treated with the drug. The committee ultimately voted against approval; 6 months later, the FDA approved Relyvrio anyway.

In April 2024, Amylyx removed Relyvrio from the market following phase 3 trial results that showed no difference between the treatment and placebo.

The drug manufacturer Sarepta Therapeutics, which develops treatments for genetic conditions such as DMD, has a history of working with — and funding — patient advocacy groups. The company encourages nonprofits to apply for grants or sponsorship on its website. At a 2016 advisory committee, when Sarepta was seeking approval of its first DMD therapy eteplirsen (Exondys 51), 52 speakers, most from patient advocacy groups, pleaded for the drug’s approval. When the panel voted no, Sarepta mobilized families to pressure the agency. Exondys was eventually approved.

In June, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, unilaterally gave final expanded approval to Sarepta Therapeutics’ gene therapy Elevidys for DMD. Dr. Marks overrode his own FDA reviewers, who said the product lacked substantial evidence of efficacy. He acknowledged the drug had not met its primary endpoint but said he found secondary and exploratory endpoints “compelling” and cited an unmet medical need.

In an opinion piece in The Washington Post, Aaron Kesselheim, MD, JD, MPH, the director of the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, Boston, Massachusetts, and a former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, questioned the approval stating that it undermined both public trust and manufacturers’ incentives to do the hard work of proving effectiveness.
 

Patient Voices the ‘Secret Sauce’

Drugmakers aren’t alone in seeing the value of having patients speak directly to government entities. When the Michael J. Fox Foundation wanted to gather cosponsors for the National Plan to End Parkinson’s Act, which President Joe Biden signed into law in July, it recruited and trained patients and caregivers for congressional meetings, said Ted Thompson, senior vice president of public policy at the foundation.

Having those individuals “making the personal case for how this disease affects their families ... was really the secret sauce,” in garnering a large number of cosponsors and getting legislation signed into law within 2 years of its introduction, Mr. Thompson told this news organization.

ALS advocacy groups launched a similar campaign to secure passage of the Accelerating Access to Critical Therapies for ALS Act in 2021.

Both pieces of legislation seek to set a federal agenda for developing new therapies in neurodegenerative diseases, in part by directing the FDA and NIH to fund research, engage patients more directly, and form public-private partnerships and councils to spur innovation.

But some said patient advocates are still coming far too late to the party.

“By the time you hear from patient groups at the meetings at the FDA, often the best opportunities for their input are long past,” Leah Zoe Gibson Rand, DPhil, a research scientist with the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, told this news organization. There should be more focus on the patient perspective earlier in drug development and trial design.

“There are some things that the patient voice could uniquely tell the agency,” said Holly Fernandez Lynch, JD, associate professor of medical ethics and health policy at the University of Pennsylvania. Patients can give insight on what it means to live with a disease, what symptoms are particularly burdensome, and which endpoints matter.

But, she said, “listening to the patient voice cannot mean that FDA just steps aside and lets anything on the market that patients are willing to try.” Individuals “who lack good treatment options have a very good reason to want to try things that haven’t yet been proven.”

If the FDA allows drugs on the market just because patients are willing to try, “5 or 10 years down the road, it’s not at all clear that we would end up with drugs that are better, or drugs that work, or drugs that we know anything more about,” said Dr. Lynch.
 

Does Taking Industry Money Equal Conflicts of Interest?

Many patient advocacy organizations receive funding from drug companies, medical device makers, or other industry sources, but they aren’t always transparent about how much or from which companies, according to studies.

The Alzheimer’s Association continued to push for the approval of aducanumab, even as the group received millions of dollars from the drugmakers. The association was accused of failing to disclose the potential conflict. It still lobbied for approval, even after the FDA advisers in 2020 voted against the drug.

It is not uncommon for individuals who speak in favor of a product’s approval to receive money for transportation and/or lodging from the drug’s manufacturer. In 2018, Dr. McCoy and colleagues reported in JAMA Internal Medicine that, between 2009 and 2017, a quarter of the speakers at the Anesthetic and Analgesic Drug Products Advisory Committee had conflicts of interest (COIs), mostly from industry, and that they were not disclosed in approximately 20% of the instances.

In a 2017 study of 104 large patient advocacy organizations published in The New England Journal of Medicine, Dr. McCoy and colleagues reported that 83% had received funds from industry. At least 39% had a current or former industry executive on the governing board, and 12% had a current or former industry executive in a board leadership position. Of the 104, 38 were focused on cancer and 13 on neurologic conditions. Of these, only 12% had published policies for managing institutional COIs.

Dr. McCoy emphasized the industry’s reliance on partnering with patient groups, particularly during FDA advisory committee meetings. “The sponsors wouldn’t be paying for patients to show up and give these testimonies if they didn’t think it made a difference. The audience isn’t just panel members; it’s also agency officials and maybe elected officials as well.”

“The Fox Foundation, with a $300 million-plus budget, gets about $5-$6 million a year from industry,” said Mr. Thompson. The money is earmarked for the organization’s Parkinson’s Disease Education Consortium; none goes toward advocacy. And, “the foundation has never specifically endorsed a product or device.”

When organizations that receive industry funding back a particular product, “it does appear to be [a conflict], and whether it is an actual one or not, appearances sometimes are all that matter,” said Mr. Thompson.

Dr. Lynch said accepting industry money “is a really significant conflict.” While advocates might need that money to fund advocacy efforts or make grants to advance research priorities, the acceptance might hinder willingness to demand evidence or to complain about a product’s price tag. “You don’t want to bite the hand that feeds you, right?”

Both Dr. McCoy and Dr. Lynch said patient groups — and individual patients — should at a minimum disclose industry funding, especially when speaking at an advisory committee.

Federal agencies and members of Congress actively seek patient input when considering legislation and funding priorities. But the individuals testifying at an advisory committee aren’t likely to represent all patients, and there’s a danger that they are just the loudest voices, said Dr. McCoy.

“We need to think more carefully about how we actually understand the preferences of a big, diverse patient population,” he said.

Dr. Lynch agreed.

Within the ALS community, “a lot of people who take different perspectives than some of those that are the leading voices get shouted down, and their voices get drowned out, and they get attacked on social media,” she said.

The group may be at the table, “but they’re just one voice at the table,” she said.

Dr. McCoy reported that his wife works for the Leukemia & Lymphoma Society, a patient advocacy organization. Dr. Rand reported no relevant financial relationships. Dr. Lynch received funding from Arnold Ventures and the Greenwall Foundation for work related to the FDA and patient advocacy.

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

Advocacy groups for patients with neurologic disorders have become a common feature in the landscape of drug and device development and federal research funding allocation.

On Capitol Hill, advocates have racked up some impressive legislative wins that aim to set a federal agenda for developing new medications.

At the Food and Drug Administration (FDA), advocacy groups played a significant role in several recent high-profile and controversial approvals for drugs for Alzheimer’s disease, Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS).

Such gains suggest these groups are growing in power. But with these wins come questions about whether large advocacy organizations — some of which receive significant industry funding — wield too much influence.

“You need to think very carefully about how you open these processes up to greater patient involvement,” Matthew S. McCoy, PhD, assistant professor of medical ethics and health policy at the University of Pennsylvania, Philadelphia, told this news organization. It’s important not to “end up with a situation where it’s the best-connected, the most well-resourced, the most-savvy patient organizations that are able to exercise outsize influence.”

Just because a group has deep pockets does not mean that its priorities align with the disease burden. And not every patient population is represented by a professionalized patient advocacy organization, Dr. McCoy noted. “There is the potential for the rich to get richer.”
 

A Seat at the Table

Long ago, the FDA and the National Institutes of Health (NIH) began giving patients a seat at the table, in part because of the path blazed by AIDS activists in the late 1980s and early 1990s, said Dr. McCoy.

Patient advocacy is often visible during FDA advisory committee meetings. The agency usually allows an hour, sometimes more, for members of the public to express support or concerns about the product being reviewed. Patients and caregivers — often aided by advocacy organizations — also submit hundreds, sometimes thousands, of letters before a product review.

The Alzheimer’s Association spent years advocating for approval of the anti-amyloid agent aducanumab (Aduhelm, Biogen/Eisai). In 2020, the organization urged patients and caregivers to submit written and oral testimony to the FDA advisory panel that was reviewing the drug. Despite patients’ pleas, the panel ultimately declined to support the drug’s approval, citing safety concerns and limited evidence of efficacy.

As controversy swirled around the medication — which had the potential for life-threatening brain swelling — advocates continued to apply pressure. Going against the expert panel’s recommendation, in June 2021, the FDA granted accelerated approval prompting three of the panelists to resign in protest.

Aducanumab’s initial price — $56,000 a year — was seen as a major threat to the viability of Medicare. Still, the Alzheimer’s Association stood behind the decision to approve the drug. But by early 2024, Biogen/Eisai said they would stop selling aducanumab, citing other priorities.

Once again patient advocates showed up in March 2022 when the FDA advisers were reviewing Amylyx Pharmaceuticals’ ALS drug Relyvrio (sodium phenylbutyrate and taurursodiol). Trials had showed limited efficacy, but patients testified they would accept greater risk for a chance to be treated with the drug. The committee ultimately voted against approval; 6 months later, the FDA approved Relyvrio anyway.

In April 2024, Amylyx removed Relyvrio from the market following phase 3 trial results that showed no difference between the treatment and placebo.

The drug manufacturer Sarepta Therapeutics, which develops treatments for genetic conditions such as DMD, has a history of working with — and funding — patient advocacy groups. The company encourages nonprofits to apply for grants or sponsorship on its website. At a 2016 advisory committee, when Sarepta was seeking approval of its first DMD therapy eteplirsen (Exondys 51), 52 speakers, most from patient advocacy groups, pleaded for the drug’s approval. When the panel voted no, Sarepta mobilized families to pressure the agency. Exondys was eventually approved.

In June, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, unilaterally gave final expanded approval to Sarepta Therapeutics’ gene therapy Elevidys for DMD. Dr. Marks overrode his own FDA reviewers, who said the product lacked substantial evidence of efficacy. He acknowledged the drug had not met its primary endpoint but said he found secondary and exploratory endpoints “compelling” and cited an unmet medical need.

In an opinion piece in The Washington Post, Aaron Kesselheim, MD, JD, MPH, the director of the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, Boston, Massachusetts, and a former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, questioned the approval stating that it undermined both public trust and manufacturers’ incentives to do the hard work of proving effectiveness.
 

Patient Voices the ‘Secret Sauce’

Drugmakers aren’t alone in seeing the value of having patients speak directly to government entities. When the Michael J. Fox Foundation wanted to gather cosponsors for the National Plan to End Parkinson’s Act, which President Joe Biden signed into law in July, it recruited and trained patients and caregivers for congressional meetings, said Ted Thompson, senior vice president of public policy at the foundation.

Having those individuals “making the personal case for how this disease affects their families ... was really the secret sauce,” in garnering a large number of cosponsors and getting legislation signed into law within 2 years of its introduction, Mr. Thompson told this news organization.

ALS advocacy groups launched a similar campaign to secure passage of the Accelerating Access to Critical Therapies for ALS Act in 2021.

Both pieces of legislation seek to set a federal agenda for developing new therapies in neurodegenerative diseases, in part by directing the FDA and NIH to fund research, engage patients more directly, and form public-private partnerships and councils to spur innovation.

But some said patient advocates are still coming far too late to the party.

“By the time you hear from patient groups at the meetings at the FDA, often the best opportunities for their input are long past,” Leah Zoe Gibson Rand, DPhil, a research scientist with the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, told this news organization. There should be more focus on the patient perspective earlier in drug development and trial design.

“There are some things that the patient voice could uniquely tell the agency,” said Holly Fernandez Lynch, JD, associate professor of medical ethics and health policy at the University of Pennsylvania. Patients can give insight on what it means to live with a disease, what symptoms are particularly burdensome, and which endpoints matter.

But, she said, “listening to the patient voice cannot mean that FDA just steps aside and lets anything on the market that patients are willing to try.” Individuals “who lack good treatment options have a very good reason to want to try things that haven’t yet been proven.”

If the FDA allows drugs on the market just because patients are willing to try, “5 or 10 years down the road, it’s not at all clear that we would end up with drugs that are better, or drugs that work, or drugs that we know anything more about,” said Dr. Lynch.
 

Does Taking Industry Money Equal Conflicts of Interest?

Many patient advocacy organizations receive funding from drug companies, medical device makers, or other industry sources, but they aren’t always transparent about how much or from which companies, according to studies.

The Alzheimer’s Association continued to push for the approval of aducanumab, even as the group received millions of dollars from the drugmakers. The association was accused of failing to disclose the potential conflict. It still lobbied for approval, even after the FDA advisers in 2020 voted against the drug.

It is not uncommon for individuals who speak in favor of a product’s approval to receive money for transportation and/or lodging from the drug’s manufacturer. In 2018, Dr. McCoy and colleagues reported in JAMA Internal Medicine that, between 2009 and 2017, a quarter of the speakers at the Anesthetic and Analgesic Drug Products Advisory Committee had conflicts of interest (COIs), mostly from industry, and that they were not disclosed in approximately 20% of the instances.

In a 2017 study of 104 large patient advocacy organizations published in The New England Journal of Medicine, Dr. McCoy and colleagues reported that 83% had received funds from industry. At least 39% had a current or former industry executive on the governing board, and 12% had a current or former industry executive in a board leadership position. Of the 104, 38 were focused on cancer and 13 on neurologic conditions. Of these, only 12% had published policies for managing institutional COIs.

Dr. McCoy emphasized the industry’s reliance on partnering with patient groups, particularly during FDA advisory committee meetings. “The sponsors wouldn’t be paying for patients to show up and give these testimonies if they didn’t think it made a difference. The audience isn’t just panel members; it’s also agency officials and maybe elected officials as well.”

“The Fox Foundation, with a $300 million-plus budget, gets about $5-$6 million a year from industry,” said Mr. Thompson. The money is earmarked for the organization’s Parkinson’s Disease Education Consortium; none goes toward advocacy. And, “the foundation has never specifically endorsed a product or device.”

When organizations that receive industry funding back a particular product, “it does appear to be [a conflict], and whether it is an actual one or not, appearances sometimes are all that matter,” said Mr. Thompson.

Dr. Lynch said accepting industry money “is a really significant conflict.” While advocates might need that money to fund advocacy efforts or make grants to advance research priorities, the acceptance might hinder willingness to demand evidence or to complain about a product’s price tag. “You don’t want to bite the hand that feeds you, right?”

Both Dr. McCoy and Dr. Lynch said patient groups — and individual patients — should at a minimum disclose industry funding, especially when speaking at an advisory committee.

Federal agencies and members of Congress actively seek patient input when considering legislation and funding priorities. But the individuals testifying at an advisory committee aren’t likely to represent all patients, and there’s a danger that they are just the loudest voices, said Dr. McCoy.

“We need to think more carefully about how we actually understand the preferences of a big, diverse patient population,” he said.

Dr. Lynch agreed.

Within the ALS community, “a lot of people who take different perspectives than some of those that are the leading voices get shouted down, and their voices get drowned out, and they get attacked on social media,” she said.

The group may be at the table, “but they’re just one voice at the table,” she said.

Dr. McCoy reported that his wife works for the Leukemia & Lymphoma Society, a patient advocacy organization. Dr. Rand reported no relevant financial relationships. Dr. Lynch received funding from Arnold Ventures and the Greenwall Foundation for work related to the FDA and patient advocacy.

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

Advocacy groups for patients with neurologic disorders have become a common feature in the landscape of drug and device development and federal research funding allocation.

On Capitol Hill, advocates have racked up some impressive legislative wins that aim to set a federal agenda for developing new medications.

At the Food and Drug Administration (FDA), advocacy groups played a significant role in several recent high-profile and controversial approvals for drugs for Alzheimer’s disease, Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS).

Such gains suggest these groups are growing in power. But with these wins come questions about whether large advocacy organizations — some of which receive significant industry funding — wield too much influence.

“You need to think very carefully about how you open these processes up to greater patient involvement,” Matthew S. McCoy, PhD, assistant professor of medical ethics and health policy at the University of Pennsylvania, Philadelphia, told this news organization. It’s important not to “end up with a situation where it’s the best-connected, the most well-resourced, the most-savvy patient organizations that are able to exercise outsize influence.”

Just because a group has deep pockets does not mean that its priorities align with the disease burden. And not every patient population is represented by a professionalized patient advocacy organization, Dr. McCoy noted. “There is the potential for the rich to get richer.”
 

A Seat at the Table

Long ago, the FDA and the National Institutes of Health (NIH) began giving patients a seat at the table, in part because of the path blazed by AIDS activists in the late 1980s and early 1990s, said Dr. McCoy.

Patient advocacy is often visible during FDA advisory committee meetings. The agency usually allows an hour, sometimes more, for members of the public to express support or concerns about the product being reviewed. Patients and caregivers — often aided by advocacy organizations — also submit hundreds, sometimes thousands, of letters before a product review.

The Alzheimer’s Association spent years advocating for approval of the anti-amyloid agent aducanumab (Aduhelm, Biogen/Eisai). In 2020, the organization urged patients and caregivers to submit written and oral testimony to the FDA advisory panel that was reviewing the drug. Despite patients’ pleas, the panel ultimately declined to support the drug’s approval, citing safety concerns and limited evidence of efficacy.

As controversy swirled around the medication — which had the potential for life-threatening brain swelling — advocates continued to apply pressure. Going against the expert panel’s recommendation, in June 2021, the FDA granted accelerated approval prompting three of the panelists to resign in protest.

Aducanumab’s initial price — $56,000 a year — was seen as a major threat to the viability of Medicare. Still, the Alzheimer’s Association stood behind the decision to approve the drug. But by early 2024, Biogen/Eisai said they would stop selling aducanumab, citing other priorities.

Once again patient advocates showed up in March 2022 when the FDA advisers were reviewing Amylyx Pharmaceuticals’ ALS drug Relyvrio (sodium phenylbutyrate and taurursodiol). Trials had showed limited efficacy, but patients testified they would accept greater risk for a chance to be treated with the drug. The committee ultimately voted against approval; 6 months later, the FDA approved Relyvrio anyway.

In April 2024, Amylyx removed Relyvrio from the market following phase 3 trial results that showed no difference between the treatment and placebo.

The drug manufacturer Sarepta Therapeutics, which develops treatments for genetic conditions such as DMD, has a history of working with — and funding — patient advocacy groups. The company encourages nonprofits to apply for grants or sponsorship on its website. At a 2016 advisory committee, when Sarepta was seeking approval of its first DMD therapy eteplirsen (Exondys 51), 52 speakers, most from patient advocacy groups, pleaded for the drug’s approval. When the panel voted no, Sarepta mobilized families to pressure the agency. Exondys was eventually approved.

In June, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, unilaterally gave final expanded approval to Sarepta Therapeutics’ gene therapy Elevidys for DMD. Dr. Marks overrode his own FDA reviewers, who said the product lacked substantial evidence of efficacy. He acknowledged the drug had not met its primary endpoint but said he found secondary and exploratory endpoints “compelling” and cited an unmet medical need.

In an opinion piece in The Washington Post, Aaron Kesselheim, MD, JD, MPH, the director of the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, Boston, Massachusetts, and a former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, questioned the approval stating that it undermined both public trust and manufacturers’ incentives to do the hard work of proving effectiveness.
 

Patient Voices the ‘Secret Sauce’

Drugmakers aren’t alone in seeing the value of having patients speak directly to government entities. When the Michael J. Fox Foundation wanted to gather cosponsors for the National Plan to End Parkinson’s Act, which President Joe Biden signed into law in July, it recruited and trained patients and caregivers for congressional meetings, said Ted Thompson, senior vice president of public policy at the foundation.

Having those individuals “making the personal case for how this disease affects their families ... was really the secret sauce,” in garnering a large number of cosponsors and getting legislation signed into law within 2 years of its introduction, Mr. Thompson told this news organization.

ALS advocacy groups launched a similar campaign to secure passage of the Accelerating Access to Critical Therapies for ALS Act in 2021.

Both pieces of legislation seek to set a federal agenda for developing new therapies in neurodegenerative diseases, in part by directing the FDA and NIH to fund research, engage patients more directly, and form public-private partnerships and councils to spur innovation.

But some said patient advocates are still coming far too late to the party.

“By the time you hear from patient groups at the meetings at the FDA, often the best opportunities for their input are long past,” Leah Zoe Gibson Rand, DPhil, a research scientist with the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, told this news organization. There should be more focus on the patient perspective earlier in drug development and trial design.

“There are some things that the patient voice could uniquely tell the agency,” said Holly Fernandez Lynch, JD, associate professor of medical ethics and health policy at the University of Pennsylvania. Patients can give insight on what it means to live with a disease, what symptoms are particularly burdensome, and which endpoints matter.

But, she said, “listening to the patient voice cannot mean that FDA just steps aside and lets anything on the market that patients are willing to try.” Individuals “who lack good treatment options have a very good reason to want to try things that haven’t yet been proven.”

If the FDA allows drugs on the market just because patients are willing to try, “5 or 10 years down the road, it’s not at all clear that we would end up with drugs that are better, or drugs that work, or drugs that we know anything more about,” said Dr. Lynch.
 

Does Taking Industry Money Equal Conflicts of Interest?

Many patient advocacy organizations receive funding from drug companies, medical device makers, or other industry sources, but they aren’t always transparent about how much or from which companies, according to studies.

The Alzheimer’s Association continued to push for the approval of aducanumab, even as the group received millions of dollars from the drugmakers. The association was accused of failing to disclose the potential conflict. It still lobbied for approval, even after the FDA advisers in 2020 voted against the drug.

It is not uncommon for individuals who speak in favor of a product’s approval to receive money for transportation and/or lodging from the drug’s manufacturer. In 2018, Dr. McCoy and colleagues reported in JAMA Internal Medicine that, between 2009 and 2017, a quarter of the speakers at the Anesthetic and Analgesic Drug Products Advisory Committee had conflicts of interest (COIs), mostly from industry, and that they were not disclosed in approximately 20% of the instances.

In a 2017 study of 104 large patient advocacy organizations published in The New England Journal of Medicine, Dr. McCoy and colleagues reported that 83% had received funds from industry. At least 39% had a current or former industry executive on the governing board, and 12% had a current or former industry executive in a board leadership position. Of the 104, 38 were focused on cancer and 13 on neurologic conditions. Of these, only 12% had published policies for managing institutional COIs.

Dr. McCoy emphasized the industry’s reliance on partnering with patient groups, particularly during FDA advisory committee meetings. “The sponsors wouldn’t be paying for patients to show up and give these testimonies if they didn’t think it made a difference. The audience isn’t just panel members; it’s also agency officials and maybe elected officials as well.”

“The Fox Foundation, with a $300 million-plus budget, gets about $5-$6 million a year from industry,” said Mr. Thompson. The money is earmarked for the organization’s Parkinson’s Disease Education Consortium; none goes toward advocacy. And, “the foundation has never specifically endorsed a product or device.”

When organizations that receive industry funding back a particular product, “it does appear to be [a conflict], and whether it is an actual one or not, appearances sometimes are all that matter,” said Mr. Thompson.

Dr. Lynch said accepting industry money “is a really significant conflict.” While advocates might need that money to fund advocacy efforts or make grants to advance research priorities, the acceptance might hinder willingness to demand evidence or to complain about a product’s price tag. “You don’t want to bite the hand that feeds you, right?”

Both Dr. McCoy and Dr. Lynch said patient groups — and individual patients — should at a minimum disclose industry funding, especially when speaking at an advisory committee.

Federal agencies and members of Congress actively seek patient input when considering legislation and funding priorities. But the individuals testifying at an advisory committee aren’t likely to represent all patients, and there’s a danger that they are just the loudest voices, said Dr. McCoy.

“We need to think more carefully about how we actually understand the preferences of a big, diverse patient population,” he said.

Dr. Lynch agreed.

Within the ALS community, “a lot of people who take different perspectives than some of those that are the leading voices get shouted down, and their voices get drowned out, and they get attacked on social media,” she said.

The group may be at the table, “but they’re just one voice at the table,” she said.

Dr. McCoy reported that his wife works for the Leukemia & Lymphoma Society, a patient advocacy organization. Dr. Rand reported no relevant financial relationships. Dr. Lynch received funding from Arnold Ventures and the Greenwall Foundation for work related to the FDA and patient advocacy.

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

TOPLINE:

Older adults with untreated hypertension have a 36% increased risk for Alzheimer’s disease (AD) compared with those without hypertension and a 42% increased risk for AD compared with those with treated hypertension.

METHODOLOGY:

• In this meta-analysis, researchers analyzed the data of 31,250 participants aged 60 years or older (mean age, 72.1 years; 41% men) from 14 community-based studies across 14 countries.
• Mean follow-up was 4.2 years, and blood pressure measurements, hypertension diagnosis, and antihypertensive medication use were recorded.
• Overall, 35.9% had no history of hypertension or antihypertensive medication use, 50.7% had a history of hypertension with antihypertensive medication use, and 9.4% had a history of hypertension without antihypertensive medication use.
• The main outcomes were AD and non-AD dementia.

TAKEAWAY:

• In total, 1415 participants developed AD, and 681 developed non-AD dementia.
• Participants with untreated hypertension had a 36% increased risk for AD compared with healthy controls (hazard ratio [HR], 1.36; P = .041) and a 42% increased risk for AD (HR, 1.42; P = .013) compared with those with treated hypertension.
• Compared with healthy controls, patients with treated hypertension did not show an elevated risk for AD (HR, 0.961; P = .6644).
• Patients with both treated (HR, 1.285; P = .027) and untreated (HR, 1.693; P = .003) hypertension had an increased risk for non-AD dementia compared with healthy controls. Patients with treated and untreated hypertension had a similar risk for non-AD dementia.

IN PRACTICE:

“These results suggest that treating high blood pressure as a person ages continues to be a crucial factor in reducing their risk of Alzheimer’s disease,” the lead author Matthew J. Lennon, MD, PhD, said in a press release.

SOURCE:

This study was led by Matthew J. Lennon, MD, PhD, School of Clinical Medicine, UNSW Sydney, Sydney, Australia. It was published online in Neurology.

LIMITATIONS: 

Varied definitions for hypertension across different locations might have led to discrepancies in diagnosis. Additionally, the study did not account for potential confounders such as stroke, transient ischemic attack, and heart disease, which may act as mediators rather than covariates. Furthermore, the study did not report mortality data, which may have affected the interpretation of dementia risk.

DISCLOSURES:

This research was supported by the National Institute on Aging of the National Institutes of Health. Some authors reported ties with several institutions and pharmaceutical companies outside this work. Full disclosures are available in the original article.

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

TOPLINE:

Older adults with untreated hypertension have a 36% increased risk for Alzheimer’s disease (AD) compared with those without hypertension and a 42% increased risk for AD compared with those with treated hypertension.

METHODOLOGY:

• In this meta-analysis, researchers analyzed the data of 31,250 participants aged 60 years or older (mean age, 72.1 years; 41% men) from 14 community-based studies across 14 countries.
• Mean follow-up was 4.2 years, and blood pressure measurements, hypertension diagnosis, and antihypertensive medication use were recorded.
• Overall, 35.9% had no history of hypertension or antihypertensive medication use, 50.7% had a history of hypertension with antihypertensive medication use, and 9.4% had a history of hypertension without antihypertensive medication use.
• The main outcomes were AD and non-AD dementia.

TAKEAWAY:

• In total, 1415 participants developed AD, and 681 developed non-AD dementia.
• Participants with untreated hypertension had a 36% increased risk for AD compared with healthy controls (hazard ratio [HR], 1.36; P = .041) and a 42% increased risk for AD (HR, 1.42; P = .013) compared with those with treated hypertension.
• Compared with healthy controls, patients with treated hypertension did not show an elevated risk for AD (HR, 0.961; P = .6644).
• Patients with both treated (HR, 1.285; P = .027) and untreated (HR, 1.693; P = .003) hypertension had an increased risk for non-AD dementia compared with healthy controls. Patients with treated and untreated hypertension had a similar risk for non-AD dementia.

IN PRACTICE:

“These results suggest that treating high blood pressure as a person ages continues to be a crucial factor in reducing their risk of Alzheimer’s disease,” the lead author Matthew J. Lennon, MD, PhD, said in a press release.

SOURCE:

This study was led by Matthew J. Lennon, MD, PhD, School of Clinical Medicine, UNSW Sydney, Sydney, Australia. It was published online in Neurology.

LIMITATIONS: 

Varied definitions for hypertension across different locations might have led to discrepancies in diagnosis. Additionally, the study did not account for potential confounders such as stroke, transient ischemic attack, and heart disease, which may act as mediators rather than covariates. Furthermore, the study did not report mortality data, which may have affected the interpretation of dementia risk.

DISCLOSURES:

This research was supported by the National Institute on Aging of the National Institutes of Health. Some authors reported ties with several institutions and pharmaceutical companies outside this work. Full disclosures are available in the original article.

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

TOPLINE:

Older adults with untreated hypertension have a 36% increased risk for Alzheimer’s disease (AD) compared with those without hypertension and a 42% increased risk for AD compared with those with treated hypertension.

METHODOLOGY:

• In this meta-analysis, researchers analyzed the data of 31,250 participants aged 60 years or older (mean age, 72.1 years; 41% men) from 14 community-based studies across 14 countries.
• Mean follow-up was 4.2 years, and blood pressure measurements, hypertension diagnosis, and antihypertensive medication use were recorded.
• Overall, 35.9% had no history of hypertension or antihypertensive medication use, 50.7% had a history of hypertension with antihypertensive medication use, and 9.4% had a history of hypertension without antihypertensive medication use.
• The main outcomes were AD and non-AD dementia.

TAKEAWAY:

• In total, 1415 participants developed AD, and 681 developed non-AD dementia.
• Participants with untreated hypertension had a 36% increased risk for AD compared with healthy controls (hazard ratio [HR], 1.36; P = .041) and a 42% increased risk for AD (HR, 1.42; P = .013) compared with those with treated hypertension.
• Compared with healthy controls, patients with treated hypertension did not show an elevated risk for AD (HR, 0.961; P = .6644).
• Patients with both treated (HR, 1.285; P = .027) and untreated (HR, 1.693; P = .003) hypertension had an increased risk for non-AD dementia compared with healthy controls. Patients with treated and untreated hypertension had a similar risk for non-AD dementia.

IN PRACTICE:

“These results suggest that treating high blood pressure as a person ages continues to be a crucial factor in reducing their risk of Alzheimer’s disease,” the lead author Matthew J. Lennon, MD, PhD, said in a press release.

SOURCE:

This study was led by Matthew J. Lennon, MD, PhD, School of Clinical Medicine, UNSW Sydney, Sydney, Australia. It was published online in Neurology.

LIMITATIONS: 

Varied definitions for hypertension across different locations might have led to discrepancies in diagnosis. Additionally, the study did not account for potential confounders such as stroke, transient ischemic attack, and heart disease, which may act as mediators rather than covariates. Furthermore, the study did not report mortality data, which may have affected the interpretation of dementia risk.

DISCLOSURES:

This research was supported by the National Institute on Aging of the National Institutes of Health. Some authors reported ties with several institutions and pharmaceutical companies outside this work. Full disclosures are available in the original article.

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

TOPLINE:

Age-related hearing loss and peripheral neuropathy in older adults reduce longevity both directly and indirectly by affecting balance and gait.

METHODOLOGY:

• Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
• Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
• Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
• Researchers tracked mortality data over 22 years.

TAKEAWAY:

• Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
• Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
• Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).

IN PRACTICE:

“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”

SOURCE:

The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.

LIMITATIONS:

The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.

DISCLOSURES:

The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.

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

TOPLINE:

Age-related hearing loss and peripheral neuropathy in older adults reduce longevity both directly and indirectly by affecting balance and gait.

METHODOLOGY:

• Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
• Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
• Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
• Researchers tracked mortality data over 22 years.

TAKEAWAY:

• Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
• Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
• Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).

IN PRACTICE:

“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”

SOURCE:

The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.

LIMITATIONS:

The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.

DISCLOSURES:

The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.

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

TOPLINE:

Age-related hearing loss and peripheral neuropathy in older adults reduce longevity both directly and indirectly by affecting balance and gait.

METHODOLOGY:

• Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
• Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
• Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
• Researchers tracked mortality data over 22 years.

TAKEAWAY:

• Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
• Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
• Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).

IN PRACTICE:

“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”

SOURCE:

The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.

LIMITATIONS:

The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.

DISCLOSURES:

The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.

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