Mixed Topics

The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to provide timely updates on rare disease research, diagnosis, and treatments. We extend our sincere thanks to busy health care professionals for taking time to engage with this issue, read the latest advances, and provide the best possible care for your patients. Your dedication is an inspiration, and we value the impact you make in the lives of others.

The year 2023 marks the 40th anniversary of the Orphan Drug Act (ODA), landmark legislation that incentivized drug companies to dedicate more resources towards the development of therapies for people with rare conditions. At the same time, we celebrate NORD’s 40th anniversary. The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community. For 4 decades, NORD has worked tirelessly to drive supportive policies, advance medical research, and provide education and services for the now 30 million Americans with a rare disease, of which half are children.

In this issue of the Rare Neurological Disease Special Report, you will learn more about the history of the Orphan Drug Act and the founding of NORD. You will also find articles from rare disease specialists on specific diseases and some of the newest therapies approved under the ODA for conditions such as Friedreich ataxia, Fabry disease, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis. Also in the issue are articles about stiff person syndrome and Guillain-Barré syndrome and COVID vaccination.

We invite you to visit NORD’s webpage (www.rarediseases.org) to access resources for yourself and the patients and families you serve. NORD’s Continuing Medical Education Video Library offers cost-free, for-credit, on-demand rare disease courses developed in collaboration with Platform Q Health. NORD’s Caring for Rare quarterly newsletter provides updates on educational opportunities, events, and issues important for the rare disease community. NORD’s Rare Disease Database provides expert-reviewed reports on rare diseases in patient-friendly language.

As we celebrate the incredible progress made over the past 40 years, we also recognize that more than 95% of rare conditions still lack effective therapies. Continued research, development of new orphan products, and advances in treatment and care are needed. NORD will remain steadfast in its commitment to driving progress, inspiring innovation, and providing services for the rare community. We are deeply appreciative of the support you provide to people living with neurological conditions and encourage you to contact NORD any time we can be helpful to you.


Edward Neilan, MD, PhD
NORD’s Chief Medical Officer

The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to provide timely updates on rare disease research, diagnosis, and treatments. We extend our sincere thanks to busy health care professionals for taking time to engage with this issue, read the latest advances, and provide the best possible care for your patients. Your dedication is an inspiration, and we value the impact you make in the lives of others.

The year 2023 marks the 40th anniversary of the Orphan Drug Act (ODA), landmark legislation that incentivized drug companies to dedicate more resources towards the development of therapies for people with rare conditions. At the same time, we celebrate NORD’s 40th anniversary. The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community. For 4 decades, NORD has worked tirelessly to drive supportive policies, advance medical research, and provide education and services for the now 30 million Americans with a rare disease, of which half are children.

In this issue of the Rare Neurological Disease Special Report, you will learn more about the history of the Orphan Drug Act and the founding of NORD. You will also find articles from rare disease specialists on specific diseases and some of the newest therapies approved under the ODA for conditions such as Friedreich ataxia, Fabry disease, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis. Also in the issue are articles about stiff person syndrome and Guillain-Barré syndrome and COVID vaccination.

We invite you to visit NORD’s webpage (www.rarediseases.org) to access resources for yourself and the patients and families you serve. NORD’s Continuing Medical Education Video Library offers cost-free, for-credit, on-demand rare disease courses developed in collaboration with Platform Q Health. NORD’s Caring for Rare quarterly newsletter provides updates on educational opportunities, events, and issues important for the rare disease community. NORD’s Rare Disease Database provides expert-reviewed reports on rare diseases in patient-friendly language.

As we celebrate the incredible progress made over the past 40 years, we also recognize that more than 95% of rare conditions still lack effective therapies. Continued research, development of new orphan products, and advances in treatment and care are needed. NORD will remain steadfast in its commitment to driving progress, inspiring innovation, and providing services for the rare community. We are deeply appreciative of the support you provide to people living with neurological conditions and encourage you to contact NORD any time we can be helpful to you.


Edward Neilan, MD, PhD
NORD’s Chief Medical Officer

The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to provide timely updates on rare disease research, diagnosis, and treatments. We extend our sincere thanks to busy health care professionals for taking time to engage with this issue, read the latest advances, and provide the best possible care for your patients. Your dedication is an inspiration, and we value the impact you make in the lives of others.

The year 2023 marks the 40th anniversary of the Orphan Drug Act (ODA), landmark legislation that incentivized drug companies to dedicate more resources towards the development of therapies for people with rare conditions. At the same time, we celebrate NORD’s 40th anniversary. The coalition of rare disease advocates who sparked rare disease advocacy and convinced lawmakers to pass the ODA in 1983 established NORD that same year to provide an ongoing, unified voice for the needs of the rare disease community. For 4 decades, NORD has worked tirelessly to drive supportive policies, advance medical research, and provide education and services for the now 30 million Americans with a rare disease, of which half are children.

In this issue of the Rare Neurological Disease Special Report, you will learn more about the history of the Orphan Drug Act and the founding of NORD. You will also find articles from rare disease specialists on specific diseases and some of the newest therapies approved under the ODA for conditions such as Friedreich ataxia, Fabry disease, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis. Also in the issue are articles about stiff person syndrome and Guillain-Barré syndrome and COVID vaccination.

We invite you to visit NORD’s webpage (www.rarediseases.org) to access resources for yourself and the patients and families you serve. NORD’s Continuing Medical Education Video Library offers cost-free, for-credit, on-demand rare disease courses developed in collaboration with Platform Q Health. NORD’s Caring for Rare quarterly newsletter provides updates on educational opportunities, events, and issues important for the rare disease community. NORD’s Rare Disease Database provides expert-reviewed reports on rare diseases in patient-friendly language.

As we celebrate the incredible progress made over the past 40 years, we also recognize that more than 95% of rare conditions still lack effective therapies. Continued research, development of new orphan products, and advances in treatment and care are needed. NORD will remain steadfast in its commitment to driving progress, inspiring innovation, and providing services for the rare community. We are deeply appreciative of the support you provide to people living with neurological conditions and encourage you to contact NORD any time we can be helpful to you.


Edward Neilan, MD, PhD
NORD’s Chief Medical Officer

2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act and the formation of the National Organization for Rare Disorders (NORD). 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report. While Neurology Reviews covers rare disease news throughout the year (see our Rare Disease Roundup in this issue), it is in our annual supplement where our rare disease news coverage and our partnership with NORD truly shines.

In this issue we take pride in taking a deeper look at some of the rare neurological diseases that have made headlines as well as the therapeutic advances and research breakthroughs that continue to benefit patients and the rare disease community as a whole. While I would prefer to humbly serve the rare disease community through our news coverage and educational efforts, I would be remiss if I didn’t mention that our 2022 Rare Neurological Disease Special Report won a Silver Regional Award in the category of annual supplement in the American Society of Business Publication Editors (Azbee) yearly competition. With that moment of bragging aside, I invite you to read this year’s issue, and I thank you for the success that this supplement has enjoyed since it launched in 2015.

Glenn S. Williams,
VP, Group Editor, Neurology Reviews and MDedge Neurology

2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act and the formation of the National Organization for Rare Disorders (NORD). 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report. While Neurology Reviews covers rare disease news throughout the year (see our Rare Disease Roundup in this issue), it is in our annual supplement where our rare disease news coverage and our partnership with NORD truly shines.

In this issue we take pride in taking a deeper look at some of the rare neurological diseases that have made headlines as well as the therapeutic advances and research breakthroughs that continue to benefit patients and the rare disease community as a whole. While I would prefer to humbly serve the rare disease community through our news coverage and educational efforts, I would be remiss if I didn’t mention that our 2022 Rare Neurological Disease Special Report won a Silver Regional Award in the category of annual supplement in the American Society of Business Publication Editors (Azbee) yearly competition. With that moment of bragging aside, I invite you to read this year’s issue, and I thank you for the success that this supplement has enjoyed since it launched in 2015.

Glenn S. Williams,
VP, Group Editor, Neurology Reviews and MDedge Neurology

2023 is indeed a noteworthy year. As you will read in this issue, it marks the 40th anniversary of the landmark Orphan Drug Act and the formation of the National Organization for Rare Disorders (NORD). 2023 also marks the 30th anniversary of Neurology Reviews, the parent publication of the Rare Neurological Disease Special Report. While Neurology Reviews covers rare disease news throughout the year (see our Rare Disease Roundup in this issue), it is in our annual supplement where our rare disease news coverage and our partnership with NORD truly shines.

In this issue we take pride in taking a deeper look at some of the rare neurological diseases that have made headlines as well as the therapeutic advances and research breakthroughs that continue to benefit patients and the rare disease community as a whole. While I would prefer to humbly serve the rare disease community through our news coverage and educational efforts, I would be remiss if I didn’t mention that our 2022 Rare Neurological Disease Special Report won a Silver Regional Award in the category of annual supplement in the American Society of Business Publication Editors (Azbee) yearly competition. With that moment of bragging aside, I invite you to read this year’s issue, and I thank you for the success that this supplement has enjoyed since it launched in 2015.

Glenn S. Williams,
VP, Group Editor, Neurology Reviews and MDedge Neurology

New guidelines on determining brain death offer the first updated recommendations in more than a decade for adult and pediatric patients.

The consensus practice guideline on brain death, also known as death by neurologic criteria (BD/DNC), was developed by a panel of 20 experts from different specialties, institutions, and medical societies.

As with previous guidelines, the updated version stipulates that brain death should be declared when a patient with a known cause of catastrophic brain injury has permanent loss of function of the brain, including the brain stem, which results in coma, brain stem areflexia, and apnea in the setting of an adequate stimulus.

But the updated version also clarifies questions on neurological examinations and apnea testing and offers new guidance on pre-evaluation targets for blood pressure and body temperature and evaluating brain death in patients who are pregnant, are on extracorporeal membrane oxygenation, or have an injury to the base of the brain.

Also, for the first time, the guidance clarifies that clinicians don’t need to obtain consent before performing a brain death evaluation, unless institutional policy, state laws, or regulations stipulate otherwise.

“The 2023 guidelines will be considered the standard of care in the U.S.,” lead author David M. Greer, MD, chair and chief of neurology, Boston University, and chief of neurology, Boston Medical Center, said in an interview. “Each hospital in the U.S. is responsible for its own policy for BD/DNC determination, and our hope is that they will quickly revise their policies in accordance with this new national standard.”

The guidelines, which are accompanied by a three-page checklist and a free digital app, were published online in Neurology.
 

Four years in the making

Work on the 85 recommendations in the new report began more than 4 years ago as a collaborative effort by the American Academy of Neurology, the American Academy of Pediatrics, the Child Neurology Society, and the Society of Critical Care Medicine.

A lack of high-quality evidence on brain death determination led panelists to devise an evidence-informed formal consensus process to develop the guidelines, which involved three rounds of anonymous voting on each recommendation and the rationales behind them.

The strength of each recommendation was based on the level of consensus reached through voting, with Level A denoting a recommendation that “must” be followed, Level B one that “should” be followed, and Level C one that “may” be followed.

The majority of recommendations received an A or B rating. Only one recommendation, about whether a second clinical exam is needed in adults, garnered a C rating.

In children, the guidelines recommend that clinicians must perform two clinical examinations and two apnea tests 12 hours apart. In adults, only one exam is required. Both of those recommendations were rated Level A. A recommendation for a second exam in adults received the single Level C rating.
 

A uniform set of guidelines?

The new guidelines replace adult practice guidance published by AAN in 2010 and guideline for infants and children released in 2011 by AAP, CNS, and SCCM, and for the first time combine brain death guidelines for adult and pediatric patients into one document.

“It is important for clinicians to review the new guideline carefully and ensure their hospital brain death guidelines are updated to be consistent with the new guideline in order to prevent inaccurate determinations of death,” guidelines coauthor Ariane Lewis, MD, NYU Langone Health, New York, said in an interview.

The 1981 Uniform Determination of Death Act (UDDA) is the legal foundation for the declaration of BD/DNC in the United States, but it only stipulates that brain death determination must be made in accordance with accepted medical standards.

There is no single national standard, and states and hospitals are free to adopt their own, which many have done. One goal of the new guidelines was to create a uniform set of guidelines that all institutions follow.

“This is a step toward having a set of guidelines that are accepted by most of the societies and clinical specialties involved in this sort of diagnosis,” that could lead to a national-level policy, Fernando Goldenberg, MD, professor of neurology and director of neuroscience critical care, University of Chicago Medicine, said in an interview.

Dr. Goldenberg was not part of the panel that developed the updated guidelines, but was a coauthor of a consensus statement from the World Brain Death Project in 2020.

Developing a singular global guideline for brain death determination is unlikely, Dr. Goldenberg said. Policies vary widely across the world, and some countries don’t even recognize brain death.

“But this attempts to unify things at the U.S. level, which is very important,” he said.
 

Permanent vs. irreversible

Dr. Goldenberg said that combining adult and pediatric guidelines into one document will be very helpful for clinicians like him who treat patients from age 16 years and up.

The expanded guidance on apnea testing, recommendations on specific ancillary tests to use or avoid, and inclusion of language stipulating that prior consent is not needed to perform a brain death evaluation are also useful.

He also noted that the section on credentialing and training of clinicians who perform BD/DNC evaluations recognizes advanced practice providers, the first time he recalls seeing these professionals included in brain death guidelines.

However, the panel’s decision to use the term “permanent” to describe loss of brain function instead of “irreversible” gave Dr. Goldenberg pause.

The UDDA provides that an individual is declared legally dead when “circulatory and respiratory functions irreversibly stop; or all functions of the entire brain, including the brain stem, irreversibly stop.”

Earlier in October, the American College of Physicians released a position paper on cardiorespiratory death determination that called for a revision of the UDDA language.

The ACP suggested that “irreversibly” be replaced with “permanently” with regard to the cessation of circulatory and respiratory functions, but that “irreversible” be kept in the description of brain death.

“Permanent means that there is damage that is potentially reversible and irreversible means that the damage is so profound, it cannot be reversed even if an attempt to do so is performed,” Dr. Goldenberg said.

Even though the World Brain Death Project, on which he worked, also used “permanent” to describe brain function loss, Dr. Goldenberg said he aligns with ACP’s position.

“The understanding of brain death is that the damage is so profound, it is irreversible, even if you were to try,” he said. “Therefore, I think that the most appropriate term for brain death should be irreversible as opposed to permanent.”

The report was funded by the American Academy of Neurology. Dr. Greer has received travel funding from Boston University; serves as editor-in-chief for Seminars in Neurology; receives publishing royalties for 50 Studies Every Neurologist Should Know and Successful Leadership in Academic Medicine; has received honoraria from AAN; has received research funding from Becton, Dickinson, and Company; and has served as expert witness in legal proceedings. Dr. Lewis has received honoraria from AAN and Neurodiem, serves as Neurology deputy editor of disputes and debates, and serves as deputy editor of seminars in Neurology. Dr. Goldenberg reported no relevant financial relationships.

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

New guidelines on determining brain death offer the first updated recommendations in more than a decade for adult and pediatric patients.

The consensus practice guideline on brain death, also known as death by neurologic criteria (BD/DNC), was developed by a panel of 20 experts from different specialties, institutions, and medical societies.

As with previous guidelines, the updated version stipulates that brain death should be declared when a patient with a known cause of catastrophic brain injury has permanent loss of function of the brain, including the brain stem, which results in coma, brain stem areflexia, and apnea in the setting of an adequate stimulus.

But the updated version also clarifies questions on neurological examinations and apnea testing and offers new guidance on pre-evaluation targets for blood pressure and body temperature and evaluating brain death in patients who are pregnant, are on extracorporeal membrane oxygenation, or have an injury to the base of the brain.

Also, for the first time, the guidance clarifies that clinicians don’t need to obtain consent before performing a brain death evaluation, unless institutional policy, state laws, or regulations stipulate otherwise.

“The 2023 guidelines will be considered the standard of care in the U.S.,” lead author David M. Greer, MD, chair and chief of neurology, Boston University, and chief of neurology, Boston Medical Center, said in an interview. “Each hospital in the U.S. is responsible for its own policy for BD/DNC determination, and our hope is that they will quickly revise their policies in accordance with this new national standard.”

The guidelines, which are accompanied by a three-page checklist and a free digital app, were published online in Neurology.
 

Four years in the making

Work on the 85 recommendations in the new report began more than 4 years ago as a collaborative effort by the American Academy of Neurology, the American Academy of Pediatrics, the Child Neurology Society, and the Society of Critical Care Medicine.

A lack of high-quality evidence on brain death determination led panelists to devise an evidence-informed formal consensus process to develop the guidelines, which involved three rounds of anonymous voting on each recommendation and the rationales behind them.

The strength of each recommendation was based on the level of consensus reached through voting, with Level A denoting a recommendation that “must” be followed, Level B one that “should” be followed, and Level C one that “may” be followed.

The majority of recommendations received an A or B rating. Only one recommendation, about whether a second clinical exam is needed in adults, garnered a C rating.

In children, the guidelines recommend that clinicians must perform two clinical examinations and two apnea tests 12 hours apart. In adults, only one exam is required. Both of those recommendations were rated Level A. A recommendation for a second exam in adults received the single Level C rating.
 

A uniform set of guidelines?

The new guidelines replace adult practice guidance published by AAN in 2010 and guideline for infants and children released in 2011 by AAP, CNS, and SCCM, and for the first time combine brain death guidelines for adult and pediatric patients into one document.

“It is important for clinicians to review the new guideline carefully and ensure their hospital brain death guidelines are updated to be consistent with the new guideline in order to prevent inaccurate determinations of death,” guidelines coauthor Ariane Lewis, MD, NYU Langone Health, New York, said in an interview.

The 1981 Uniform Determination of Death Act (UDDA) is the legal foundation for the declaration of BD/DNC in the United States, but it only stipulates that brain death determination must be made in accordance with accepted medical standards.

There is no single national standard, and states and hospitals are free to adopt their own, which many have done. One goal of the new guidelines was to create a uniform set of guidelines that all institutions follow.

“This is a step toward having a set of guidelines that are accepted by most of the societies and clinical specialties involved in this sort of diagnosis,” that could lead to a national-level policy, Fernando Goldenberg, MD, professor of neurology and director of neuroscience critical care, University of Chicago Medicine, said in an interview.

Dr. Goldenberg was not part of the panel that developed the updated guidelines, but was a coauthor of a consensus statement from the World Brain Death Project in 2020.

Developing a singular global guideline for brain death determination is unlikely, Dr. Goldenberg said. Policies vary widely across the world, and some countries don’t even recognize brain death.

“But this attempts to unify things at the U.S. level, which is very important,” he said.
 

Permanent vs. irreversible

Dr. Goldenberg said that combining adult and pediatric guidelines into one document will be very helpful for clinicians like him who treat patients from age 16 years and up.

The expanded guidance on apnea testing, recommendations on specific ancillary tests to use or avoid, and inclusion of language stipulating that prior consent is not needed to perform a brain death evaluation are also useful.

He also noted that the section on credentialing and training of clinicians who perform BD/DNC evaluations recognizes advanced practice providers, the first time he recalls seeing these professionals included in brain death guidelines.

However, the panel’s decision to use the term “permanent” to describe loss of brain function instead of “irreversible” gave Dr. Goldenberg pause.

The UDDA provides that an individual is declared legally dead when “circulatory and respiratory functions irreversibly stop; or all functions of the entire brain, including the brain stem, irreversibly stop.”

Earlier in October, the American College of Physicians released a position paper on cardiorespiratory death determination that called for a revision of the UDDA language.

The ACP suggested that “irreversibly” be replaced with “permanently” with regard to the cessation of circulatory and respiratory functions, but that “irreversible” be kept in the description of brain death.

“Permanent means that there is damage that is potentially reversible and irreversible means that the damage is so profound, it cannot be reversed even if an attempt to do so is performed,” Dr. Goldenberg said.

Even though the World Brain Death Project, on which he worked, also used “permanent” to describe brain function loss, Dr. Goldenberg said he aligns with ACP’s position.

“The understanding of brain death is that the damage is so profound, it is irreversible, even if you were to try,” he said. “Therefore, I think that the most appropriate term for brain death should be irreversible as opposed to permanent.”

The report was funded by the American Academy of Neurology. Dr. Greer has received travel funding from Boston University; serves as editor-in-chief for Seminars in Neurology; receives publishing royalties for 50 Studies Every Neurologist Should Know and Successful Leadership in Academic Medicine; has received honoraria from AAN; has received research funding from Becton, Dickinson, and Company; and has served as expert witness in legal proceedings. Dr. Lewis has received honoraria from AAN and Neurodiem, serves as Neurology deputy editor of disputes and debates, and serves as deputy editor of seminars in Neurology. Dr. Goldenberg reported no relevant financial relationships.

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

New guidelines on determining brain death offer the first updated recommendations in more than a decade for adult and pediatric patients.

The consensus practice guideline on brain death, also known as death by neurologic criteria (BD/DNC), was developed by a panel of 20 experts from different specialties, institutions, and medical societies.

As with previous guidelines, the updated version stipulates that brain death should be declared when a patient with a known cause of catastrophic brain injury has permanent loss of function of the brain, including the brain stem, which results in coma, brain stem areflexia, and apnea in the setting of an adequate stimulus.

But the updated version also clarifies questions on neurological examinations and apnea testing and offers new guidance on pre-evaluation targets for blood pressure and body temperature and evaluating brain death in patients who are pregnant, are on extracorporeal membrane oxygenation, or have an injury to the base of the brain.

Also, for the first time, the guidance clarifies that clinicians don’t need to obtain consent before performing a brain death evaluation, unless institutional policy, state laws, or regulations stipulate otherwise.

“The 2023 guidelines will be considered the standard of care in the U.S.,” lead author David M. Greer, MD, chair and chief of neurology, Boston University, and chief of neurology, Boston Medical Center, said in an interview. “Each hospital in the U.S. is responsible for its own policy for BD/DNC determination, and our hope is that they will quickly revise their policies in accordance with this new national standard.”

The guidelines, which are accompanied by a three-page checklist and a free digital app, were published online in Neurology.
 

Four years in the making

Work on the 85 recommendations in the new report began more than 4 years ago as a collaborative effort by the American Academy of Neurology, the American Academy of Pediatrics, the Child Neurology Society, and the Society of Critical Care Medicine.

A lack of high-quality evidence on brain death determination led panelists to devise an evidence-informed formal consensus process to develop the guidelines, which involved three rounds of anonymous voting on each recommendation and the rationales behind them.

The strength of each recommendation was based on the level of consensus reached through voting, with Level A denoting a recommendation that “must” be followed, Level B one that “should” be followed, and Level C one that “may” be followed.

The majority of recommendations received an A or B rating. Only one recommendation, about whether a second clinical exam is needed in adults, garnered a C rating.

In children, the guidelines recommend that clinicians must perform two clinical examinations and two apnea tests 12 hours apart. In adults, only one exam is required. Both of those recommendations were rated Level A. A recommendation for a second exam in adults received the single Level C rating.
 

A uniform set of guidelines?

The new guidelines replace adult practice guidance published by AAN in 2010 and guideline for infants and children released in 2011 by AAP, CNS, and SCCM, and for the first time combine brain death guidelines for adult and pediatric patients into one document.

“It is important for clinicians to review the new guideline carefully and ensure their hospital brain death guidelines are updated to be consistent with the new guideline in order to prevent inaccurate determinations of death,” guidelines coauthor Ariane Lewis, MD, NYU Langone Health, New York, said in an interview.

The 1981 Uniform Determination of Death Act (UDDA) is the legal foundation for the declaration of BD/DNC in the United States, but it only stipulates that brain death determination must be made in accordance with accepted medical standards.

There is no single national standard, and states and hospitals are free to adopt their own, which many have done. One goal of the new guidelines was to create a uniform set of guidelines that all institutions follow.

“This is a step toward having a set of guidelines that are accepted by most of the societies and clinical specialties involved in this sort of diagnosis,” that could lead to a national-level policy, Fernando Goldenberg, MD, professor of neurology and director of neuroscience critical care, University of Chicago Medicine, said in an interview.

Dr. Goldenberg was not part of the panel that developed the updated guidelines, but was a coauthor of a consensus statement from the World Brain Death Project in 2020.

Developing a singular global guideline for brain death determination is unlikely, Dr. Goldenberg said. Policies vary widely across the world, and some countries don’t even recognize brain death.

“But this attempts to unify things at the U.S. level, which is very important,” he said.
 

Permanent vs. irreversible

Dr. Goldenberg said that combining adult and pediatric guidelines into one document will be very helpful for clinicians like him who treat patients from age 16 years and up.

The expanded guidance on apnea testing, recommendations on specific ancillary tests to use or avoid, and inclusion of language stipulating that prior consent is not needed to perform a brain death evaluation are also useful.

He also noted that the section on credentialing and training of clinicians who perform BD/DNC evaluations recognizes advanced practice providers, the first time he recalls seeing these professionals included in brain death guidelines.

However, the panel’s decision to use the term “permanent” to describe loss of brain function instead of “irreversible” gave Dr. Goldenberg pause.

The UDDA provides that an individual is declared legally dead when “circulatory and respiratory functions irreversibly stop; or all functions of the entire brain, including the brain stem, irreversibly stop.”

Earlier in October, the American College of Physicians released a position paper on cardiorespiratory death determination that called for a revision of the UDDA language.

The ACP suggested that “irreversibly” be replaced with “permanently” with regard to the cessation of circulatory and respiratory functions, but that “irreversible” be kept in the description of brain death.

“Permanent means that there is damage that is potentially reversible and irreversible means that the damage is so profound, it cannot be reversed even if an attempt to do so is performed,” Dr. Goldenberg said.

Even though the World Brain Death Project, on which he worked, also used “permanent” to describe brain function loss, Dr. Goldenberg said he aligns with ACP’s position.

“The understanding of brain death is that the damage is so profound, it is irreversible, even if you were to try,” he said. “Therefore, I think that the most appropriate term for brain death should be irreversible as opposed to permanent.”

The report was funded by the American Academy of Neurology. Dr. Greer has received travel funding from Boston University; serves as editor-in-chief for Seminars in Neurology; receives publishing royalties for 50 Studies Every Neurologist Should Know and Successful Leadership in Academic Medicine; has received honoraria from AAN; has received research funding from Becton, Dickinson, and Company; and has served as expert witness in legal proceedings. Dr. Lewis has received honoraria from AAN and Neurodiem, serves as Neurology deputy editor of disputes and debates, and serves as deputy editor of seminars in Neurology. Dr. Goldenberg reported no relevant financial relationships.

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

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Rosacea with Demodex mites

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Rosacea with Demodex mites

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Rosacea with Demodex mites

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; nlefevre@health.missouri.edu

A fixed drug eruption (FDE) is a rare cutaneous and/or mucosal reaction caused by ingestion of a drug. This is a delayed hypersensitivity reaction in which lesions present in the same location upon repeated intake of the offending drug. The lesions typically present within 30 minutes to 8 hours of administration of the drug. These reactions can be considered allergic or pseudo-allergic, in which case, there is no notable adaptive immune response. CD8+ T cells appear to play a role in the epidermal injury via release of interferons and interactions with other inflammatory cells.

Courtesy Lucas Shapiro and Dr. Igor Chaplik

There are numerous drugs that can precipitate these findings. NSAIDs; antibiotics, such as tetracyclines, sulfonamides; and phenytoin are common offenders. In the case of our patient, naproxen was the offending medication.

The classic presentation of FDE features annular, erythematous to violaceous macules on the skin or mucosa that can be asymptomatic or can produce burning, pain, or pruritus. The most common locations include the trunk and extremities, but the palms, soles, face, scalp, and mucosa can also be impacted. The oral mucosa seems to be the most common mucosal location. Intravenous administration of a drug is associated with more severe symptoms. Systemic symptoms are typically absent, and the eruption may initially be in one location, but may appear elsewhere upon repeated exposure to the offending medication.

The differential diagnosis includes arthropod bite reactions, urticaria, and erythema multiforme. Although FDEs are typically a clinical diagnosis, the histopathology will commonly show a vacuolar interface dermatitis. Furthermore, a variety of immune cells can be found, including neutrophilic, eosinophilic, and lymphocytic infiltrate. A combination of two or more histological patterns often favors the diagnosis of FDE.

Steroid creams can be prescribed to decrease the inflammatory reaction and improve symptoms; however, the definitive treatment of this condition is cessation of the offending agent. Postinflammatory hyperpigmentation is a common symptom after resolution of the condition, and it may take months to fade away. Further darkening can be prevented by practicing sun safety measures such as wearing sunblock, covering the affected areas, and avoiding prolonged sun exposure.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Igor Chaplik, DO, Aesthetix Dermatology, Fort Lauderdale. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Shaker G et al. Cureus. 2022 Aug 23;14(8):e28299.

Srivastava R et al. Indian J Dent. 2015 Apr-Jun;6(2):103-6.

Weyers W, Metze D. Dermatol Pract Concept. 2011 Jan 31;1(1):33-47.

A fixed drug eruption (FDE) is a rare cutaneous and/or mucosal reaction caused by ingestion of a drug. This is a delayed hypersensitivity reaction in which lesions present in the same location upon repeated intake of the offending drug. The lesions typically present within 30 minutes to 8 hours of administration of the drug. These reactions can be considered allergic or pseudo-allergic, in which case, there is no notable adaptive immune response. CD8+ T cells appear to play a role in the epidermal injury via release of interferons and interactions with other inflammatory cells.

Courtesy Lucas Shapiro and Dr. Igor Chaplik

There are numerous drugs that can precipitate these findings. NSAIDs; antibiotics, such as tetracyclines, sulfonamides; and phenytoin are common offenders. In the case of our patient, naproxen was the offending medication.

The classic presentation of FDE features annular, erythematous to violaceous macules on the skin or mucosa that can be asymptomatic or can produce burning, pain, or pruritus. The most common locations include the trunk and extremities, but the palms, soles, face, scalp, and mucosa can also be impacted. The oral mucosa seems to be the most common mucosal location. Intravenous administration of a drug is associated with more severe symptoms. Systemic symptoms are typically absent, and the eruption may initially be in one location, but may appear elsewhere upon repeated exposure to the offending medication.

The differential diagnosis includes arthropod bite reactions, urticaria, and erythema multiforme. Although FDEs are typically a clinical diagnosis, the histopathology will commonly show a vacuolar interface dermatitis. Furthermore, a variety of immune cells can be found, including neutrophilic, eosinophilic, and lymphocytic infiltrate. A combination of two or more histological patterns often favors the diagnosis of FDE.

Steroid creams can be prescribed to decrease the inflammatory reaction and improve symptoms; however, the definitive treatment of this condition is cessation of the offending agent. Postinflammatory hyperpigmentation is a common symptom after resolution of the condition, and it may take months to fade away. Further darkening can be prevented by practicing sun safety measures such as wearing sunblock, covering the affected areas, and avoiding prolonged sun exposure.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Igor Chaplik, DO, Aesthetix Dermatology, Fort Lauderdale. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Shaker G et al. Cureus. 2022 Aug 23;14(8):e28299.

Srivastava R et al. Indian J Dent. 2015 Apr-Jun;6(2):103-6.

Weyers W, Metze D. Dermatol Pract Concept. 2011 Jan 31;1(1):33-47.

A fixed drug eruption (FDE) is a rare cutaneous and/or mucosal reaction caused by ingestion of a drug. This is a delayed hypersensitivity reaction in which lesions present in the same location upon repeated intake of the offending drug. The lesions typically present within 30 minutes to 8 hours of administration of the drug. These reactions can be considered allergic or pseudo-allergic, in which case, there is no notable adaptive immune response. CD8+ T cells appear to play a role in the epidermal injury via release of interferons and interactions with other inflammatory cells.

Courtesy Lucas Shapiro and Dr. Igor Chaplik

There are numerous drugs that can precipitate these findings. NSAIDs; antibiotics, such as tetracyclines, sulfonamides; and phenytoin are common offenders. In the case of our patient, naproxen was the offending medication.

The classic presentation of FDE features annular, erythematous to violaceous macules on the skin or mucosa that can be asymptomatic or can produce burning, pain, or pruritus. The most common locations include the trunk and extremities, but the palms, soles, face, scalp, and mucosa can also be impacted. The oral mucosa seems to be the most common mucosal location. Intravenous administration of a drug is associated with more severe symptoms. Systemic symptoms are typically absent, and the eruption may initially be in one location, but may appear elsewhere upon repeated exposure to the offending medication.

The differential diagnosis includes arthropod bite reactions, urticaria, and erythema multiforme. Although FDEs are typically a clinical diagnosis, the histopathology will commonly show a vacuolar interface dermatitis. Furthermore, a variety of immune cells can be found, including neutrophilic, eosinophilic, and lymphocytic infiltrate. A combination of two or more histological patterns often favors the diagnosis of FDE.

Steroid creams can be prescribed to decrease the inflammatory reaction and improve symptoms; however, the definitive treatment of this condition is cessation of the offending agent. Postinflammatory hyperpigmentation is a common symptom after resolution of the condition, and it may take months to fade away. Further darkening can be prevented by practicing sun safety measures such as wearing sunblock, covering the affected areas, and avoiding prolonged sun exposure.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Igor Chaplik, DO, Aesthetix Dermatology, Fort Lauderdale. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Shaker G et al. Cureus. 2022 Aug 23;14(8):e28299.

Srivastava R et al. Indian J Dent. 2015 Apr-Jun;6(2):103-6.

Weyers W, Metze D. Dermatol Pract Concept. 2011 Jan 31;1(1):33-47.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.² The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.² The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.² The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org