Neurology Reviews

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

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

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

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

In a shifting landscape in dementia risk factors, cardiovascular health is now taking precedence.

That’s according to researchers from University College London (UCL) in the United Kingdom who analyzed 27 papers about dementia that had data collected over more than 70 years. They calculated what share of dementia cases were due to different risk factors. Their findings were recently published in the Lancet Public Health.

Top risk factors for dementia over the years have been hypertension, obesity, diabetes, education, and smoking, according to a news release on the findings. But the prevalence of risk factors has changed over the decades.

Researchers said smoking and education have become less important risk factors because of “population-level interventions,” such as stop-smoking campaigns and compulsory public education. On the other hand, obesity and diabetes rates have increased and become bigger risk factors.

Hypertension remains the greatest risk factor, even though doctors and public health groups are putting more emphasis on managing the condition, the study said.

“Cardiovascular risk factors may have contributed more to dementia risk over time, so these deserve more targeted action for future dementia prevention efforts,” said Naaheed Mukadam, PhD, an associate professor at UCL and the lead author of the study.

Eliminating modifiable risk factors could theoretically prevent 40% of dementia cases, the release said. 

The CDC says that an estimated 5.8 million people in the United States have Alzheimer’s disease and related dementias, including 5.6 million people ages 65 and older and about 200,000 under age 65. The UCL release said an estimated 944,000 in the U.K. have dementia. 

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

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A work group convened by the Alzheimer’s Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer’s disease, including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

“Plasma markers are here now, and it’s very important to incorporate them into the criteria for diagnosis,” said senior author Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

The revised criteria are the first updates since 2018.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease, and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer’s Association. 

“These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer’s and we are able to measure those changes,” Dr. Jack added. 

The 2024 revised criteria for diagnosis and staging of Alzheimer’s disease were published online in Alzheimer’s & Dementia. 
 

Core Biomarkers Defined

The revised criteria define Alzheimer’s disease as a biologic process that begins with the appearance of Alzheimer’s disease neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized Alzheimer’s disease biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in Alzheimer’s disease but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with Alzheimer’s disease.

Core Alzheimer’s biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and “accurate” plasma biomarkers, such as p-tau217. 

“An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer’s disease and to inform clinical decision making [sic] throughout the disease continuum,” the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers “increase confidence that Alzheimer’s disease is contributing to symptoms,” the work group noted. 

The revised criteria give clinicians “the flexibility to use plasma or PET scans or CSF,” Dr. Carrillo said. “They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics.” 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic Alzheimer’s disease stages. 
 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of Alzheimer’s disease biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical Alzheimer’s disease, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of Alzheimer’s disease that reflect current science.

“This is just the beginning,” said Dr. Carrillo. “This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science.”

This also serves as a “springboard” for the Alzheimer’s Association to create formal clinical guidelines. “That will come, hopefully, over the next 12 months. We’ll be working on it, and we hope to have that in 2025,” Dr. Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

“The biologically based diagnosis of Alzheimer’s disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment,” the work group wrote in a related commentary published online in Nature Medicine. 

Recent diagnostics and therapeutic developments “herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods,” they continued. “An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer’s Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson’s Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article.

 A version of this article appeared on Medscape.com.

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

A tool routinely used to evaluate concussion in college athletes fails to accurately diagnose the condition in many cases, a new study showed.

Investigators found that almost half of athletes diagnosed with a concussion tested normally on the Sports Concussion Assessment Tool 5 (SCAT5), the recommended tool for measuring cognitive skills in concussion evaluations. The most accurate measure of concussion was symptoms reported by the athletes.

“If you don’t do well on the cognitive exam, it suggests you have a concussion. But many people who are concussed do fine on the exam,” lead author Kimberly Harmon, MD, professor of family medicine and section head of sports medicine at the University of Washington School of Medicine, Seattle, said in a news release.

The study was published online in JAMA Network Open.

Introduced in 2004, the SCAT was created to standardize the collection of information clinicians use to diagnose concussion, including evaluation of symptoms, orientation, and balance. It also uses a 10-word list to assess immediate memory and delayed recall.

Dr. Harmon’s own experiences as a team physician led her to wonder about the accuracy of the cognitive screening portion of the SCAT. She saw that “some people were concussed, and they did well on the recall test. Some people weren’t concussed, and they didn’t do well. So I thought we should study it,” she said.

Investigators compared 92 National Collegiate Athletic Association (NCAA) Division 1 athletes who had sustained a concussion between 2020 and 2022 and had a concussion evaluation within 48 hours to 92 matched nonconcussed teammates (overall cohort, 52% men). Most concussions occurred in those who played football, followed by volleyball.

All athletes had previously completed NCAA-required baseline concussion screenings. Participants completed the SCAT5 screening test within 2 weeks of the incident concussion.

No significant differences were found between the baseline scores of athletes with and without concussion. Moreover, responses on the word recall section of the SCAT5 held little predictive value for concussion.

Nearly half (45%) of athletes with concussion performed at or even above their baseline cognitive report, which the authors said highlights the limitations of the cognitive components of SCAT5.

The most accurate predictor of concussion was participants’ responses to questions about their symptoms.

“If you get hit in the head and go to the sideline and say, ‘I have a headache, I’m dizzy, I don’t feel right,’ I can say with pretty good assurance that you have a concussion,” Dr. Harmon continued. “I don’t need to do any testing.”

Unfortunately, the problem is “that some athletes don’t want to come out. They don’t report their symptoms or may not recognize their symptoms. So then you need an objective, accurate test to tell you whether you can safely put the athlete back on the field. We don’t have that right now.”

The study did not control for concussion history, and the all–Division 1 cohort means the findings may not be generalizable to other athletes.

Nevertheless, investigators said the study “affirms that reported symptoms are the most sensitive indicator of concussion, and there are limitations to the objective cognitive testing included in the SCAT.” They concluded that concussion “remains a clinical diagnosis that should be based on a thorough review of signs, symptoms, and clinical findings.”

This study was funded in part by donations from University of Washington alumni Jack and Luellen Cherneski and the Chisholm Foundation. Dr. Harmon reported no relevant financial relationships.

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

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

She was young, neatly dressed, professional. I don’t remember her name, though she handed me a business card as soon as I stepped up to the front window.

I thought she was a new drug rep to my territory, and I usually try to say “hi” when they first come in. They’re just doing their job, and I don’t mind chatting for a few minutes.

But she, as it turned out, was here for a whole new thing. Taking out a glossy brochure, she dived into a spiel about my offering a medical credit card through my office. I would get paid quickly, I might even get some extra money from patient interest payments, it is convenient for patients, win-win situation all around, yadda yadda yadda.

I smiled, thanked her for coming in, but told her this wasn’t a good fit for my practice.

I’m well aware that keeping a small practice afloat ain’t easy. Medicine is one of the few fields (unless you’re strictly doing cash pay) where we can’t raise prices to keep up with inflation. Well, we can, but what we get paid won’t change. That’s the nature of dealing with Medicare and insurance. What you charge and what you’ll get (and have to accept) are generally not the same.

But even so, I try to stick with what I know — being a neurologist. I’m not here to offer a range of financial services. I have neither the time, nor interest, to run a patient’s copay while trying to sell them on a medical credit card.

For that matter I’m not going to set up shop selling vitamin supplements, hangover-curing infusions, endorsing products on X, or any of the other dubious things touted as “thinking outside the box” ways to increase revenue.

I suppose some will say I’m old-fashioned, or this is why my practice operates on a thin margin, or that I’m focusing more on patients than business. I don’t mind. Caring for patients is why I’m here.

I also hear the argument that if I don’t market a medical credit card (or whatever), someone else will. That’s fine. Let them. I wish them good luck. It’s just not for me.

Like I’ve said in the past, I’m an old dog, but a happy one. I’ll leave the new tricks to someone else.
 

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

She was young, neatly dressed, professional. I don’t remember her name, though she handed me a business card as soon as I stepped up to the front window.

I thought she was a new drug rep to my territory, and I usually try to say “hi” when they first come in. They’re just doing their job, and I don’t mind chatting for a few minutes.

But she, as it turned out, was here for a whole new thing. Taking out a glossy brochure, she dived into a spiel about my offering a medical credit card through my office. I would get paid quickly, I might even get some extra money from patient interest payments, it is convenient for patients, win-win situation all around, yadda yadda yadda.

I smiled, thanked her for coming in, but told her this wasn’t a good fit for my practice.

I’m well aware that keeping a small practice afloat ain’t easy. Medicine is one of the few fields (unless you’re strictly doing cash pay) where we can’t raise prices to keep up with inflation. Well, we can, but what we get paid won’t change. That’s the nature of dealing with Medicare and insurance. What you charge and what you’ll get (and have to accept) are generally not the same.

But even so, I try to stick with what I know — being a neurologist. I’m not here to offer a range of financial services. I have neither the time, nor interest, to run a patient’s copay while trying to sell them on a medical credit card.

For that matter I’m not going to set up shop selling vitamin supplements, hangover-curing infusions, endorsing products on X, or any of the other dubious things touted as “thinking outside the box” ways to increase revenue.

I suppose some will say I’m old-fashioned, or this is why my practice operates on a thin margin, or that I’m focusing more on patients than business. I don’t mind. Caring for patients is why I’m here.

I also hear the argument that if I don’t market a medical credit card (or whatever), someone else will. That’s fine. Let them. I wish them good luck. It’s just not for me.

Like I’ve said in the past, I’m an old dog, but a happy one. I’ll leave the new tricks to someone else.
 

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

She was young, neatly dressed, professional. I don’t remember her name, though she handed me a business card as soon as I stepped up to the front window.

I thought she was a new drug rep to my territory, and I usually try to say “hi” when they first come in. They’re just doing their job, and I don’t mind chatting for a few minutes.

But she, as it turned out, was here for a whole new thing. Taking out a glossy brochure, she dived into a spiel about my offering a medical credit card through my office. I would get paid quickly, I might even get some extra money from patient interest payments, it is convenient for patients, win-win situation all around, yadda yadda yadda.

I smiled, thanked her for coming in, but told her this wasn’t a good fit for my practice.

I’m well aware that keeping a small practice afloat ain’t easy. Medicine is one of the few fields (unless you’re strictly doing cash pay) where we can’t raise prices to keep up with inflation. Well, we can, but what we get paid won’t change. That’s the nature of dealing with Medicare and insurance. What you charge and what you’ll get (and have to accept) are generally not the same.

But even so, I try to stick with what I know — being a neurologist. I’m not here to offer a range of financial services. I have neither the time, nor interest, to run a patient’s copay while trying to sell them on a medical credit card.

For that matter I’m not going to set up shop selling vitamin supplements, hangover-curing infusions, endorsing products on X, or any of the other dubious things touted as “thinking outside the box” ways to increase revenue.

I suppose some will say I’m old-fashioned, or this is why my practice operates on a thin margin, or that I’m focusing more on patients than business. I don’t mind. Caring for patients is why I’m here.

I also hear the argument that if I don’t market a medical credit card (or whatever), someone else will. That’s fine. Let them. I wish them good luck. It’s just not for me.

Like I’ve said in the past, I’m an old dog, but a happy one. I’ll leave the new tricks to someone else.
 

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

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Bruce Jancin/MDedge News

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Bruce Jancin/MDedge News

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Bruce Jancin/MDedge News

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

The Food and Drug Administration (FDA) has issued new draft guidance that does not require additional switching studies for biosimilars seeking interchangeability. These studies were previously recommended to demonstrate that switching between the biosimilar and its reference product showed no greater risk than using the reference product alone.

“The recommendations in today’s draft guidance, when finalized, will provide clarity and transparency about the FDA’s thinking and align the review and approval process with existing and emerging science,” said Sarah Yim, MD, director of the FDA’s Office of Therapeutic Biologics and Biosimilars in a statement on June 20. “We have gained valuable experience reviewing both biosimilar and interchangeable biosimilar medications over the past 10 years. Both biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval and both are as safe and effective as the reference product.”

An interchangeable status allows a biosimilar product to be swapped with the reference product without involvement from the prescribing provider, depending on state law.

While switching studies were not required under previous FDA guidance, the 2019 document did state that the agency “expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use.”

However, of the 13 biosimilars that received interchangeability status, 9 did not include switching study data.

“Experience has shown that, for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product,” the FDA stated. The agency’s investigators also conducted a systematic review of switching studies, which found no differences in risk for death, serious adverse events, and treatment discontinuations in participants switched between biosimilars and reference products and those that remained on reference products.

“Additionally, today’s analytical tools can accurately evaluate the structure and effects [of] biologic products, both in the lab (in vitro) and in living organisms (in vivo) with more precision and sensitivity than switching studies,” the agency noted.

The FDA is now calling for commentary on these draft recommendations to be submitted by Aug. 20, 2024.

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

The Food and Drug Administration (FDA) has issued new draft guidance that does not require additional switching studies for biosimilars seeking interchangeability. These studies were previously recommended to demonstrate that switching between the biosimilar and its reference product showed no greater risk than using the reference product alone.

“The recommendations in today’s draft guidance, when finalized, will provide clarity and transparency about the FDA’s thinking and align the review and approval process with existing and emerging science,” said Sarah Yim, MD, director of the FDA’s Office of Therapeutic Biologics and Biosimilars in a statement on June 20. “We have gained valuable experience reviewing both biosimilar and interchangeable biosimilar medications over the past 10 years. Both biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval and both are as safe and effective as the reference product.”

An interchangeable status allows a biosimilar product to be swapped with the reference product without involvement from the prescribing provider, depending on state law.

While switching studies were not required under previous FDA guidance, the 2019 document did state that the agency “expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use.”

However, of the 13 biosimilars that received interchangeability status, 9 did not include switching study data.

“Experience has shown that, for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product,” the FDA stated. The agency’s investigators also conducted a systematic review of switching studies, which found no differences in risk for death, serious adverse events, and treatment discontinuations in participants switched between biosimilars and reference products and those that remained on reference products.

“Additionally, today’s analytical tools can accurately evaluate the structure and effects [of] biologic products, both in the lab (in vitro) and in living organisms (in vivo) with more precision and sensitivity than switching studies,” the agency noted.

The FDA is now calling for commentary on these draft recommendations to be submitted by Aug. 20, 2024.

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

The Food and Drug Administration (FDA) has issued new draft guidance that does not require additional switching studies for biosimilars seeking interchangeability. These studies were previously recommended to demonstrate that switching between the biosimilar and its reference product showed no greater risk than using the reference product alone.

“The recommendations in today’s draft guidance, when finalized, will provide clarity and transparency about the FDA’s thinking and align the review and approval process with existing and emerging science,” said Sarah Yim, MD, director of the FDA’s Office of Therapeutic Biologics and Biosimilars in a statement on June 20. “We have gained valuable experience reviewing both biosimilar and interchangeable biosimilar medications over the past 10 years. Both biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval and both are as safe and effective as the reference product.”

An interchangeable status allows a biosimilar product to be swapped with the reference product without involvement from the prescribing provider, depending on state law.

While switching studies were not required under previous FDA guidance, the 2019 document did state that the agency “expects that applications generally will include data from a switching study or studies in one or more appropriate conditions of use.”

However, of the 13 biosimilars that received interchangeability status, 9 did not include switching study data.

“Experience has shown that, for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product,” the FDA stated. The agency’s investigators also conducted a systematic review of switching studies, which found no differences in risk for death, serious adverse events, and treatment discontinuations in participants switched between biosimilars and reference products and those that remained on reference products.

“Additionally, today’s analytical tools can accurately evaluate the structure and effects [of] biologic products, both in the lab (in vitro) and in living organisms (in vivo) with more precision and sensitivity than switching studies,” the agency noted.

The FDA is now calling for commentary on these draft recommendations to be submitted by Aug. 20, 2024.

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

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

Certain medications that are used to treat benign prostatic hyperplasia (BPH) are associated with a reduced risk for dementia with Lewy bodies (DLB), the second most common neurodegenerative type of dementia after Alzheimer’s disease.

Investigators found older men taking alpha-1 blockers terazosin, doxazosin, or alfuzosin (Tz/Dz/Az) were 40% less likely to develop DLB than those taking tamsulosin and 37% less likely than men taking the 5-alpha reductase inhibitors (5ARI) finasteride and dutasteride.

“These results are exciting because right now there are no drugs to prevent or treat dementia with Lewy bodies,” study investigator Jacob E. Simmering, PhD, of the University of Iowa in Iowa City, said in a press release. “If we can determine that an existing drug can offer protection against this debilitating disease, that has the potential to greatly reduce its effects.”

The findings were published online in Neurology.
 

Increasing ATP Neuroprotective?

In recent years, investigators have speculated that improving metabolic activity in the brain may reduce the risk for Parkinson’s disease (PD). 

In previous studies, the use of Tz/Dz/Az resulted in the activation of phosphoglycerate kinase-1 (PKG1), which increases the availability of adenosine triphosphate (ATP).

There have been case reports of PD being linked to mutations affecting PGK1. Researchers speculate that increased ATP availability in neurons resulting from the activation of PKG1 allows cells to better adapt to aging and synuclein aggregation.

To investigate whether glycolysis-enhancing drugs might be neuroprotective in those with DLB, investigators conducted a retrospective cohort study using a commercial health insurance claims database and a Medicare supplemental health claims database to follow a sample of men aged > 40 years taking Tz, Dz, or Az (n = 126,313), tamsulosin (n = 437,035), or a 5ARI (n = 80,158) for BPH.

Tamsulosin and 5ARI medications do not activate PKG1, so investigators used them as comparators to Tz/Dz/Az. Participants were followed from the medication initiation date until the end of enrollment in the claims databases.

After following claimants for an average of 3 years, 195 participants developed DLB who were taking Tz, Dz, or Az, a rate of 5.21 cases per 10,000 people per year.

During the follow-up period, 1286 participants taking tamsulosin developed DLB, a rate of 10.8 per 10,000 people per year, and among those taking 5ARIs, 193 cases of DLB were reported, a rate of 7.8 per 10,000 people per year.

After matching the groups by age and other health conditions that may explain differences in rates of DLB, men taking Tz/Dz/Az had a 60% lower risk than those taking tamsulosin (P < .001) and a 37% lower risk for developing DLB than those taking the 5ARI medications (P = .012).

“This emerging evidence of a protective association across a spectrum of diseases suggests a broad neuroprotective effect for Tz/Dz/Az, consistent with our hypothesized mechanism that activation of PGK1 increases brain ATP and mitigates neurodegeneration,” the authors wrote.

Study limitations include excluding women from the study, so the findings cannot be generalized to women. Claims analyses were limited to administrative data that could have been incorrect, and the analyses did not include medication dosages.

No study funding or author disclosures were reported.

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

SAN DIEGO – Researchers are unraveling the complex relationship between cardiovascular (CV)- and stroke-related outcomes in migraine with, and without, aura.

Early results of one study suggest that aura increases the risk for major adverse cerebrovascular and CV events (MACE) in those with migraine, and that this risk is particularly high in men.

“We confirmed that aura increases the risk for these cerebrovascular and cardiovascular outcomes in people with migraine and that there’s an increased risk of these MACE events in men with migraine,” said study investigator Gina Dumkrieger, PhD, principal data science analyst and assistant professor of neurology, Mayo Clinic, Phoenix, Arizona.

The findings were presented at the annual meeting of the American Headache Society.
 

Few Data on Migraine and Stroke Risk

The extent to which migraine increases the risk for stroke CV outcomes has not been extensively studied.

“We’re trying to find out whether migraine-related factors make it more likely that you’re going to have one of these events,” said Dr. Dumkrieger. “Knowing a particular factor increases the risk is something patients and medical providers would want to know.”

Using Mayo Clinic electronic health records, which cover all three sites (Florida, Minnesota, and Arizona), researchers identified individuals with migraine using diagnostic codes. They also looked at data on sex, race, and the presence of aura.

They investigated whether a history of MACE risk factors — including atrial fibrillation, diabetes, hyperlipidemia, hypertension, and tobacco use — affected risk and the potential interaction of aura with these risk factors.

MACE events included cerebral infarction, intracerebral hemorrhage, and acute myocardial infarction.

The analysis included 130,126 participants (80% women, 95% White individuals). Of these, 6% experienced a MACE event, and 94% did not.

“We confirmed that aura does increase the risk for a MACE event, and all of the known risk factors that we included were also significant,” said Dr. Dumkrieger.

Odds ratios (ORs) were 3.82 for atrial fibrillation, 3.11 for hypertension, and 3.06 for hyperlipidemia.

It was surprising, said Dr. Dumkrieger, that male sex was tied to an increased risk for a MACE event (OR, 1.40). “This is not something that was known before,” she said.

The link between migraine and ischemic stroke, particularly with aura, was stronger in women — particularly young women.

Investigators also found an interaction between male sex and aura, when it comes to MACE outcomes, said Dr. Dumkrieger. “Males in general are at higher risk, and people with aura are at higher risk. Males with aura are also at higher risk, but maybe not as much as you would think they would be. It’s not a purely additive thing. This is something we need to look into more,” she said. 

The study also revealed an interaction between aura and hypertension as well as aura and tobacco use, but here too, it was not an additive risk, said Dr. Dumkrieger. However, she added, the presence of aura does not moderate the risk for hyperlipidemia, diabetes, or atrial fibrillation.

The research also showed a significant interaction between male sex and Black race which was additive. “There’s apparently increased risk if you are male and Black or African American that’s greater than what you would expect. We should be especially concerned about these individuals,” she said.
 

Unanswered Questions

The current analysis is part of a larger study that will more closely examine these relationships. “We want to learn, for example, why aura moderates some of the risk factors but not others,” said Dr. Dumkrieger.

The researchers also plan to investigate other migraine features, including headache frequency, and headache sensations such as pulsating or throbbing.

Dr. Dumkrieger was an investigator of another study, also presented at the AHS meeting, that’s investigating the role of migraine-specific features and imaging results in the complex interrelationship between migraine and MACE risk.

That study, which also used the Mayo Clinic electronic health record data, included 60,454 migraine patients diagnosed with migraine after 2010.

Researchers divided participants into those with a MACE outcome (1107) and those without such an outcome (59,347) after at least 2 years of follow-up. They created a propensity cohort of individuals matched for age and risk factors for MACE outcome.

The final cohort consisted of 575 patients with and 652 patients without MACE outcome.

One of the most interesting early results from this study was that those with a MACE outcome had significantly more white matter hyperintensities than those with no MACE outcome, at 64% versus 51%, respectively. 

This and other findings need to be validated in a different cohort with an electronic health records database from another institution. In future, the team plans to focus on identifying specific migraine features and medications and their relative contributions to MACE risk in migraine patients.

Yet another study featured at the AHS meeting confirmed the increased risk for stroke among migraine patients using a large database with over 410,000 subjects.

Results showed stroke was more than three times more common in those with a migraine diagnosis than in those without (risk ratio, [RR] 3.23; P < .001). The RR for hemorrhagic stroke (3.15) was comparable with that of ischemic stroke (3.20).

The overall stroke RR for chronic migraine versus controls without migraine was 3.68 (P < .001). The RR for migraine with aura versus migraine without aura was 1.37 (P < .001).
 

Useful Data

Commenting on the research, Juliana VanderPluym, MD, a headache specialist at the Mayo Clinic, Phoenix, Arizona, described this new information as “very useful.”

The fact that there are more white matter lesions on MRI scans in migraine patients with MACE needs further exploration, said Dr. VanderPluym.

“Understanding how much of that relates to migraine, how much relates to other comorbid conditions, and what this all means together, is very important, particularly because MACE can be life-threatening and life-altering,” she added.

Learning how migraine medications may impact MACE risk is also something that needs to be examined in greater depth, she said. “I would think that migraines that are controlled might have a different risk for MACE than uncontrolled migraine,” she said.

The investigators reported no relevant financial conflicts of interest.

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

SAN DIEGO – Researchers are unraveling the complex relationship between cardiovascular (CV)- and stroke-related outcomes in migraine with, and without, aura.

Early results of one study suggest that aura increases the risk for major adverse cerebrovascular and CV events (MACE) in those with migraine, and that this risk is particularly high in men.

“We confirmed that aura increases the risk for these cerebrovascular and cardiovascular outcomes in people with migraine and that there’s an increased risk of these MACE events in men with migraine,” said study investigator Gina Dumkrieger, PhD, principal data science analyst and assistant professor of neurology, Mayo Clinic, Phoenix, Arizona.

The findings were presented at the annual meeting of the American Headache Society.
 

Few Data on Migraine and Stroke Risk

The extent to which migraine increases the risk for stroke CV outcomes has not been extensively studied.

“We’re trying to find out whether migraine-related factors make it more likely that you’re going to have one of these events,” said Dr. Dumkrieger. “Knowing a particular factor increases the risk is something patients and medical providers would want to know.”

Using Mayo Clinic electronic health records, which cover all three sites (Florida, Minnesota, and Arizona), researchers identified individuals with migraine using diagnostic codes. They also looked at data on sex, race, and the presence of aura.

They investigated whether a history of MACE risk factors — including atrial fibrillation, diabetes, hyperlipidemia, hypertension, and tobacco use — affected risk and the potential interaction of aura with these risk factors.

MACE events included cerebral infarction, intracerebral hemorrhage, and acute myocardial infarction.

The analysis included 130,126 participants (80% women, 95% White individuals). Of these, 6% experienced a MACE event, and 94% did not.

“We confirmed that aura does increase the risk for a MACE event, and all of the known risk factors that we included were also significant,” said Dr. Dumkrieger.

Odds ratios (ORs) were 3.82 for atrial fibrillation, 3.11 for hypertension, and 3.06 for hyperlipidemia.

It was surprising, said Dr. Dumkrieger, that male sex was tied to an increased risk for a MACE event (OR, 1.40). “This is not something that was known before,” she said.

The link between migraine and ischemic stroke, particularly with aura, was stronger in women — particularly young women.

Investigators also found an interaction between male sex and aura, when it comes to MACE outcomes, said Dr. Dumkrieger. “Males in general are at higher risk, and people with aura are at higher risk. Males with aura are also at higher risk, but maybe not as much as you would think they would be. It’s not a purely additive thing. This is something we need to look into more,” she said. 

The study also revealed an interaction between aura and hypertension as well as aura and tobacco use, but here too, it was not an additive risk, said Dr. Dumkrieger. However, she added, the presence of aura does not moderate the risk for hyperlipidemia, diabetes, or atrial fibrillation.

The research also showed a significant interaction between male sex and Black race which was additive. “There’s apparently increased risk if you are male and Black or African American that’s greater than what you would expect. We should be especially concerned about these individuals,” she said.
 

Unanswered Questions

The current analysis is part of a larger study that will more closely examine these relationships. “We want to learn, for example, why aura moderates some of the risk factors but not others,” said Dr. Dumkrieger.

The researchers also plan to investigate other migraine features, including headache frequency, and headache sensations such as pulsating or throbbing.

Dr. Dumkrieger was an investigator of another study, also presented at the AHS meeting, that’s investigating the role of migraine-specific features and imaging results in the complex interrelationship between migraine and MACE risk.

That study, which also used the Mayo Clinic electronic health record data, included 60,454 migraine patients diagnosed with migraine after 2010.

Researchers divided participants into those with a MACE outcome (1107) and those without such an outcome (59,347) after at least 2 years of follow-up. They created a propensity cohort of individuals matched for age and risk factors for MACE outcome.

The final cohort consisted of 575 patients with and 652 patients without MACE outcome.

One of the most interesting early results from this study was that those with a MACE outcome had significantly more white matter hyperintensities than those with no MACE outcome, at 64% versus 51%, respectively. 

This and other findings need to be validated in a different cohort with an electronic health records database from another institution. In future, the team plans to focus on identifying specific migraine features and medications and their relative contributions to MACE risk in migraine patients.

Yet another study featured at the AHS meeting confirmed the increased risk for stroke among migraine patients using a large database with over 410,000 subjects.

Results showed stroke was more than three times more common in those with a migraine diagnosis than in those without (risk ratio, [RR] 3.23; P < .001). The RR for hemorrhagic stroke (3.15) was comparable with that of ischemic stroke (3.20).

The overall stroke RR for chronic migraine versus controls without migraine was 3.68 (P < .001). The RR for migraine with aura versus migraine without aura was 1.37 (P < .001).
 

Useful Data

Commenting on the research, Juliana VanderPluym, MD, a headache specialist at the Mayo Clinic, Phoenix, Arizona, described this new information as “very useful.”

The fact that there are more white matter lesions on MRI scans in migraine patients with MACE needs further exploration, said Dr. VanderPluym.

“Understanding how much of that relates to migraine, how much relates to other comorbid conditions, and what this all means together, is very important, particularly because MACE can be life-threatening and life-altering,” she added.

Learning how migraine medications may impact MACE risk is also something that needs to be examined in greater depth, she said. “I would think that migraines that are controlled might have a different risk for MACE than uncontrolled migraine,” she said.

The investigators reported no relevant financial conflicts of interest.

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

SAN DIEGO – Researchers are unraveling the complex relationship between cardiovascular (CV)- and stroke-related outcomes in migraine with, and without, aura.

Early results of one study suggest that aura increases the risk for major adverse cerebrovascular and CV events (MACE) in those with migraine, and that this risk is particularly high in men.

“We confirmed that aura increases the risk for these cerebrovascular and cardiovascular outcomes in people with migraine and that there’s an increased risk of these MACE events in men with migraine,” said study investigator Gina Dumkrieger, PhD, principal data science analyst and assistant professor of neurology, Mayo Clinic, Phoenix, Arizona.

The findings were presented at the annual meeting of the American Headache Society.
 

Few Data on Migraine and Stroke Risk

The extent to which migraine increases the risk for stroke CV outcomes has not been extensively studied.

“We’re trying to find out whether migraine-related factors make it more likely that you’re going to have one of these events,” said Dr. Dumkrieger. “Knowing a particular factor increases the risk is something patients and medical providers would want to know.”

Using Mayo Clinic electronic health records, which cover all three sites (Florida, Minnesota, and Arizona), researchers identified individuals with migraine using diagnostic codes. They also looked at data on sex, race, and the presence of aura.

They investigated whether a history of MACE risk factors — including atrial fibrillation, diabetes, hyperlipidemia, hypertension, and tobacco use — affected risk and the potential interaction of aura with these risk factors.

MACE events included cerebral infarction, intracerebral hemorrhage, and acute myocardial infarction.

The analysis included 130,126 participants (80% women, 95% White individuals). Of these, 6% experienced a MACE event, and 94% did not.

“We confirmed that aura does increase the risk for a MACE event, and all of the known risk factors that we included were also significant,” said Dr. Dumkrieger.

Odds ratios (ORs) were 3.82 for atrial fibrillation, 3.11 for hypertension, and 3.06 for hyperlipidemia.

It was surprising, said Dr. Dumkrieger, that male sex was tied to an increased risk for a MACE event (OR, 1.40). “This is not something that was known before,” she said.

The link between migraine and ischemic stroke, particularly with aura, was stronger in women — particularly young women.

Investigators also found an interaction between male sex and aura, when it comes to MACE outcomes, said Dr. Dumkrieger. “Males in general are at higher risk, and people with aura are at higher risk. Males with aura are also at higher risk, but maybe not as much as you would think they would be. It’s not a purely additive thing. This is something we need to look into more,” she said. 

The study also revealed an interaction between aura and hypertension as well as aura and tobacco use, but here too, it was not an additive risk, said Dr. Dumkrieger. However, she added, the presence of aura does not moderate the risk for hyperlipidemia, diabetes, or atrial fibrillation.

The research also showed a significant interaction between male sex and Black race which was additive. “There’s apparently increased risk if you are male and Black or African American that’s greater than what you would expect. We should be especially concerned about these individuals,” she said.
 

Unanswered Questions

The current analysis is part of a larger study that will more closely examine these relationships. “We want to learn, for example, why aura moderates some of the risk factors but not others,” said Dr. Dumkrieger.

The researchers also plan to investigate other migraine features, including headache frequency, and headache sensations such as pulsating or throbbing.

Dr. Dumkrieger was an investigator of another study, also presented at the AHS meeting, that’s investigating the role of migraine-specific features and imaging results in the complex interrelationship between migraine and MACE risk.

That study, which also used the Mayo Clinic electronic health record data, included 60,454 migraine patients diagnosed with migraine after 2010.

Researchers divided participants into those with a MACE outcome (1107) and those without such an outcome (59,347) after at least 2 years of follow-up. They created a propensity cohort of individuals matched for age and risk factors for MACE outcome.

The final cohort consisted of 575 patients with and 652 patients without MACE outcome.

One of the most interesting early results from this study was that those with a MACE outcome had significantly more white matter hyperintensities than those with no MACE outcome, at 64% versus 51%, respectively. 

This and other findings need to be validated in a different cohort with an electronic health records database from another institution. In future, the team plans to focus on identifying specific migraine features and medications and their relative contributions to MACE risk in migraine patients.

Yet another study featured at the AHS meeting confirmed the increased risk for stroke among migraine patients using a large database with over 410,000 subjects.

Results showed stroke was more than three times more common in those with a migraine diagnosis than in those without (risk ratio, [RR] 3.23; P < .001). The RR for hemorrhagic stroke (3.15) was comparable with that of ischemic stroke (3.20).

The overall stroke RR for chronic migraine versus controls without migraine was 3.68 (P < .001). The RR for migraine with aura versus migraine without aura was 1.37 (P < .001).
 

Useful Data

Commenting on the research, Juliana VanderPluym, MD, a headache specialist at the Mayo Clinic, Phoenix, Arizona, described this new information as “very useful.”

The fact that there are more white matter lesions on MRI scans in migraine patients with MACE needs further exploration, said Dr. VanderPluym.

“Understanding how much of that relates to migraine, how much relates to other comorbid conditions, and what this all means together, is very important, particularly because MACE can be life-threatening and life-altering,” she added.

Learning how migraine medications may impact MACE risk is also something that needs to be examined in greater depth, she said. “I would think that migraines that are controlled might have a different risk for MACE than uncontrolled migraine,” she said.

The investigators reported no relevant financial conflicts of interest.

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

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.