MDedge Neurology

Patients overwhelmingly found telemedicine care for headache a satisfactory and beneficial experience during the COVID-19 pandemic, according to a study presented at the American Headache Society’s 2021 annual meeting. Most patients who used telemedicine said they would like to continue using it after the pandemic, though the study also revealed barriers to care for a small percentage of respondents.

“Telemedicine minimizes the physical and geographic barriers to health care, preserves personal protective equipment, and prevents the spread of COVID-19 by allowing encounters to happen in a socially distanced way,” said Chia-Chun Chiang, MD, assistant professor of neurology at Mayo Clinic in Rochester, Minn. “Telemedicine provides patients with opportunities to gain better control of their headache disorders while not having to commit to the time to travel and risk of exposure to COVID-19.” If insurance coverage for virtual care were rolled back, “patients and multiple levels of health care providers would be significantly affected,” she said.

The research relied on findings from a 15-question survey distributed by the nonprofit American Migraine Foundation through email and social media to more than 100,000 people. Among the 1,172 patients who responded to the survey, 1,098 had complete responses, and 86.6% were female.

The vast majority of these patients (93.8%) had had a previous diagnosis of a headache. Just over half (57.5%) said they used telemedicine during the study period, with most of those visits (85.5%) being follow-up care and 14.5% involving a new patient visit.

Among those who did not use telemedicine, most (56.1%) said they didn’t need a visit. However, a quarter of these respondents (25.2%) said they didn’t know telemedicine was an option, and 12.9% said they would have preferred telemedicine but it wasn’t offered by their doctors. A smaller proportion (3.5%) said they wanted to use virtual care but that their insurance did not cover it, and nearly as many (2.2%) said they wanted telemedicine but didn’t have the technology needed to use it.

“The COVID-19 pandemic has highlighted that reliable Internet service has contributed to disparities in access in many ways, including health care via telemedicine,” Dr. Chiang said. “Those who are not able to afford Internet, lack proficiency in the use of technology, or have cognitive impairment might not be able to utilize telemedicine.”

Among those who did receive telemedicine care for headache, about a third (34.4%) received care from a general neurologist while 43.7% saw a headache specialist and nearly a third (30.7%) saw a primary care provider. The remaining visits included 11.3% who saw headache nurse practitioners and 3.2% who saw headache nurses.

Most patients did not have a new or changed diagnosis at their visit; only 7.4% received a new headache diagnosis during their telemedicine appointment. Though 43.7% had no change to their therapy, a little more than half of patients (52.4%) received a new treatment, a finding that caught the interest of Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and past president of the International Headache Society.

“The techniques used [in virtual visits] were good enough for the caregiver to make critical decisions about how the patient was doing and what new treatment might be better for them,” said Dr. Rapoport, who was not involved in the research. “I believe that most headache specialists will gradually resume in office visits,” he said, but “this study shows it would be okay for some or most of the revisits to continue to be done virtually.”

The vast majority of patients rated their care as “very good” (62.1%) or “good” (20.7%). Less satisfied responses included 10.5% who felt their experience was “fair,” 3.6% who said it was “poor,” and 3.1% who gave other responses.

These results fit with the experience of Dr. Rapoport and of Paul B. Rizzoli, MD, associate professor of neurology at Harvard Medical School and clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital, both in Boston.

“Telemedicine worked better than we anticipated,” said Dr. Rizzoli when asked for comment. “I was especially surprised how comfortable I became with its use for many, but not all, new patients. While I don’t expect it to replace in-person visits, I do expect that it will and should be a permanent part of our care going forward, especially for follow-up visits.”

The findings supported that expectation as well: An overwhelming majority of those who responded to the survey (89.8%) also said they would like to keep receiving telemedicine care for their headache care and treatment. This percentage was split evenly between those who said they would like to always receive care virtually and those who would only want to use it for some appointments. A smaller proportion said they did not want to keep using virtual care (7.1%) or weren’t sure (3.1%).

“Telemedicine has become an essential tool for patients and a wide variety of clinicians,” Dr. Chiang reported during her presentation. “Telemedicine facilitated headache care for many patients during the COVID-19 pandemic, resulting in high patient satisfaction rates and a desire to continue to utilize telemedicine for future headache care for those who responded to the online survey.”

Dr. Rapoport noted that a particular benefit of telemedicine in his practice is avoiding transportation issues.

“In Santa Monica and Los Angeles, my patients coming from 10 or more miles away usually have to contend with difficult traffic, which created stress and often made them late and upset the office schedule,” Dr. Rapoport said. “I found that virtual visits were almost always shorter, on time, and were as effective for the patient as an in-person visit.”

Dr. Chiang drew attention, however, to the barriers to care found in the study, including not having or knowing of telemedicine as an option, and not having access to the technology or insurance coverage needed to take advantage of it. She listed three ways to address those challenges and increase health care accessibility to patients:
 

• Expand insurance coverage to reimburse telemedicine even after the pandemic.
• Widely promote and broadcast the use of virtual care.
• Make Internet access a priority as a necessity in society and expand access.

Dr. Rizzoli also noted some ways to improve telemedicine. “We could easily develop improved means of delivering vital signs and other bio-information over telemedicine to improve decision-making,” he said. “A difficult task going forward will be to fix legal questions associated with virtual visits across state lines which, especially in the small New England states, come up frequently and are currently illegal.”

Dr. Rapoport noted ways that patients can facilitate effective telemedicine visits. “Doctors should insist that patients keep careful records of their headaches, triggers, medicines, etc., either on paper or preferably via an app on their smartphones, which is usually always accessible,” Dr. Rapoport said. “With good data and a good electronic connection, the visit should go well.”

Among the study’s limitations were a comparatively small response rate (1.11% of those invited to participate) and ascertainment bias.

“The take-home message from the experience is that this turns out to be an effective, efficient and accepted means of delivering care that should be developed further,” Dr. Rizzoli said.

No external funding was noted. Dr. Chiang and Dr. Rizzoli had no disclosures. Dr. Rapoport has advised AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano, and is on the speakers bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries.

Patients overwhelmingly found telemedicine care for headache a satisfactory and beneficial experience during the COVID-19 pandemic, according to a study presented at the American Headache Society’s 2021 annual meeting. Most patients who used telemedicine said they would like to continue using it after the pandemic, though the study also revealed barriers to care for a small percentage of respondents.

“Telemedicine minimizes the physical and geographic barriers to health care, preserves personal protective equipment, and prevents the spread of COVID-19 by allowing encounters to happen in a socially distanced way,” said Chia-Chun Chiang, MD, assistant professor of neurology at Mayo Clinic in Rochester, Minn. “Telemedicine provides patients with opportunities to gain better control of their headache disorders while not having to commit to the time to travel and risk of exposure to COVID-19.” If insurance coverage for virtual care were rolled back, “patients and multiple levels of health care providers would be significantly affected,” she said.

The research relied on findings from a 15-question survey distributed by the nonprofit American Migraine Foundation through email and social media to more than 100,000 people. Among the 1,172 patients who responded to the survey, 1,098 had complete responses, and 86.6% were female.

The vast majority of these patients (93.8%) had had a previous diagnosis of a headache. Just over half (57.5%) said they used telemedicine during the study period, with most of those visits (85.5%) being follow-up care and 14.5% involving a new patient visit.

Among those who did not use telemedicine, most (56.1%) said they didn’t need a visit. However, a quarter of these respondents (25.2%) said they didn’t know telemedicine was an option, and 12.9% said they would have preferred telemedicine but it wasn’t offered by their doctors. A smaller proportion (3.5%) said they wanted to use virtual care but that their insurance did not cover it, and nearly as many (2.2%) said they wanted telemedicine but didn’t have the technology needed to use it.

“The COVID-19 pandemic has highlighted that reliable Internet service has contributed to disparities in access in many ways, including health care via telemedicine,” Dr. Chiang said. “Those who are not able to afford Internet, lack proficiency in the use of technology, or have cognitive impairment might not be able to utilize telemedicine.”

Among those who did receive telemedicine care for headache, about a third (34.4%) received care from a general neurologist while 43.7% saw a headache specialist and nearly a third (30.7%) saw a primary care provider. The remaining visits included 11.3% who saw headache nurse practitioners and 3.2% who saw headache nurses.

Most patients did not have a new or changed diagnosis at their visit; only 7.4% received a new headache diagnosis during their telemedicine appointment. Though 43.7% had no change to their therapy, a little more than half of patients (52.4%) received a new treatment, a finding that caught the interest of Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and past president of the International Headache Society.

“The techniques used [in virtual visits] were good enough for the caregiver to make critical decisions about how the patient was doing and what new treatment might be better for them,” said Dr. Rapoport, who was not involved in the research. “I believe that most headache specialists will gradually resume in office visits,” he said, but “this study shows it would be okay for some or most of the revisits to continue to be done virtually.”

The vast majority of patients rated their care as “very good” (62.1%) or “good” (20.7%). Less satisfied responses included 10.5% who felt their experience was “fair,” 3.6% who said it was “poor,” and 3.1% who gave other responses.

These results fit with the experience of Dr. Rapoport and of Paul B. Rizzoli, MD, associate professor of neurology at Harvard Medical School and clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital, both in Boston.

“Telemedicine worked better than we anticipated,” said Dr. Rizzoli when asked for comment. “I was especially surprised how comfortable I became with its use for many, but not all, new patients. While I don’t expect it to replace in-person visits, I do expect that it will and should be a permanent part of our care going forward, especially for follow-up visits.”

The findings supported that expectation as well: An overwhelming majority of those who responded to the survey (89.8%) also said they would like to keep receiving telemedicine care for their headache care and treatment. This percentage was split evenly between those who said they would like to always receive care virtually and those who would only want to use it for some appointments. A smaller proportion said they did not want to keep using virtual care (7.1%) or weren’t sure (3.1%).

“Telemedicine has become an essential tool for patients and a wide variety of clinicians,” Dr. Chiang reported during her presentation. “Telemedicine facilitated headache care for many patients during the COVID-19 pandemic, resulting in high patient satisfaction rates and a desire to continue to utilize telemedicine for future headache care for those who responded to the online survey.”

Dr. Rapoport noted that a particular benefit of telemedicine in his practice is avoiding transportation issues.

“In Santa Monica and Los Angeles, my patients coming from 10 or more miles away usually have to contend with difficult traffic, which created stress and often made them late and upset the office schedule,” Dr. Rapoport said. “I found that virtual visits were almost always shorter, on time, and were as effective for the patient as an in-person visit.”

Dr. Chiang drew attention, however, to the barriers to care found in the study, including not having or knowing of telemedicine as an option, and not having access to the technology or insurance coverage needed to take advantage of it. She listed three ways to address those challenges and increase health care accessibility to patients:
 

• Expand insurance coverage to reimburse telemedicine even after the pandemic.
• Widely promote and broadcast the use of virtual care.
• Make Internet access a priority as a necessity in society and expand access.

Dr. Rizzoli also noted some ways to improve telemedicine. “We could easily develop improved means of delivering vital signs and other bio-information over telemedicine to improve decision-making,” he said. “A difficult task going forward will be to fix legal questions associated with virtual visits across state lines which, especially in the small New England states, come up frequently and are currently illegal.”

Dr. Rapoport noted ways that patients can facilitate effective telemedicine visits. “Doctors should insist that patients keep careful records of their headaches, triggers, medicines, etc., either on paper or preferably via an app on their smartphones, which is usually always accessible,” Dr. Rapoport said. “With good data and a good electronic connection, the visit should go well.”

Among the study’s limitations were a comparatively small response rate (1.11% of those invited to participate) and ascertainment bias.

“The take-home message from the experience is that this turns out to be an effective, efficient and accepted means of delivering care that should be developed further,” Dr. Rizzoli said.

No external funding was noted. Dr. Chiang and Dr. Rizzoli had no disclosures. Dr. Rapoport has advised AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano, and is on the speakers bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries.

Patients overwhelmingly found telemedicine care for headache a satisfactory and beneficial experience during the COVID-19 pandemic, according to a study presented at the American Headache Society’s 2021 annual meeting. Most patients who used telemedicine said they would like to continue using it after the pandemic, though the study also revealed barriers to care for a small percentage of respondents.

“Telemedicine minimizes the physical and geographic barriers to health care, preserves personal protective equipment, and prevents the spread of COVID-19 by allowing encounters to happen in a socially distanced way,” said Chia-Chun Chiang, MD, assistant professor of neurology at Mayo Clinic in Rochester, Minn. “Telemedicine provides patients with opportunities to gain better control of their headache disorders while not having to commit to the time to travel and risk of exposure to COVID-19.” If insurance coverage for virtual care were rolled back, “patients and multiple levels of health care providers would be significantly affected,” she said.

The research relied on findings from a 15-question survey distributed by the nonprofit American Migraine Foundation through email and social media to more than 100,000 people. Among the 1,172 patients who responded to the survey, 1,098 had complete responses, and 86.6% were female.

The vast majority of these patients (93.8%) had had a previous diagnosis of a headache. Just over half (57.5%) said they used telemedicine during the study period, with most of those visits (85.5%) being follow-up care and 14.5% involving a new patient visit.

Among those who did not use telemedicine, most (56.1%) said they didn’t need a visit. However, a quarter of these respondents (25.2%) said they didn’t know telemedicine was an option, and 12.9% said they would have preferred telemedicine but it wasn’t offered by their doctors. A smaller proportion (3.5%) said they wanted to use virtual care but that their insurance did not cover it, and nearly as many (2.2%) said they wanted telemedicine but didn’t have the technology needed to use it.

“The COVID-19 pandemic has highlighted that reliable Internet service has contributed to disparities in access in many ways, including health care via telemedicine,” Dr. Chiang said. “Those who are not able to afford Internet, lack proficiency in the use of technology, or have cognitive impairment might not be able to utilize telemedicine.”

Among those who did receive telemedicine care for headache, about a third (34.4%) received care from a general neurologist while 43.7% saw a headache specialist and nearly a third (30.7%) saw a primary care provider. The remaining visits included 11.3% who saw headache nurse practitioners and 3.2% who saw headache nurses.

Most patients did not have a new or changed diagnosis at their visit; only 7.4% received a new headache diagnosis during their telemedicine appointment. Though 43.7% had no change to their therapy, a little more than half of patients (52.4%) received a new treatment, a finding that caught the interest of Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and past president of the International Headache Society.

“The techniques used [in virtual visits] were good enough for the caregiver to make critical decisions about how the patient was doing and what new treatment might be better for them,” said Dr. Rapoport, who was not involved in the research. “I believe that most headache specialists will gradually resume in office visits,” he said, but “this study shows it would be okay for some or most of the revisits to continue to be done virtually.”

The vast majority of patients rated their care as “very good” (62.1%) or “good” (20.7%). Less satisfied responses included 10.5% who felt their experience was “fair,” 3.6% who said it was “poor,” and 3.1% who gave other responses.

These results fit with the experience of Dr. Rapoport and of Paul B. Rizzoli, MD, associate professor of neurology at Harvard Medical School and clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital, both in Boston.

“Telemedicine worked better than we anticipated,” said Dr. Rizzoli when asked for comment. “I was especially surprised how comfortable I became with its use for many, but not all, new patients. While I don’t expect it to replace in-person visits, I do expect that it will and should be a permanent part of our care going forward, especially for follow-up visits.”

The findings supported that expectation as well: An overwhelming majority of those who responded to the survey (89.8%) also said they would like to keep receiving telemedicine care for their headache care and treatment. This percentage was split evenly between those who said they would like to always receive care virtually and those who would only want to use it for some appointments. A smaller proportion said they did not want to keep using virtual care (7.1%) or weren’t sure (3.1%).

“Telemedicine has become an essential tool for patients and a wide variety of clinicians,” Dr. Chiang reported during her presentation. “Telemedicine facilitated headache care for many patients during the COVID-19 pandemic, resulting in high patient satisfaction rates and a desire to continue to utilize telemedicine for future headache care for those who responded to the online survey.”

Dr. Rapoport noted that a particular benefit of telemedicine in his practice is avoiding transportation issues.

“In Santa Monica and Los Angeles, my patients coming from 10 or more miles away usually have to contend with difficult traffic, which created stress and often made them late and upset the office schedule,” Dr. Rapoport said. “I found that virtual visits were almost always shorter, on time, and were as effective for the patient as an in-person visit.”

Dr. Chiang drew attention, however, to the barriers to care found in the study, including not having or knowing of telemedicine as an option, and not having access to the technology or insurance coverage needed to take advantage of it. She listed three ways to address those challenges and increase health care accessibility to patients:
 

• Expand insurance coverage to reimburse telemedicine even after the pandemic.
• Widely promote and broadcast the use of virtual care.
• Make Internet access a priority as a necessity in society and expand access.

Dr. Rizzoli also noted some ways to improve telemedicine. “We could easily develop improved means of delivering vital signs and other bio-information over telemedicine to improve decision-making,” he said. “A difficult task going forward will be to fix legal questions associated with virtual visits across state lines which, especially in the small New England states, come up frequently and are currently illegal.”

Dr. Rapoport noted ways that patients can facilitate effective telemedicine visits. “Doctors should insist that patients keep careful records of their headaches, triggers, medicines, etc., either on paper or preferably via an app on their smartphones, which is usually always accessible,” Dr. Rapoport said. “With good data and a good electronic connection, the visit should go well.”

Among the study’s limitations were a comparatively small response rate (1.11% of those invited to participate) and ascertainment bias.

“The take-home message from the experience is that this turns out to be an effective, efficient and accepted means of delivering care that should be developed further,” Dr. Rizzoli said.

No external funding was noted. Dr. Chiang and Dr. Rizzoli had no disclosures. Dr. Rapoport has advised AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano, and is on the speakers bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries.

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

A 56-year-old woman with type 2 diabetes presents for evaluation of painful neuropathy. She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?

A. Vitamin B₁₂ deficiency

B. Diabetic neuropathy

C. Insulin neuritis

D. Charcot-Marie-Tooth disease

The most likely cause

In this case, certainly considering vitamin B₁₂ deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B₁₂ levels, and the American Diabetes Association has advised that regular monitoring of vitamin B₁₂ levels should be done on patients who are on long-term metformin.¹

Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
 

Research on TIN

Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.² All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.

Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.³

A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.

A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.

Siddique and colleagues reported on three cases with very different clinical presentations of TIN.⁴ One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.

Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.²

Pearl

Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.

2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.

3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.

4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.

A 56-year-old woman with type 2 diabetes presents for evaluation of painful neuropathy. She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?

A. Vitamin B₁₂ deficiency

B. Diabetic neuropathy

C. Insulin neuritis

D. Charcot-Marie-Tooth disease

The most likely cause

In this case, certainly considering vitamin B₁₂ deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B₁₂ levels, and the American Diabetes Association has advised that regular monitoring of vitamin B₁₂ levels should be done on patients who are on long-term metformin.¹

Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
 

Research on TIN

Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.² All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.

Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.³

A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.

A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.

Siddique and colleagues reported on three cases with very different clinical presentations of TIN.⁴ One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.

Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.²

Pearl

Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.

2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.

3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.

4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.

A 56-year-old woman with type 2 diabetes presents for evaluation of painful neuropathy. She has had a diagnosis of type 2 diabetes for the past 4 years. She initially presented with polyuria/polydipsia and a hemoglobin A1c level of 9.5. She has previously not tolerated metformin, and did not want to take any subsequent medications. She was seen 4 months ago and at that time had an A1c level of 12.5. She decided she wanted to really treat her diabetes as well as she could. She started consuming a low carbohydrate diet, restarted metformin and began using a continuous glucose monitor. She also started taking nighttime glargine insulin, and mealtime insulin apart. She reports she lost 20 pounds over the past 4 months, her blood sugars now run between 100-120 fasting, and up to 180 before meals. She has had a severe, sharp pain in both of her feet over the past month that is interfering with sleep and makes walking painful for her. An exam reveals hyperesthesia of both feet, and her A1c level is 7.5. What is the most likely cause of her neuropathic symptoms?

A. Vitamin B₁₂ deficiency

B. Diabetic neuropathy

C. Insulin neuritis

D. Charcot-Marie-Tooth disease

The most likely cause

In this case, certainly considering vitamin B₁₂ deficiency is reasonable. It is highly unlikely though, given the rapidity of onset of symptoms, and that the patient has been on metformin for a very short period of time. Chronic metformin use is associated with low B₁₂ levels, and the American Diabetes Association has advised that regular monitoring of vitamin B₁₂ levels should be done on patients who are on long-term metformin.¹

Diabetic neuropathy is also unlikely, given the rapidity of symptoms in this patient. What is most likely in this patient is treatment-induced neuropathy (TIN), first described with the name “insulin neuritis”.
 

Research on TIN

Gibbons and colleagues evaluated 16 patients with diabetes with recent marked, rapid improvement in glycemic control who developed a sudden, painful neuropathy.² All developed symptoms within 8 weeks of intensive glucose control, with 69% having autonomic dysfunction as well, and all developing worsening retinopathy.

Gibbons and Freeman did a retrospective study of patients referred to a diabetic neuropathy clinic over a 5-year period to try to understand how prevalent TIN is.³

A total of 954 patients were evaluated for diabetic neuropathy. Treatment induced neuropathy was defined as a painful neuropathy and/or autonomic dysfunction occurring within 8 weeks of intensified treatment and a drop of the A1c level greater than 2 over a 3-month period.

A total of 104 patients (10.9%) met the criteria for treatment induced neuropathy. Patients who had a decrease in A1c had a much greater chance of developing a painful or autonomic neuropathy than patients who had no change in A1c (P < .0001). The same patients had a much higher risk of developing retinopathy (P < .001). The greater the reduction in A1c, the greater the risk. Patients whose A1c decreased by 2%-3% over 3 months had an absolute risk of 20%, whereas those with a A1c decease of greater than 4% had an 80% absolute risk.

Siddique and colleagues reported on three cases with very different clinical presentations of TIN.⁴ One patient had an acute third nerve palsy, another patient had a lumbosacral radiculoplexus neuropathy, and the third patient presented with a diffuse painful sensory neuropathy and postural hypotension.

Most patients improve over time from their neuropathic symptoms, with better recovery in patients with type 1 diabetes.²

Pearl

Strongly consider treatment induced neuropathy in your patients with diabetes who present with acute painful neuropathy and/or autonomic dysfunction in the setting of rapid improvement of glucose control.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S90-102.

2. Gibbons CH and Freeman R. Ann Neurol 2010; 67:534–41.

3. Gibbons CH and Freeman R. Brain. 2015;138:43-52.

4. Siddique N et al. Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020:19-0140.

Subthalamic nucleus deep brain stimulation (STN-DBS) continues to be effective for patients with Parkinson’s disease more than 15 years after device implantation, with significant improvement in motor complications and a stable reduction in dopaminergic drug use, new research indicates.

“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.

“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.

The study was published online June 2 in Neurology.
 

‘Don’t delay’

The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.

The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.

Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.

There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.

“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.

“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.

“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
 

A revolutionary treatment

The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”

Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.

Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.

Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.

Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.

Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.

“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.

The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.

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

Subthalamic nucleus deep brain stimulation (STN-DBS) continues to be effective for patients with Parkinson’s disease more than 15 years after device implantation, with significant improvement in motor complications and a stable reduction in dopaminergic drug use, new research indicates.

“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.

“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.

The study was published online June 2 in Neurology.
 

‘Don’t delay’

The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.

The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.

Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.

There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.

“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.

“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.

“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
 

A revolutionary treatment

The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”

Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.

Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.

Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.

Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.

Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.

“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.

The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.

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

Subthalamic nucleus deep brain stimulation (STN-DBS) continues to be effective for patients with Parkinson’s disease more than 15 years after device implantation, with significant improvement in motor complications and a stable reduction in dopaminergic drug use, new research indicates.

“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.

“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.

The study was published online June 2 in Neurology.
 

‘Don’t delay’

The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.

The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.

Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.

There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.

“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.

“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.

“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
 

A revolutionary treatment

The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”

Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.

Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.

Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.

Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.

Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.

“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.

The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.

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

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

The Food and Drug Administration has approved marketing for a device that will help diagnose autism spectrum disorder (ASD) in children between the ages of 18 months and 5 years old who exhibit potential symptoms.

Cognoa ASD Diagnosis Aid is a machine learning–based software program that receives information from parents or caregivers, video analysts, and health care providers to assist physicians in evaluating whether a child is at risk of having autism.

Autism is a developmental disorder that can cause social, communication, and behavioral challenges, according to the Centers for Disease Control and Prevention. The disorder affects about 1 in 54 children. The disorder is difficult to diagnose because there isn’t a medical test to diagnose the it. Instead, physicians have to look at a child’s developmental history and behavior to make a diagnosis.

Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the FDA.

“[ASD] can delay a child’s physical, cognitive, and social development, including motor skill development, learning, communication, and interacting with others. The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said in a statement. “Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”

The safety and efficacy of the Cognoa ASD Diagnosis Aid was assessed in a study of 425 patients between the ages of 18 months and 5 years old. For the study, researchers compared the diagnostic assessments made by the device to those made by a panel of clinical experts who used the current standard ASD diagnostic process. The device diagnosed 32% of the children with either a “Positive for ASD” or a “Negative for ASD” result. Researchers found that the device matched the panel’s conclusions for 81% of the patients who received a positive diagnosis. For those who received a negative diagnosis, the device matched the panel’s conclusions for 98% of the patients. In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.

Cognoa ASD Diagnosis Aid has three main components. One component includes a mobile app for caregivers to answer questions about the child’s behavioral problems and to upload videos of the child. The next component is a video analysis portal for specialists to view and analyze uploaded videos of patients. Another component is a portal for health care providers that allows them to enter answers to preloaded questions about behavior problems, track the information provided by parents, and review a report of the results.

After the machine learning–based device processes the information provided by parents and health care providers, it reports either a positive or a negative diagnosis. If there is insufficient information to make either a positive or a negative diagnosis, the ASD Diagnostic AID will report that no result can be generated.

Some of the risks associated with this device include misdiagnosis and delayed diagnosis of ASD because of a false-positive or false-negative result, or when no result is generated. Researchers said a false-positive result occurred in 15 out of 303 study subjects without ASD and a false-negative result occurred in 1 out of 122 study subjects with ASD.

The FDA emphasized that the device is indicated to aid physicians in the process of diagnosing ASD in children. This means it shouldn’t be treated as a standalone diagnostic device, but as an adjunct to the diagnostic process.

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]