Medicare beneficiaries living in the Mississippi–Ohio River valley had a higher risk of developing Parkinson’s disease, compared with other regions of the United States, according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

The association was attributed to concentrations of particulate matter (PM) _2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.

Barrow Neurological Institute

“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”

Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM_2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM_2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m³ and the group with the highest exposure having an average annual exposure of 19 mcg/m³.

In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM_2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).

The results showed the nationwide average annual PM_2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM_2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM_2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM_2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM_2.5 between approximately 12-19 mcg/m³.

Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
 

A focus on air pollution

Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.

“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.

Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”

“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”

“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”

Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”

One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.

“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.

Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.

Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.

*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.

Medicare beneficiaries living in the Mississippi–Ohio River valley had a higher risk of developing Parkinson’s disease, compared with other regions of the United States, according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

The association was attributed to concentrations of particulate matter (PM) _2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.

Barrow Neurological Institute

“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”

Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM_2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM_2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m³ and the group with the highest exposure having an average annual exposure of 19 mcg/m³.

In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM_2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).

The results showed the nationwide average annual PM_2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM_2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM_2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM_2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM_2.5 between approximately 12-19 mcg/m³.

Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
 

A focus on air pollution

Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.

“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.

Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”

“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”

“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”

Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”

One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.

“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.

Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.

Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.

*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.

Medicare beneficiaries living in the Mississippi–Ohio River valley had a higher risk of developing Parkinson’s disease, compared with other regions of the United States, according to findings from a study that was released ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

The association was attributed to concentrations of particulate matter (PM) _2.5 in the Mississippi–Ohio River valley, which was on average higher than in other areas, but that didn’t entirely explain the increase in Parkinson’s disease in that region, Brittany Krzyzanowski, PhD, a postdoctoral research fellow in the neuroepidemiology research program of the department of neurology at Barrow Neurological Institute, Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.

Barrow Neurological Institute

“This study revealed Parkinson’s disease hot spots in the Mississippi–Ohio River valley, a region that has some of the highest levels of air pollution in the nation,” she said, “but we also still find a relationship between air pollution and Parkinson’s risk in the regions in the western half of the United States where Parkinson’s disease and air pollution levels are relatively low.”

Dr. Krzyzanowski and colleagues evaluated 22,546,965 Medicare beneficiaries in 2009, using a multimethod approach that included geospatial analytical techniques to categorize their exposure to PM_2.5 based on age, sex, race, smoking status, and health care usage. The researchers also performed individual-level case-control analysis to assess PM_2.5 results at the county level. The Medicare beneficiaries were grouped according to average exposure, with the lowest group having an average annual exposure of 5 mcg/m³ and the group with the highest exposure having an average annual exposure of 19 mcg/m³.

In total, researchers identified 83,674 Medicare beneficiaries with incident Parkinson’s disease, with 434 new cases per 100,000 people in the highest exposure group, compared with 359 new cases per 100,000 people in the lowest-exposure group. The relative risk for Parkinson’s disease increased in the highest quartile of PM_2.5 by 25%, compared with the lowest quartile after adjusting for factors such as age, smoking status, and health care usage (95% confidence interval, 20%–29%).

The results showed the nationwide average annual PM_2.5 was associated with incident Parkinson’s disease, and the Rocky Mountain region carried a strong association between PM_2.5 and Parkson’s disease with a 16% increase in risk per level of exposure to PM_2.5. While the Mississippi-Ohio River valley was also associated with Parkinson’s disease, there was a weaker association between PM_2.5 and Parkinson’s disease, which the researchers attributed to a “ceiling effect” of PM_2.5 between approximately 12-19 mcg/m³.

Dr. Krzyzanowski said that use of a large-population-based dataset and high-resolution location data were major strengths of the study. “Having this level of information leaves less room for uncertainty in our measures and analyses,” she said. “Our study also leveraged innovative geographic information systems which allowed us to refine local patterns of disease by using population behavior and demographic information (such as smoking and age) to ensure that we could provide the most accurate map representation available to date.”
 

A focus on air pollution

Existing research in examining the etiology of Parkinson’s mainly focused on exposure to pesticides,* Dr. Krzyzanowski explained, and “consists of studies using relatively small populations and low-resolution air pollution data.” Genetics is another possible cause, she noted, but only explains some Parkinson’s disease cases.

“Our work suggests that we should also be looking at air pollution as a contributor in the development of Parkinson’s disease,” she said.

Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), who was not involved with the study, said that evidence is mounting that “air pollution may be an important causal factor in Parkinson’s and especially Alzheimer’s disease.”

“This study by a well-regarded group of researchers adds epidemiological evidence for that association,” he said. Another strength is that the study was conducted in the United States, as many epidemiological studies evaluating air pollution and Parkinson’s disease have been performed outside the country because of “a dearth of reliable data sources.”

“This study, along with others, suggest that some of the important environmental toxicants tied to brain disease may be inhaled,” Dr. Dorsey said. “The nose may be the front door to the brain.”

Dr. Krzyzanowski said the next step in their research is further examination of different types of air pollution. “Air pollution contains a variety of toxic components which vary from region to region. Understanding the different components in air pollution and how they interact with climate, temperature, and topography could help explain the regional differences we observed.”

One potential limitation in the study is a lag between air pollution exposure and development of Parkinson’s disease, Dr. Dorsey noted.

“Here, it looks like (but I am not certain) that the investigators looked at current air pollution levels and new cases of Parkinson’s. Ideally, for incident cases of Parkinson’s disease, we would want to know historical data on exposure to air pollution,” he said.

Future studies should include prospective evaluation of adults as well as babies and children who have been exposed to both high and low levels of air pollution. That kind of study “would be incredibly valuable for determining the role of an important environmental toxicant in many brain diseases, including stroke, Alzheimer’s, and Parkinson’s,” he said.

Dr. Krzyzanowski and Dr. Dorsey reported no relevant financial disclosures. This study was supported by grants from the Department of Defense, the National Institute of Environmental Health Sciences, and The Michael J. Fox Foundation for Parkinson’s Research.

*Correction, 4/14/23: An earlier version of this article mischaracterized the disease that was the subject of this research.

Women with better indicators of cardiovascular health at midlife saw reduced risk of later dementia, according to results of a study that was released early, ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

Epidemiologist Pamela M. Rist, ScD, assistant professor of medicine at Harvard Medical School and associate epidemiologist at Brigham and Women’s Hospital, both in Boston, and colleagues, used data from 13,720 women whose mean age was 54 when they enrolled in the Harvard-based Women’s Health Study between 1992 and 1995. Subjects in that study were followed up in 2004.

Brigham and Women's Hospital

Putting ‘Life’s Simple 7’ to the test

Dr. Rist and colleagues used the Harvard data to discern how well closely women conformed, during the initial study period and at 10-year follow up, to what the American Heart Association describes as “Life’s Simple 7,” a list of behavioral and biometric measures that indicate and predict cardiovascular health. The measures include four modifiable behaviors – not smoking, healthy weight, a healthy diet, and being physically active – along with three biometric measures of blood pressure, cholesterol, and blood sugar (AHA has since added a sleep component).

Researchers assigned women one point for each desirable habit or measure on the list, with subjects’ average Simple 7 score at baseline 4.3, and 4.2 at 10 years’ follow-up.

The investigators then looked at Medicare data for the study subjects from 2011 to 2018 – approximately 20 years after their enrollment in the Women’s Health Study – seeking dementia diagnoses. Some 13% of the study cohort (n = 1,771) had gone on to develop dementia.

Each point on the Simple 7 score at baseline corresponded with a 6% reduction in later dementia risk, Dr. Rist and her colleagues found after adjusting for variables including age and education (odds ratio per one unit change in score, 0.94; 95% CI, 0.90-0.98). This effect was similar for Simple 7 scores measured at 10 years of follow-up (OR, 0.95; 95% CI, 0.91-1.00).

“It can be empowering for people to know that by taking steps such as exercising for a half an hour a day or keeping their blood pressure under control, they can reduce their risk of dementia,” Dr. Rist said in a statement on the findings.
 

‘A simple take-home message’

Reached for comment, Andrew E. Budson, MD, chief of cognitive-behavioral neurology at the VA Boston Healthcare System, praised Dr. Rist and colleagues’ study as one that “builds on existing knowledge to provide a simple take-home message that empowers women to take control of their dementia risk.”

VA Boston Healthcare System

Each of the seven known risk factors – being active, eating better, maintaining a healthy weight, not smoking, maintaining a healthy blood pressure, controlling cholesterol, and having low blood sugar – “was associated with a 6% reduced risk of dementia,” Dr. Budson continued. “So, women who work to address all seven risk factors can reduce their risk of developing dementia by 42%: a huge amount. Moreover, although this study only looked at women, I am confident that if men follow this same advice they will also be able to reduce their risk of dementia, although we don’t know if the size of the effect will be the same.”

Dr. Rist and colleagues’ study was supported by the National Institutes of Health. None of the study authors reported conflicts of interest. Dr. Budson has reported receiving past compensation as a speaker for Eli Lilly.

Women with better indicators of cardiovascular health at midlife saw reduced risk of later dementia, according to results of a study that was released early, ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

Epidemiologist Pamela M. Rist, ScD, assistant professor of medicine at Harvard Medical School and associate epidemiologist at Brigham and Women’s Hospital, both in Boston, and colleagues, used data from 13,720 women whose mean age was 54 when they enrolled in the Harvard-based Women’s Health Study between 1992 and 1995. Subjects in that study were followed up in 2004.

Brigham and Women's Hospital

Putting ‘Life’s Simple 7’ to the test

Dr. Rist and colleagues used the Harvard data to discern how well closely women conformed, during the initial study period and at 10-year follow up, to what the American Heart Association describes as “Life’s Simple 7,” a list of behavioral and biometric measures that indicate and predict cardiovascular health. The measures include four modifiable behaviors – not smoking, healthy weight, a healthy diet, and being physically active – along with three biometric measures of blood pressure, cholesterol, and blood sugar (AHA has since added a sleep component).

Researchers assigned women one point for each desirable habit or measure on the list, with subjects’ average Simple 7 score at baseline 4.3, and 4.2 at 10 years’ follow-up.

The investigators then looked at Medicare data for the study subjects from 2011 to 2018 – approximately 20 years after their enrollment in the Women’s Health Study – seeking dementia diagnoses. Some 13% of the study cohort (n = 1,771) had gone on to develop dementia.

Each point on the Simple 7 score at baseline corresponded with a 6% reduction in later dementia risk, Dr. Rist and her colleagues found after adjusting for variables including age and education (odds ratio per one unit change in score, 0.94; 95% CI, 0.90-0.98). This effect was similar for Simple 7 scores measured at 10 years of follow-up (OR, 0.95; 95% CI, 0.91-1.00).

“It can be empowering for people to know that by taking steps such as exercising for a half an hour a day or keeping their blood pressure under control, they can reduce their risk of dementia,” Dr. Rist said in a statement on the findings.
 

‘A simple take-home message’

Reached for comment, Andrew E. Budson, MD, chief of cognitive-behavioral neurology at the VA Boston Healthcare System, praised Dr. Rist and colleagues’ study as one that “builds on existing knowledge to provide a simple take-home message that empowers women to take control of their dementia risk.”

VA Boston Healthcare System

Each of the seven known risk factors – being active, eating better, maintaining a healthy weight, not smoking, maintaining a healthy blood pressure, controlling cholesterol, and having low blood sugar – “was associated with a 6% reduced risk of dementia,” Dr. Budson continued. “So, women who work to address all seven risk factors can reduce their risk of developing dementia by 42%: a huge amount. Moreover, although this study only looked at women, I am confident that if men follow this same advice they will also be able to reduce their risk of dementia, although we don’t know if the size of the effect will be the same.”

Dr. Rist and colleagues’ study was supported by the National Institutes of Health. None of the study authors reported conflicts of interest. Dr. Budson has reported receiving past compensation as a speaker for Eli Lilly.

Women with better indicators of cardiovascular health at midlife saw reduced risk of later dementia, according to results of a study that was released early, ahead of its scheduled presentation at the annual meeting of the American Academy of Neurology.

Epidemiologist Pamela M. Rist, ScD, assistant professor of medicine at Harvard Medical School and associate epidemiologist at Brigham and Women’s Hospital, both in Boston, and colleagues, used data from 13,720 women whose mean age was 54 when they enrolled in the Harvard-based Women’s Health Study between 1992 and 1995. Subjects in that study were followed up in 2004.

Brigham and Women's Hospital

Putting ‘Life’s Simple 7’ to the test

Dr. Rist and colleagues used the Harvard data to discern how well closely women conformed, during the initial study period and at 10-year follow up, to what the American Heart Association describes as “Life’s Simple 7,” a list of behavioral and biometric measures that indicate and predict cardiovascular health. The measures include four modifiable behaviors – not smoking, healthy weight, a healthy diet, and being physically active – along with three biometric measures of blood pressure, cholesterol, and blood sugar (AHA has since added a sleep component).

Researchers assigned women one point for each desirable habit or measure on the list, with subjects’ average Simple 7 score at baseline 4.3, and 4.2 at 10 years’ follow-up.

The investigators then looked at Medicare data for the study subjects from 2011 to 2018 – approximately 20 years after their enrollment in the Women’s Health Study – seeking dementia diagnoses. Some 13% of the study cohort (n = 1,771) had gone on to develop dementia.

Each point on the Simple 7 score at baseline corresponded with a 6% reduction in later dementia risk, Dr. Rist and her colleagues found after adjusting for variables including age and education (odds ratio per one unit change in score, 0.94; 95% CI, 0.90-0.98). This effect was similar for Simple 7 scores measured at 10 years of follow-up (OR, 0.95; 95% CI, 0.91-1.00).

“It can be empowering for people to know that by taking steps such as exercising for a half an hour a day or keeping their blood pressure under control, they can reduce their risk of dementia,” Dr. Rist said in a statement on the findings.
 

‘A simple take-home message’

Reached for comment, Andrew E. Budson, MD, chief of cognitive-behavioral neurology at the VA Boston Healthcare System, praised Dr. Rist and colleagues’ study as one that “builds on existing knowledge to provide a simple take-home message that empowers women to take control of their dementia risk.”

VA Boston Healthcare System

Each of the seven known risk factors – being active, eating better, maintaining a healthy weight, not smoking, maintaining a healthy blood pressure, controlling cholesterol, and having low blood sugar – “was associated with a 6% reduced risk of dementia,” Dr. Budson continued. “So, women who work to address all seven risk factors can reduce their risk of developing dementia by 42%: a huge amount. Moreover, although this study only looked at women, I am confident that if men follow this same advice they will also be able to reduce their risk of dementia, although we don’t know if the size of the effect will be the same.”

Dr. Rist and colleagues’ study was supported by the National Institutes of Health. None of the study authors reported conflicts of interest. Dr. Budson has reported receiving past compensation as a speaker for Eli Lilly.

I’m not going to get rich off Mike.

Of course, I’m not going to get rich off anyone, nor do I want to. I’m not here to rip anyone off.

Mike goes back with me, roughly 23 years.

He was born with cerebral palsy and refractory seizures. His birth mother gave him up quickly, and he was adopted by a couple who knew what they were getting into (to me that constitutes sainthood).

Over the years Mike has done his best to buck the odds. He’s tried to stay employed, in spite of his physical limitations, working variously as a janitor, grocery courtesy clerk, and store greeter. He tells me that he can still work and wants to, even with having to rely on public transportation.

By the time he came to me he’d been through several neurologists and even more failed epilepsy drugs. His brain MRI and EEGs showed multifocal seizures from numerous inoperable cortical heterotopias.

I dabbled with a few newer drugs at the time for him, without success. Finally, I reached for the neurological equivalent of unstable dynamite – Felbatol (felbamate).

As it often does, it worked. One of my attendings in training (you, Bob) told me it was the home-run drug. When nothing else worked, it might – but you had to handle it carefully.

Fortunately, after 23 years, that hasn’t happened. Mike’s labs have looked good. His seizures have dropped from several a week to a few per year.

Ten years ago Mike had to change insurance to one I don’t take, and had me forward his records to another neurologist. That office told him they don’t handle Felbatol. As did another. And another.

Mike, understandably, doesn’t want to change meds. This is the only drug that’s given him a decent quality of life, and let him have a job. That’s pretty important to him.

So, I see him for free now, once or twice a year. Sometimes he offers me a token payment of $5-$10, but I turn it down. He needs it more than I do, for bus fair to my office if nothing else.

I’m sure some would be critical of me, saying that I should be more open to new drugs and treatments. I am, believe me. But Mike can’t afford many of them, or the loss of work they’d entail if his seizures worsen. He doesn’t want to take that chance, and I don’t blame him.

Of course, none of us can see everyone for free. In fact, he’s the only one I do. I’m not greedy, but I also have to pay my rent, staff, and mortgage.

But taking money from Mike, who’s come up on the short end of the stick in so many ways, doesn’t seem right. I can’t do it, and really don’t want to.

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

I’m not going to get rich off Mike.

Of course, I’m not going to get rich off anyone, nor do I want to. I’m not here to rip anyone off.

Mike goes back with me, roughly 23 years.

He was born with cerebral palsy and refractory seizures. His birth mother gave him up quickly, and he was adopted by a couple who knew what they were getting into (to me that constitutes sainthood).

Over the years Mike has done his best to buck the odds. He’s tried to stay employed, in spite of his physical limitations, working variously as a janitor, grocery courtesy clerk, and store greeter. He tells me that he can still work and wants to, even with having to rely on public transportation.

By the time he came to me he’d been through several neurologists and even more failed epilepsy drugs. His brain MRI and EEGs showed multifocal seizures from numerous inoperable cortical heterotopias.

I dabbled with a few newer drugs at the time for him, without success. Finally, I reached for the neurological equivalent of unstable dynamite – Felbatol (felbamate).

As it often does, it worked. One of my attendings in training (you, Bob) told me it was the home-run drug. When nothing else worked, it might – but you had to handle it carefully.

Fortunately, after 23 years, that hasn’t happened. Mike’s labs have looked good. His seizures have dropped from several a week to a few per year.

Ten years ago Mike had to change insurance to one I don’t take, and had me forward his records to another neurologist. That office told him they don’t handle Felbatol. As did another. And another.

Mike, understandably, doesn’t want to change meds. This is the only drug that’s given him a decent quality of life, and let him have a job. That’s pretty important to him.

So, I see him for free now, once or twice a year. Sometimes he offers me a token payment of $5-$10, but I turn it down. He needs it more than I do, for bus fair to my office if nothing else.

I’m sure some would be critical of me, saying that I should be more open to new drugs and treatments. I am, believe me. But Mike can’t afford many of them, or the loss of work they’d entail if his seizures worsen. He doesn’t want to take that chance, and I don’t blame him.

Of course, none of us can see everyone for free. In fact, he’s the only one I do. I’m not greedy, but I also have to pay my rent, staff, and mortgage.

But taking money from Mike, who’s come up on the short end of the stick in so many ways, doesn’t seem right. I can’t do it, and really don’t want to.

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

I’m not going to get rich off Mike.

Of course, I’m not going to get rich off anyone, nor do I want to. I’m not here to rip anyone off.

Mike goes back with me, roughly 23 years.

He was born with cerebral palsy and refractory seizures. His birth mother gave him up quickly, and he was adopted by a couple who knew what they were getting into (to me that constitutes sainthood).

Over the years Mike has done his best to buck the odds. He’s tried to stay employed, in spite of his physical limitations, working variously as a janitor, grocery courtesy clerk, and store greeter. He tells me that he can still work and wants to, even with having to rely on public transportation.

By the time he came to me he’d been through several neurologists and even more failed epilepsy drugs. His brain MRI and EEGs showed multifocal seizures from numerous inoperable cortical heterotopias.

I dabbled with a few newer drugs at the time for him, without success. Finally, I reached for the neurological equivalent of unstable dynamite – Felbatol (felbamate).

As it often does, it worked. One of my attendings in training (you, Bob) told me it was the home-run drug. When nothing else worked, it might – but you had to handle it carefully.

Fortunately, after 23 years, that hasn’t happened. Mike’s labs have looked good. His seizures have dropped from several a week to a few per year.

Ten years ago Mike had to change insurance to one I don’t take, and had me forward his records to another neurologist. That office told him they don’t handle Felbatol. As did another. And another.

Mike, understandably, doesn’t want to change meds. This is the only drug that’s given him a decent quality of life, and let him have a job. That’s pretty important to him.

So, I see him for free now, once or twice a year. Sometimes he offers me a token payment of $5-$10, but I turn it down. He needs it more than I do, for bus fair to my office if nothing else.

I’m sure some would be critical of me, saying that I should be more open to new drugs and treatments. I am, believe me. But Mike can’t afford many of them, or the loss of work they’d entail if his seizures worsen. He doesn’t want to take that chance, and I don’t blame him.

Of course, none of us can see everyone for free. In fact, he’s the only one I do. I’m not greedy, but I also have to pay my rent, staff, and mortgage.

But taking money from Mike, who’s come up on the short end of the stick in so many ways, doesn’t seem right. I can’t do it, and really don’t want to.

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

A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.

While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.

I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.

With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.

I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.

Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.

Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?

The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.

Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.

While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.

I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.

With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.

I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.

Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.

Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?

The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.

Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.

While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.

I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.

With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.

I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.

Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.

Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?

The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.

Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Despite the ability of some couples to pull together and manage through the COVID-19 pandemic, other couples and families failed to thrive. Increasing divorce rates have been noted nationwide with many disagreements being specifically about COVID.¹

A review of over 1 million tweets, between April 12 and July 16, 2020, found an increase in calls to hotlines and increased reports of a variety of types of family violence. There were also more inquiries about social services for family violence, an increased presence from social movements, and more domestic violence-related news.²

The literature addressing family violence uses a variety of terms, so here are some definitions.

Domestic violence is defined as a pattern of behaviors used to gain or maintain power and control. Broadly speaking, domestic violence includes elder abuse, sibling abuse, child abuse, intimate partner abuse, parent abuse, and can also include people who don’t necessarily live together but who have an intimate relationship. Domestic violence centers use the Power and Control Wheel (see graphic) developed by the Domestic Abuse Intervention Project in Duluth, Minn., to describe how domestic violence occurs.

Intimate partner violence is more specific, referring to violence that happens between people in an ongoing or former intimate or romantic relationship, and is a subcategory of domestic violence.

Coercive control is the use of power for control and compliance. It is a dynamic and systematic process described in the top left corner of the Power and Control Wheel. Overt control occurs with the implication that “if you don’t follow the rules, I’ll kill you.” More subtle control is when obedience is forced through monopolizing resources, dictating preferred choices, microregulating a partner’s behavior, and deprivation of supports needed to exercise independent judgment.

Domestic Abuse Intervention Project

All interpersonal relationships have elements of persuasion and influence; however, the goal of coercive relationships is to maintain power and control. It is a dynamic of the relationship. Coercive control emphasizes the systematic, organized, multifaceted, and patterned nature of this interpersonal dynamic and can be considered to originate in the patriarchal dynamic where men control women.

Most professionals who work in this interdisciplinary area now refer to domestic violence as coercive control. Victimizers target women whom they sense they can control to get their own needs met. They are disinclined to invest in relationships with women who stress their own points of view, who do not readily accept blame when there is a disagreement, and who offer nurturing only when it is reciprocated.

In my office, if I think there are elements of coercion in a relationship, I bring out the Power and Control Wheel and the patient and I go over it. Good education is our responsibility. However, we all have met women who decide to stay in unhealthy relationships.
 

Assessing people who stay in coercive relationships

Fear

The most important first step is to assess safety. Are they afraid of increased violence if they challenge their partner? Restraining orders or other legal deterrents may not offer solace, as many women are clear that their spouse will come after them, if not tomorrow, then next week, or even next month. They are sure that they will not be safe.

In these cases, I go over safety steps with them so that if they decide to go, they will be prepared. I bring out the “safety box,” which includes the following action steps:

• Memorize important phone numbers of people to call in an emergency.
• If your children are old enough, teach them important phone numbers, including when to dial 911.
• If you can, open your own bank account.
• Stay in touch with friends. Get to know your neighbors. Don’t cut yourself off from people, even if you feel like you want to be alone.
• Rehearse your escape plan until you know it by heart.
• Leave a set of car keys, extra money, a change of clothes and copies of important documents with a trusted friend or relative: your own and your children’s birth certificates, children’s school and medical records, bank books, welfare identification, passport/green card, immigration papers, social security card, lease agreements or mortgage payment books, insurance papers, important addresses, and telephone numbers.
• Keep information about domestic violence in a safe place, where your abuser won’t find it, but where you can get it when you need to review it.

Some women may acknowledge that the risk of physical violence is not the determining factor in their decision to stay and have difficulty explaining why they choose to stay. I suggest that we then consider the following frames that have their origin in the study of the impact of trauma.
 

Shame

From this lens, abusive events are humiliating experiences, now represented as shame experiences. Humiliation and shame hide hostile feelings that the patient is not able to acknowledge.

“In shame, the self is the failure and others may reject or be critical of this exposed, flawed self.”³ Women will therefore remain attached to an abuser to avoid the exposure of their defective self.

Action steps: Empathic engagement and acknowledgment of shame and humiliation are key. For someone to overcome shame, they must face their sense of their defective self and have strategies to manage these feelings. The development of such strategies is the next step.
 

Trauma repetition and trauma bonding

Women subjected to domestic violence often respond with incapacitating traumatic syndromes. The concept of “trauma repetition” is suggested as a cause of vulnerability to repeated abuse, and “trauma bonding” is the term for the intense and tenacious bond that can form between abusers and victims.⁴

Trauma bonding implies that a sense of safety and closeness and secure attachment can only be reached through highly abusive engagement; anything else is experienced as “superficial, cold, or irrelevant.”⁵ Trauma bonding may have its origins in emotional neglect, according to self reports of 116 women.⁶Action steps: The literature on trauma is growing and many patients will benefit from good curated sources. Having a good list of books and website on hand is important. Discussion and exploration of the impact of trauma will be needed, and can be provided by someone who is available on a consistent and frequent basis. This work may be time consuming and difficult.
 

Some asides

1. Some psychiatrists proffer the explanation that these women who stay must be masochistic. The misogynistic concept of masochism still haunts the halls of psychiatry. It is usually offered as a way to dismiss these women’s concerns.

2. One of the obstacles to recognizing chronic mistreatment in relationships is that most abusive men simply “do not seem like abusers.” They have many good qualities, including times of kindness, warmth, and humor, especially in the initial period of a relationship. An abuser’s friends may think the world of him. He may have a successful work life and have no problems with drugs or alcohol. He may simply not fit anyone’s image of a cruel or intimidating person. So, when a woman feels her relationship spinning out of control, it may not occur to her that her partner is an abuser. Even if she does consider her partner to be overly controlling, others may question her perception.

3. Neutrality in family courts is systemic sexism/misogyny. When it comes to domestic violence, family courts tend to split the difference. Stephanie Brandt, MD, notes that even after decades, mental health professionals often have an extremely superficial and outdated view of what comprises domestic violence. The assumption that it is violence alone that matters has formed the basis of much clinical and legal confusion.⁷ As an analyst, she has gone against the grain of a favored neutrality and become active in the courts, noting the secondary victimization that occurs when a woman enters the legal system.

In summary, psychiatrists must reclaim our expertise in systemic dynamics and point out the role of systemic misogyny. Justices and other court officials need to be educated. Ideally, justice should be based on the equality of men and women in a society free of systemic misogyny. Unfortunately our society has not yet reached this position. In the meanwhile, we must think systemically about interpersonal dynamics. This is our lane. This should not be controversial.

Dr. Heru is professor of psychiatry at the University of Colorado at Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose. Contact Dr. Heru at [email protected]. Dr. Heru would like to thank Dr. Stephanie Brandt for discussing this topic with her and supporting this work.

References

1. Ellyatt H. Arguing with your partner over Covid? You’re not alone, with the pandemic straining many relationships. 2022 Jan 21. https://www.cnbc.com/2022/01/21/covid-has-put-pressures-and-strains-on-relationships.html

2. Xue J et al. J Med Internet Res. 2020 Nov 6;22(11):e24361. doi: 10.2196/24361.

3. Dorahy MJ. J Trauma Dissociation. 2017 May-Jun;18(3):383-96. doi: 10.1080/15299732.2017.1295422.

4. Dutton DG and Painter SL. Victimology. 1981 Jan;6(1):139-55.

5. Sachs A. J Trauma Dissociation. 2017 May-Jun;18(3):319-39. doi: 10.1080/15299732.2017.1295400.

6. Krüger C and Fletcher L. J Trauma Dissociation. 2017 May-Jun;18(3):356-72. doi: 10.1080/15299732.2017.1295420.

7. Brandt S and Rudden M. Int J Appl Psychoanal Studies. 2020 Sept;17(3):215-31. doi: 10.1002/aps.1671.








 

Despite the ability of some couples to pull together and manage through the COVID-19 pandemic, other couples and families failed to thrive. Increasing divorce rates have been noted nationwide with many disagreements being specifically about COVID.¹

A review of over 1 million tweets, between April 12 and July 16, 2020, found an increase in calls to hotlines and increased reports of a variety of types of family violence. There were also more inquiries about social services for family violence, an increased presence from social movements, and more domestic violence-related news.²

The literature addressing family violence uses a variety of terms, so here are some definitions.

Domestic violence is defined as a pattern of behaviors used to gain or maintain power and control. Broadly speaking, domestic violence includes elder abuse, sibling abuse, child abuse, intimate partner abuse, parent abuse, and can also include people who don’t necessarily live together but who have an intimate relationship. Domestic violence centers use the Power and Control Wheel (see graphic) developed by the Domestic Abuse Intervention Project in Duluth, Minn., to describe how domestic violence occurs.

Intimate partner violence is more specific, referring to violence that happens between people in an ongoing or former intimate or romantic relationship, and is a subcategory of domestic violence.

Coercive control is the use of power for control and compliance. It is a dynamic and systematic process described in the top left corner of the Power and Control Wheel. Overt control occurs with the implication that “if you don’t follow the rules, I’ll kill you.” More subtle control is when obedience is forced through monopolizing resources, dictating preferred choices, microregulating a partner’s behavior, and deprivation of supports needed to exercise independent judgment.

Domestic Abuse Intervention Project

All interpersonal relationships have elements of persuasion and influence; however, the goal of coercive relationships is to maintain power and control. It is a dynamic of the relationship. Coercive control emphasizes the systematic, organized, multifaceted, and patterned nature of this interpersonal dynamic and can be considered to originate in the patriarchal dynamic where men control women.

Most professionals who work in this interdisciplinary area now refer to domestic violence as coercive control. Victimizers target women whom they sense they can control to get their own needs met. They are disinclined to invest in relationships with women who stress their own points of view, who do not readily accept blame when there is a disagreement, and who offer nurturing only when it is reciprocated.

In my office, if I think there are elements of coercion in a relationship, I bring out the Power and Control Wheel and the patient and I go over it. Good education is our responsibility. However, we all have met women who decide to stay in unhealthy relationships.
 

Assessing people who stay in coercive relationships

Fear

The most important first step is to assess safety. Are they afraid of increased violence if they challenge their partner? Restraining orders or other legal deterrents may not offer solace, as many women are clear that their spouse will come after them, if not tomorrow, then next week, or even next month. They are sure that they will not be safe.

In these cases, I go over safety steps with them so that if they decide to go, they will be prepared. I bring out the “safety box,” which includes the following action steps:

• Memorize important phone numbers of people to call in an emergency.
• If your children are old enough, teach them important phone numbers, including when to dial 911.
• If you can, open your own bank account.
• Stay in touch with friends. Get to know your neighbors. Don’t cut yourself off from people, even if you feel like you want to be alone.
• Rehearse your escape plan until you know it by heart.
• Leave a set of car keys, extra money, a change of clothes and copies of important documents with a trusted friend or relative: your own and your children’s birth certificates, children’s school and medical records, bank books, welfare identification, passport/green card, immigration papers, social security card, lease agreements or mortgage payment books, insurance papers, important addresses, and telephone numbers.
• Keep information about domestic violence in a safe place, where your abuser won’t find it, but where you can get it when you need to review it.

Some women may acknowledge that the risk of physical violence is not the determining factor in their decision to stay and have difficulty explaining why they choose to stay. I suggest that we then consider the following frames that have their origin in the study of the impact of trauma.
 

Shame

From this lens, abusive events are humiliating experiences, now represented as shame experiences. Humiliation and shame hide hostile feelings that the patient is not able to acknowledge.

“In shame, the self is the failure and others may reject or be critical of this exposed, flawed self.”³ Women will therefore remain attached to an abuser to avoid the exposure of their defective self.

Action steps: Empathic engagement and acknowledgment of shame and humiliation are key. For someone to overcome shame, they must face their sense of their defective self and have strategies to manage these feelings. The development of such strategies is the next step.
 

Trauma repetition and trauma bonding

Women subjected to domestic violence often respond with incapacitating traumatic syndromes. The concept of “trauma repetition” is suggested as a cause of vulnerability to repeated abuse, and “trauma bonding” is the term for the intense and tenacious bond that can form between abusers and victims.⁴

Trauma bonding implies that a sense of safety and closeness and secure attachment can only be reached through highly abusive engagement; anything else is experienced as “superficial, cold, or irrelevant.”⁵ Trauma bonding may have its origins in emotional neglect, according to self reports of 116 women.⁶Action steps: The literature on trauma is growing and many patients will benefit from good curated sources. Having a good list of books and website on hand is important. Discussion and exploration of the impact of trauma will be needed, and can be provided by someone who is available on a consistent and frequent basis. This work may be time consuming and difficult.
 

Some asides

1. Some psychiatrists proffer the explanation that these women who stay must be masochistic. The misogynistic concept of masochism still haunts the halls of psychiatry. It is usually offered as a way to dismiss these women’s concerns.

2. One of the obstacles to recognizing chronic mistreatment in relationships is that most abusive men simply “do not seem like abusers.” They have many good qualities, including times of kindness, warmth, and humor, especially in the initial period of a relationship. An abuser’s friends may think the world of him. He may have a successful work life and have no problems with drugs or alcohol. He may simply not fit anyone’s image of a cruel or intimidating person. So, when a woman feels her relationship spinning out of control, it may not occur to her that her partner is an abuser. Even if she does consider her partner to be overly controlling, others may question her perception.

3. Neutrality in family courts is systemic sexism/misogyny. When it comes to domestic violence, family courts tend to split the difference. Stephanie Brandt, MD, notes that even after decades, mental health professionals often have an extremely superficial and outdated view of what comprises domestic violence. The assumption that it is violence alone that matters has formed the basis of much clinical and legal confusion.⁷ As an analyst, she has gone against the grain of a favored neutrality and become active in the courts, noting the secondary victimization that occurs when a woman enters the legal system.

In summary, psychiatrists must reclaim our expertise in systemic dynamics and point out the role of systemic misogyny. Justices and other court officials need to be educated. Ideally, justice should be based on the equality of men and women in a society free of systemic misogyny. Unfortunately our society has not yet reached this position. In the meanwhile, we must think systemically about interpersonal dynamics. This is our lane. This should not be controversial.

Dr. Heru is professor of psychiatry at the University of Colorado at Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose. Contact Dr. Heru at [email protected]. Dr. Heru would like to thank Dr. Stephanie Brandt for discussing this topic with her and supporting this work.

References

1. Ellyatt H. Arguing with your partner over Covid? You’re not alone, with the pandemic straining many relationships. 2022 Jan 21. https://www.cnbc.com/2022/01/21/covid-has-put-pressures-and-strains-on-relationships.html

2. Xue J et al. J Med Internet Res. 2020 Nov 6;22(11):e24361. doi: 10.2196/24361.

3. Dorahy MJ. J Trauma Dissociation. 2017 May-Jun;18(3):383-96. doi: 10.1080/15299732.2017.1295422.

4. Dutton DG and Painter SL. Victimology. 1981 Jan;6(1):139-55.

5. Sachs A. J Trauma Dissociation. 2017 May-Jun;18(3):319-39. doi: 10.1080/15299732.2017.1295400.

6. Krüger C and Fletcher L. J Trauma Dissociation. 2017 May-Jun;18(3):356-72. doi: 10.1080/15299732.2017.1295420.

7. Brandt S and Rudden M. Int J Appl Psychoanal Studies. 2020 Sept;17(3):215-31. doi: 10.1002/aps.1671.








 

Despite the ability of some couples to pull together and manage through the COVID-19 pandemic, other couples and families failed to thrive. Increasing divorce rates have been noted nationwide with many disagreements being specifically about COVID.¹

A review of over 1 million tweets, between April 12 and July 16, 2020, found an increase in calls to hotlines and increased reports of a variety of types of family violence. There were also more inquiries about social services for family violence, an increased presence from social movements, and more domestic violence-related news.²

The literature addressing family violence uses a variety of terms, so here are some definitions.

Domestic violence is defined as a pattern of behaviors used to gain or maintain power and control. Broadly speaking, domestic violence includes elder abuse, sibling abuse, child abuse, intimate partner abuse, parent abuse, and can also include people who don’t necessarily live together but who have an intimate relationship. Domestic violence centers use the Power and Control Wheel (see graphic) developed by the Domestic Abuse Intervention Project in Duluth, Minn., to describe how domestic violence occurs.

Intimate partner violence is more specific, referring to violence that happens between people in an ongoing or former intimate or romantic relationship, and is a subcategory of domestic violence.

Coercive control is the use of power for control and compliance. It is a dynamic and systematic process described in the top left corner of the Power and Control Wheel. Overt control occurs with the implication that “if you don’t follow the rules, I’ll kill you.” More subtle control is when obedience is forced through monopolizing resources, dictating preferred choices, microregulating a partner’s behavior, and deprivation of supports needed to exercise independent judgment.

Domestic Abuse Intervention Project

All interpersonal relationships have elements of persuasion and influence; however, the goal of coercive relationships is to maintain power and control. It is a dynamic of the relationship. Coercive control emphasizes the systematic, organized, multifaceted, and patterned nature of this interpersonal dynamic and can be considered to originate in the patriarchal dynamic where men control women.

Most professionals who work in this interdisciplinary area now refer to domestic violence as coercive control. Victimizers target women whom they sense they can control to get their own needs met. They are disinclined to invest in relationships with women who stress their own points of view, who do not readily accept blame when there is a disagreement, and who offer nurturing only when it is reciprocated.

In my office, if I think there are elements of coercion in a relationship, I bring out the Power and Control Wheel and the patient and I go over it. Good education is our responsibility. However, we all have met women who decide to stay in unhealthy relationships.
 

Assessing people who stay in coercive relationships

Fear

The most important first step is to assess safety. Are they afraid of increased violence if they challenge their partner? Restraining orders or other legal deterrents may not offer solace, as many women are clear that their spouse will come after them, if not tomorrow, then next week, or even next month. They are sure that they will not be safe.

In these cases, I go over safety steps with them so that if they decide to go, they will be prepared. I bring out the “safety box,” which includes the following action steps:

• Memorize important phone numbers of people to call in an emergency.
• If your children are old enough, teach them important phone numbers, including when to dial 911.
• If you can, open your own bank account.
• Stay in touch with friends. Get to know your neighbors. Don’t cut yourself off from people, even if you feel like you want to be alone.
• Rehearse your escape plan until you know it by heart.
• Leave a set of car keys, extra money, a change of clothes and copies of important documents with a trusted friend or relative: your own and your children’s birth certificates, children’s school and medical records, bank books, welfare identification, passport/green card, immigration papers, social security card, lease agreements or mortgage payment books, insurance papers, important addresses, and telephone numbers.
• Keep information about domestic violence in a safe place, where your abuser won’t find it, but where you can get it when you need to review it.

Some women may acknowledge that the risk of physical violence is not the determining factor in their decision to stay and have difficulty explaining why they choose to stay. I suggest that we then consider the following frames that have their origin in the study of the impact of trauma.
 

Shame

From this lens, abusive events are humiliating experiences, now represented as shame experiences. Humiliation and shame hide hostile feelings that the patient is not able to acknowledge.

“In shame, the self is the failure and others may reject or be critical of this exposed, flawed self.”³ Women will therefore remain attached to an abuser to avoid the exposure of their defective self.

Action steps: Empathic engagement and acknowledgment of shame and humiliation are key. For someone to overcome shame, they must face their sense of their defective self and have strategies to manage these feelings. The development of such strategies is the next step.
 

Trauma repetition and trauma bonding

Women subjected to domestic violence often respond with incapacitating traumatic syndromes. The concept of “trauma repetition” is suggested as a cause of vulnerability to repeated abuse, and “trauma bonding” is the term for the intense and tenacious bond that can form between abusers and victims.⁴

Trauma bonding implies that a sense of safety and closeness and secure attachment can only be reached through highly abusive engagement; anything else is experienced as “superficial, cold, or irrelevant.”⁵ Trauma bonding may have its origins in emotional neglect, according to self reports of 116 women.⁶Action steps: The literature on trauma is growing and many patients will benefit from good curated sources. Having a good list of books and website on hand is important. Discussion and exploration of the impact of trauma will be needed, and can be provided by someone who is available on a consistent and frequent basis. This work may be time consuming and difficult.
 

Some asides

1. Some psychiatrists proffer the explanation that these women who stay must be masochistic. The misogynistic concept of masochism still haunts the halls of psychiatry. It is usually offered as a way to dismiss these women’s concerns.

2. One of the obstacles to recognizing chronic mistreatment in relationships is that most abusive men simply “do not seem like abusers.” They have many good qualities, including times of kindness, warmth, and humor, especially in the initial period of a relationship. An abuser’s friends may think the world of him. He may have a successful work life and have no problems with drugs or alcohol. He may simply not fit anyone’s image of a cruel or intimidating person. So, when a woman feels her relationship spinning out of control, it may not occur to her that her partner is an abuser. Even if she does consider her partner to be overly controlling, others may question her perception.

3. Neutrality in family courts is systemic sexism/misogyny. When it comes to domestic violence, family courts tend to split the difference. Stephanie Brandt, MD, notes that even after decades, mental health professionals often have an extremely superficial and outdated view of what comprises domestic violence. The assumption that it is violence alone that matters has formed the basis of much clinical and legal confusion.⁷ As an analyst, she has gone against the grain of a favored neutrality and become active in the courts, noting the secondary victimization that occurs when a woman enters the legal system.

In summary, psychiatrists must reclaim our expertise in systemic dynamics and point out the role of systemic misogyny. Justices and other court officials need to be educated. Ideally, justice should be based on the equality of men and women in a society free of systemic misogyny. Unfortunately our society has not yet reached this position. In the meanwhile, we must think systemically about interpersonal dynamics. This is our lane. This should not be controversial.

Dr. Heru is professor of psychiatry at the University of Colorado at Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose. Contact Dr. Heru at [email protected]. Dr. Heru would like to thank Dr. Stephanie Brandt for discussing this topic with her and supporting this work.

References

1. Ellyatt H. Arguing with your partner over Covid? You’re not alone, with the pandemic straining many relationships. 2022 Jan 21. https://www.cnbc.com/2022/01/21/covid-has-put-pressures-and-strains-on-relationships.html

2. Xue J et al. J Med Internet Res. 2020 Nov 6;22(11):e24361. doi: 10.2196/24361.

3. Dorahy MJ. J Trauma Dissociation. 2017 May-Jun;18(3):383-96. doi: 10.1080/15299732.2017.1295422.

4. Dutton DG and Painter SL. Victimology. 1981 Jan;6(1):139-55.

5. Sachs A. J Trauma Dissociation. 2017 May-Jun;18(3):319-39. doi: 10.1080/15299732.2017.1295400.

6. Krüger C and Fletcher L. J Trauma Dissociation. 2017 May-Jun;18(3):356-72. doi: 10.1080/15299732.2017.1295420.

7. Brandt S and Rudden M. Int J Appl Psychoanal Studies. 2020 Sept;17(3):215-31. doi: 10.1002/aps.1671.








 

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript

Alcohol use disorder (AUD) is a chronic disease characterized by an impaired ability to control alcohol use that negatively impacts the social, occupational, and health aspects of patients’ lives.¹ It is the third leading modifiable cause of death in the United States.² About 50% of patients with AUD experience alcohol withdrawal syndrome (AWS) following abrupt cessation of alcohol use. AWS often presents with mild symptoms, such as headaches, nausea, vomiting, and anxiety. However, as many as 20% of patients experience severe and potentially life-threatening symptoms, such as tremors, delirium, hallucinations, and seizures within 48 hours of AWS onset.³

Benzodiazepines, such as lorazepam or chlordiazepoxide, are considered the gold standard for AWS.⁴ Benzodiazepines act by potentiation of γ-aminobutyric acid (GABA) receptors that produce inhibitory responses in the central nervous system (CNS). This mechanism is similar to the activity of ethanol, which acts primarily at the GABA-A receptors, resulting in facilitation of GABAergic transmission. The Clinical Institute Withdrawal Assessment (CIWA) of Alcohol scale is a commonly used tool to assess the severity of AWS and the appropriate dosing schedule of benzodiazepines.³ Multiple studies have demonstrated the superiority of using benzodiazepines, as they are beneficial for reducing withdrawal severity and incidence of delirium and seizures.^5,6

Although benzodiazepines are effective, they are associated with serious adverse effects (AEs), such as respiratory depression, excessive sedation, and abuse potential.⁴ Older patients are at higher risk of these AEs, particularly oversedation. In addition, sudden discontinuation of a benzodiazepine treatment can result in anxiety, irritability, and insomnia, which might worsen AWS.

Given the safety concerns of benzodiazepines, alternative treatments for AWS management have been investigated, including gabapentin. Previous studies have demonstrated gabapentin might be effective for mild-to-moderate AWS management.^7-9 Gabapentin exhibits its action by binding to the α2δ subunit of voltage-activated calcium channels with high affinity. Although the exact mechanism of action of gabapentin in AWS is unknown, it has been proposed that gabapentin normalizes GABA activation in the amygdala, which is associated with alcohol dependence.¹⁰ A systemic review conducted by Leung and colleagues found that gabapentin might be an option for the management of mild AWS.¹¹ However, current evidence does not support the use of gabapentin monotherapy in patients with severe AWS, a history of seizures, or those at risk of delirium tremens (DTs) since there is a higher chance of complications.

Baclofen is another medication investigated by researchers for use in patients with AWS. Baclofen works by activating the GABA-B receptor, which results in the downregulation of GABA-A activity. This results in a negative feedback loop leading to a decrease in excitatory neurotransmitters that is similar to the effect produced by alcohol.¹² However, there is limited evidence that baclofen is effective as monotherapy for the treatment of AWS. A Cochrane review previously evaluated baclofen use in AWS but found insufficient evidence of its efficacy and safety for this indication.¹³

Methods

We performed a retrospective cohort chart review at CJALFHCC. Data were collected from the facility’s electronic health record Computerized Patient Record System (CPRS). This study was approved by the Edward Hines Jr. Veterans Affairs Hospital Institutional Review Board.

Patient records were screened and included if they met the following criteria: (1) Patients aged ≥ 18 years who were hospitalized from January 1, 2014, to July 31, 2021, for the primary indication of AWS; (2) Patients who received a g/b or benzodiazepine protocol during AWS hospitalization. If a patient was admitted multiple times for AWS management, only the first admission was included for primary outcome analysis. Exclusion criteria were patients who were active-duty service members, discharged within 24 hours; patients with a primary seizure disorder; patients with known gabapentin, baclofen, or benzodiazepine allergy or intolerance. Patients who used gabapentin, baclofen, or benzodiazepines in an outpatient setting prior to AWS admission; had concurrent intoxication or overdose involving substances other than alcohol; had a concurrent regimen of gabapentin, baclofen, or benzodiazepines; or had initiation on adjuvant medications for AWS management (eg, divalproex, haloperidol, carbamazepine, or clonidine) also were excluded. Patients were categorized as those who received g/b as the initial therapy after admission or patients who received benzodiazepine therapy.

CPRS was used to collect information including baseline demographics, blood alcohol content, CIWA scores throughout hospitalization, number of admissions for alcohol detoxification in the previous year, AWS readmission within 30 days after discharge, prior treatment with g/b, history of alcohol withdrawal seizures and DTs, hospital LOS, outpatient medications for AUD treatment, rates of conversions from g/b protocol to lorazepam, and rates of transition to a higher level of care.

Statistical Analysis

Study data were stored and analyzed using an Excel spreadsheet and IBM SPSS Statistics software. LOS was compared between the g/b and benzodiazepine groups using inferential statistics. An independent 2-sample t test was used to assess the primary outcome if data were normally distributed. If the collected data were not distributed normally, the Mann-Whitney U test was used. All other continuous variables were assessed by using independent t tests and categorical variables by using χ² tests. A P value < .05 was considered statistically significant. Effect size of d = 0.42 was calculated based on a previous study with a similar research design as our study.⁹ We determined that if using an independent 2-sample t test for the primary outcome analysis, an estimated sample size of 178 subjects would provide the study with an 80% power to detect a difference at a 2-sided significance level with α = 0.05. If using the Mann-Whitney U test, 186 subjects would be required to provide identical power.

Results

We reviewed 196 patient health records, and 39 were initially excluded. The most common reason was that AWS was not the primary diagnosis for hospitalization (n = 28).

This retrospective chart review study found that LOS was shorter in patients with AWS treated with g/b compared with those treated with benzodiazepines, with no significant difference in safety outcomes such as seizures, DTs, or intensive care unit transfers. Although there was a statistically significant difference in the primary outcome between the 2 groups, it appears that patients on benzodiazepine therapy originally had more severe AWS presentation as their admission and maximum CIWA scores were statistically significantly higher compared with the g/b group. Thus, patients who were initially started on g/b had less serious AWS presentations. Based on this information we can conclude that the g/b combination may be an effective option for mild AWS management.

To our knowledge, this is the first study that has investigated the combination of g/b compared with benzodiazepines for AWS management in hospitalized patients. The research design of this project was adapted from the Bates and colleagues study that examined gabapentin monotherapy use for the treatment of patients hospitalized with AWS.⁹ We specifically used the primary outcome that they defined in their study since their LOS definition aimed to reflect clinically active withdrawal rather than simply hours of hospitalization, which would decrease the risk of confounding the primary outcome. The results of our research were similar to Bates and colleagues as they found that the gabapentin protocol appeared to be an effective and safe option compared with benzodiazepines for patients hospitalized with AWS.⁹

Limitations

This study has multiple limitations. As it was a retrospective chart review study, the data collection accuracy depends on accurate recordkeeping. Additionally, certain information was missing, such as CIWA scores for some patients. This study has limited external validity as most of the patients were older, White, and male, and the data collection was limited only to a single center. Therefore, it is uncertain whether the results of this study can be generalized to other populations. Also, this study had a small sample size, and we were not able to obtain the intended number of patients to achieve a power of 80%. Lastly, some background characteristics, such as admission and maximum CIWA scores, were not distributed equally between groups. Therefore, future studies are needed with a larger sample size that examine the LOS in the g/b group compared with the benzodiazepine group and in which CIWA scores are matched to reduce the effect of extraneous variables.

Conclusions

Gabapentin and baclofen combination seems to be an effective and safe alternative to benzodiazepines and may be considered for managing mild AWS in hospitalized patients, but additional research is needed to examine this regimen.

Acknowledgments

Research committee: Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, PharmD; Jennifer Kwon, PharmD, BCOP. Co-investigators: Zachary Rosenfeldt, PharmD, BCPS; Kaylee Caniff, PharmD, BCIDP.

Alcohol use disorder (AUD) is a chronic disease characterized by an impaired ability to control alcohol use that negatively impacts the social, occupational, and health aspects of patients’ lives.¹ It is the third leading modifiable cause of death in the United States.² About 50% of patients with AUD experience alcohol withdrawal syndrome (AWS) following abrupt cessation of alcohol use. AWS often presents with mild symptoms, such as headaches, nausea, vomiting, and anxiety. However, as many as 20% of patients experience severe and potentially life-threatening symptoms, such as tremors, delirium, hallucinations, and seizures within 48 hours of AWS onset.³

Benzodiazepines, such as lorazepam or chlordiazepoxide, are considered the gold standard for AWS.⁴ Benzodiazepines act by potentiation of γ-aminobutyric acid (GABA) receptors that produce inhibitory responses in the central nervous system (CNS). This mechanism is similar to the activity of ethanol, which acts primarily at the GABA-A receptors, resulting in facilitation of GABAergic transmission. The Clinical Institute Withdrawal Assessment (CIWA) of Alcohol scale is a commonly used tool to assess the severity of AWS and the appropriate dosing schedule of benzodiazepines.³ Multiple studies have demonstrated the superiority of using benzodiazepines, as they are beneficial for reducing withdrawal severity and incidence of delirium and seizures.^5,6

Although benzodiazepines are effective, they are associated with serious adverse effects (AEs), such as respiratory depression, excessive sedation, and abuse potential.⁴ Older patients are at higher risk of these AEs, particularly oversedation. In addition, sudden discontinuation of a benzodiazepine treatment can result in anxiety, irritability, and insomnia, which might worsen AWS.

Given the safety concerns of benzodiazepines, alternative treatments for AWS management have been investigated, including gabapentin. Previous studies have demonstrated gabapentin might be effective for mild-to-moderate AWS management.^7-9 Gabapentin exhibits its action by binding to the α2δ subunit of voltage-activated calcium channels with high affinity. Although the exact mechanism of action of gabapentin in AWS is unknown, it has been proposed that gabapentin normalizes GABA activation in the amygdala, which is associated with alcohol dependence.¹⁰ A systemic review conducted by Leung and colleagues found that gabapentin might be an option for the management of mild AWS.¹¹ However, current evidence does not support the use of gabapentin monotherapy in patients with severe AWS, a history of seizures, or those at risk of delirium tremens (DTs) since there is a higher chance of complications.

Baclofen is another medication investigated by researchers for use in patients with AWS. Baclofen works by activating the GABA-B receptor, which results in the downregulation of GABA-A activity. This results in a negative feedback loop leading to a decrease in excitatory neurotransmitters that is similar to the effect produced by alcohol.¹² However, there is limited evidence that baclofen is effective as monotherapy for the treatment of AWS. A Cochrane review previously evaluated baclofen use in AWS but found insufficient evidence of its efficacy and safety for this indication.¹³

Methods

We performed a retrospective cohort chart review at CJALFHCC. Data were collected from the facility’s electronic health record Computerized Patient Record System (CPRS). This study was approved by the Edward Hines Jr. Veterans Affairs Hospital Institutional Review Board.

Patient records were screened and included if they met the following criteria: (1) Patients aged ≥ 18 years who were hospitalized from January 1, 2014, to July 31, 2021, for the primary indication of AWS; (2) Patients who received a g/b or benzodiazepine protocol during AWS hospitalization. If a patient was admitted multiple times for AWS management, only the first admission was included for primary outcome analysis. Exclusion criteria were patients who were active-duty service members, discharged within 24 hours; patients with a primary seizure disorder; patients with known gabapentin, baclofen, or benzodiazepine allergy or intolerance. Patients who used gabapentin, baclofen, or benzodiazepines in an outpatient setting prior to AWS admission; had concurrent intoxication or overdose involving substances other than alcohol; had a concurrent regimen of gabapentin, baclofen, or benzodiazepines; or had initiation on adjuvant medications for AWS management (eg, divalproex, haloperidol, carbamazepine, or clonidine) also were excluded. Patients were categorized as those who received g/b as the initial therapy after admission or patients who received benzodiazepine therapy.

CPRS was used to collect information including baseline demographics, blood alcohol content, CIWA scores throughout hospitalization, number of admissions for alcohol detoxification in the previous year, AWS readmission within 30 days after discharge, prior treatment with g/b, history of alcohol withdrawal seizures and DTs, hospital LOS, outpatient medications for AUD treatment, rates of conversions from g/b protocol to lorazepam, and rates of transition to a higher level of care.

Statistical Analysis

Study data were stored and analyzed using an Excel spreadsheet and IBM SPSS Statistics software. LOS was compared between the g/b and benzodiazepine groups using inferential statistics. An independent 2-sample t test was used to assess the primary outcome if data were normally distributed. If the collected data were not distributed normally, the Mann-Whitney U test was used. All other continuous variables were assessed by using independent t tests and categorical variables by using χ² tests. A P value < .05 was considered statistically significant. Effect size of d = 0.42 was calculated based on a previous study with a similar research design as our study.⁹ We determined that if using an independent 2-sample t test for the primary outcome analysis, an estimated sample size of 178 subjects would provide the study with an 80% power to detect a difference at a 2-sided significance level with α = 0.05. If using the Mann-Whitney U test, 186 subjects would be required to provide identical power.

Results

We reviewed 196 patient health records, and 39 were initially excluded. The most common reason was that AWS was not the primary diagnosis for hospitalization (n = 28).

This retrospective chart review study found that LOS was shorter in patients with AWS treated with g/b compared with those treated with benzodiazepines, with no significant difference in safety outcomes such as seizures, DTs, or intensive care unit transfers. Although there was a statistically significant difference in the primary outcome between the 2 groups, it appears that patients on benzodiazepine therapy originally had more severe AWS presentation as their admission and maximum CIWA scores were statistically significantly higher compared with the g/b group. Thus, patients who were initially started on g/b had less serious AWS presentations. Based on this information we can conclude that the g/b combination may be an effective option for mild AWS management.

To our knowledge, this is the first study that has investigated the combination of g/b compared with benzodiazepines for AWS management in hospitalized patients. The research design of this project was adapted from the Bates and colleagues study that examined gabapentin monotherapy use for the treatment of patients hospitalized with AWS.⁹ We specifically used the primary outcome that they defined in their study since their LOS definition aimed to reflect clinically active withdrawal rather than simply hours of hospitalization, which would decrease the risk of confounding the primary outcome. The results of our research were similar to Bates and colleagues as they found that the gabapentin protocol appeared to be an effective and safe option compared with benzodiazepines for patients hospitalized with AWS.⁹

Limitations

This study has multiple limitations. As it was a retrospective chart review study, the data collection accuracy depends on accurate recordkeeping. Additionally, certain information was missing, such as CIWA scores for some patients. This study has limited external validity as most of the patients were older, White, and male, and the data collection was limited only to a single center. Therefore, it is uncertain whether the results of this study can be generalized to other populations. Also, this study had a small sample size, and we were not able to obtain the intended number of patients to achieve a power of 80%. Lastly, some background characteristics, such as admission and maximum CIWA scores, were not distributed equally between groups. Therefore, future studies are needed with a larger sample size that examine the LOS in the g/b group compared with the benzodiazepine group and in which CIWA scores are matched to reduce the effect of extraneous variables.

Conclusions

Gabapentin and baclofen combination seems to be an effective and safe alternative to benzodiazepines and may be considered for managing mild AWS in hospitalized patients, but additional research is needed to examine this regimen.

Acknowledgments

Research committee: Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, PharmD; Jennifer Kwon, PharmD, BCOP. Co-investigators: Zachary Rosenfeldt, PharmD, BCPS; Kaylee Caniff, PharmD, BCIDP.

Alcohol use disorder (AUD) is a chronic disease characterized by an impaired ability to control alcohol use that negatively impacts the social, occupational, and health aspects of patients’ lives.¹ It is the third leading modifiable cause of death in the United States.² About 50% of patients with AUD experience alcohol withdrawal syndrome (AWS) following abrupt cessation of alcohol use. AWS often presents with mild symptoms, such as headaches, nausea, vomiting, and anxiety. However, as many as 20% of patients experience severe and potentially life-threatening symptoms, such as tremors, delirium, hallucinations, and seizures within 48 hours of AWS onset.³

Benzodiazepines, such as lorazepam or chlordiazepoxide, are considered the gold standard for AWS.⁴ Benzodiazepines act by potentiation of γ-aminobutyric acid (GABA) receptors that produce inhibitory responses in the central nervous system (CNS). This mechanism is similar to the activity of ethanol, which acts primarily at the GABA-A receptors, resulting in facilitation of GABAergic transmission. The Clinical Institute Withdrawal Assessment (CIWA) of Alcohol scale is a commonly used tool to assess the severity of AWS and the appropriate dosing schedule of benzodiazepines.³ Multiple studies have demonstrated the superiority of using benzodiazepines, as they are beneficial for reducing withdrawal severity and incidence of delirium and seizures.^5,6

Although benzodiazepines are effective, they are associated with serious adverse effects (AEs), such as respiratory depression, excessive sedation, and abuse potential.⁴ Older patients are at higher risk of these AEs, particularly oversedation. In addition, sudden discontinuation of a benzodiazepine treatment can result in anxiety, irritability, and insomnia, which might worsen AWS.

Given the safety concerns of benzodiazepines, alternative treatments for AWS management have been investigated, including gabapentin. Previous studies have demonstrated gabapentin might be effective for mild-to-moderate AWS management.^7-9 Gabapentin exhibits its action by binding to the α2δ subunit of voltage-activated calcium channels with high affinity. Although the exact mechanism of action of gabapentin in AWS is unknown, it has been proposed that gabapentin normalizes GABA activation in the amygdala, which is associated with alcohol dependence.¹⁰ A systemic review conducted by Leung and colleagues found that gabapentin might be an option for the management of mild AWS.¹¹ However, current evidence does not support the use of gabapentin monotherapy in patients with severe AWS, a history of seizures, or those at risk of delirium tremens (DTs) since there is a higher chance of complications.

Baclofen is another medication investigated by researchers for use in patients with AWS. Baclofen works by activating the GABA-B receptor, which results in the downregulation of GABA-A activity. This results in a negative feedback loop leading to a decrease in excitatory neurotransmitters that is similar to the effect produced by alcohol.¹² However, there is limited evidence that baclofen is effective as monotherapy for the treatment of AWS. A Cochrane review previously evaluated baclofen use in AWS but found insufficient evidence of its efficacy and safety for this indication.¹³

Methods

We performed a retrospective cohort chart review at CJALFHCC. Data were collected from the facility’s electronic health record Computerized Patient Record System (CPRS). This study was approved by the Edward Hines Jr. Veterans Affairs Hospital Institutional Review Board.

Patient records were screened and included if they met the following criteria: (1) Patients aged ≥ 18 years who were hospitalized from January 1, 2014, to July 31, 2021, for the primary indication of AWS; (2) Patients who received a g/b or benzodiazepine protocol during AWS hospitalization. If a patient was admitted multiple times for AWS management, only the first admission was included for primary outcome analysis. Exclusion criteria were patients who were active-duty service members, discharged within 24 hours; patients with a primary seizure disorder; patients with known gabapentin, baclofen, or benzodiazepine allergy or intolerance. Patients who used gabapentin, baclofen, or benzodiazepines in an outpatient setting prior to AWS admission; had concurrent intoxication or overdose involving substances other than alcohol; had a concurrent regimen of gabapentin, baclofen, or benzodiazepines; or had initiation on adjuvant medications for AWS management (eg, divalproex, haloperidol, carbamazepine, or clonidine) also were excluded. Patients were categorized as those who received g/b as the initial therapy after admission or patients who received benzodiazepine therapy.

CPRS was used to collect information including baseline demographics, blood alcohol content, CIWA scores throughout hospitalization, number of admissions for alcohol detoxification in the previous year, AWS readmission within 30 days after discharge, prior treatment with g/b, history of alcohol withdrawal seizures and DTs, hospital LOS, outpatient medications for AUD treatment, rates of conversions from g/b protocol to lorazepam, and rates of transition to a higher level of care.

Statistical Analysis

Study data were stored and analyzed using an Excel spreadsheet and IBM SPSS Statistics software. LOS was compared between the g/b and benzodiazepine groups using inferential statistics. An independent 2-sample t test was used to assess the primary outcome if data were normally distributed. If the collected data were not distributed normally, the Mann-Whitney U test was used. All other continuous variables were assessed by using independent t tests and categorical variables by using χ² tests. A P value < .05 was considered statistically significant. Effect size of d = 0.42 was calculated based on a previous study with a similar research design as our study.⁹ We determined that if using an independent 2-sample t test for the primary outcome analysis, an estimated sample size of 178 subjects would provide the study with an 80% power to detect a difference at a 2-sided significance level with α = 0.05. If using the Mann-Whitney U test, 186 subjects would be required to provide identical power.

Results

We reviewed 196 patient health records, and 39 were initially excluded. The most common reason was that AWS was not the primary diagnosis for hospitalization (n = 28).

This retrospective chart review study found that LOS was shorter in patients with AWS treated with g/b compared with those treated with benzodiazepines, with no significant difference in safety outcomes such as seizures, DTs, or intensive care unit transfers. Although there was a statistically significant difference in the primary outcome between the 2 groups, it appears that patients on benzodiazepine therapy originally had more severe AWS presentation as their admission and maximum CIWA scores were statistically significantly higher compared with the g/b group. Thus, patients who were initially started on g/b had less serious AWS presentations. Based on this information we can conclude that the g/b combination may be an effective option for mild AWS management.

To our knowledge, this is the first study that has investigated the combination of g/b compared with benzodiazepines for AWS management in hospitalized patients. The research design of this project was adapted from the Bates and colleagues study that examined gabapentin monotherapy use for the treatment of patients hospitalized with AWS.⁹ We specifically used the primary outcome that they defined in their study since their LOS definition aimed to reflect clinically active withdrawal rather than simply hours of hospitalization, which would decrease the risk of confounding the primary outcome. The results of our research were similar to Bates and colleagues as they found that the gabapentin protocol appeared to be an effective and safe option compared with benzodiazepines for patients hospitalized with AWS.⁹

Limitations

This study has multiple limitations. As it was a retrospective chart review study, the data collection accuracy depends on accurate recordkeeping. Additionally, certain information was missing, such as CIWA scores for some patients. This study has limited external validity as most of the patients were older, White, and male, and the data collection was limited only to a single center. Therefore, it is uncertain whether the results of this study can be generalized to other populations. Also, this study had a small sample size, and we were not able to obtain the intended number of patients to achieve a power of 80%. Lastly, some background characteristics, such as admission and maximum CIWA scores, were not distributed equally between groups. Therefore, future studies are needed with a larger sample size that examine the LOS in the g/b group compared with the benzodiazepine group and in which CIWA scores are matched to reduce the effect of extraneous variables.

Conclusions

Gabapentin and baclofen combination seems to be an effective and safe alternative to benzodiazepines and may be considered for managing mild AWS in hospitalized patients, but additional research is needed to examine this regimen.

Acknowledgments

Research committee: Hong-Yen Vi, PharmD, BCPS; Shaiza Khan, PharmD, BCPS; Yinka Alaka, PharmD; Jennifer Kwon, PharmD, BCOP. Co-investigators: Zachary Rosenfeldt, PharmD, BCPS; Kaylee Caniff, PharmD, BCIDP.

Acute pain is a primary symptom for many patients who present to the emergency department (ED). The ED team is challenged with relieving pain while limiting harm from medications.¹ A 2017 National Health Interview Survey showed that compared with nonveterans, more veterans reported pain in the previous 3 months, and the rate of severe pain was 40% higher in the veteran group especially among those who served during the era of wars in Afghanistan and Iraq.²

The American College of Emergency Physicians guidelines pain management guidelines recommend patient-centered shared decision making that includes patient education about treatment goals and expectations, and short- and long-term risks, as well as a preference toward pharmacologic treatment with nonopioid analgesics except for patients with severe pain or pain refractory to other drug and treatment modalities.³ There is a lack of evidence regarding superior efficacy of either opioid or nonopioid analgesics; therefore, the use of nonopioid analgesics, such as oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) or central analgesics, such as acetaminophen, is preferred for treating acute pain to mitigate adverse effects (AEs) and risks associated with opioid use.^1,3,4 The US Department of Veterans Affairs (VA) and Department of Defense (DoD) guideline on managing opioid therapy for chronic pain, updated in 2017 and 2022, similarly recommends alternatives to opioids for mild-to-moderate acute pain and encourages multimodal pain care.⁵ However, use of other pharmacologic treatments, such as NSAIDs, is limited by AE profiles, patient contraindications, and severity of acute pain etiologies. There is a need for the expanded use of nonpharmacologic treatments for addressing pain in the veteran population.

The American College of Emergency Physicians guidelines recommend nonpharmacologic modalities, such as applying heat or cold, physical therapy, cognitive behavioral therapy, and acupuncture.³ A 2014 study reported that 37% to 46% of active duty and reserve military personnel use complementary and alternative medicine (CAM) for a variety of ailments, and there is increasing interest in the use of CAM as adjuncts to traditional therapies.⁶ According to one study, some CAM therapies are used significantly more by military personnel than used by civilians.⁷ However, the percentage of the veteran population using acupuncture in this study was small, and more information is needed to assess its use.

Auricular acupuncture originated in traditional Chinese medicine.⁸ Contemporary auricular acupuncture experts view this modality as a self-contained microsystem mapping portions of the ear to specific parts of the body and internal organs. The analgesic effects may be mediated through the central nervous system by local release of endorphins through nerve fiber activation and neurotransmitters—including serotonin, dopamine, and norepinephrine—leading to pre- and postsynaptic suppression of pain transmission.

Battlefield acupuncture (BFA) uses 5 set points anatomically located on each ear.⁹ Practitioners use small semipermanent, dartlike acupuncture needles. Patients could experience pain relief in a few minutes, which can last minutes, hours, days, weeks, or months depending on the pathology of the pain. This procedure developed in 2001 has been studied for different pain types and has shown benefit when used for postsurgical pain, chronic spinal cord injury−related neuropathic pain, and general chronic pain, as well as for other indications, such as insomnia, depression, and weight loss.^8,10-13 In 2018, a randomized controlled trial compared postintervention numeric rating scale (NRS) pain scores in patients presenting to the ED with acute or acute-on-chronic lower back pain who received BFA as an adjunct to standard care vs standard care alone.¹⁴ Patients receiving BFA as an adjunct to standard care were found to have mean postintervention pain scores 1.7 points lower than those receiving standard care alone. This study demonstrated that BFA was feasible and well tolerated for lower back pain in the ED as an adjunct to standard care. The study was limited by the adjunct use of BFA rather than as monotherapy and by the practitioners’ discretion regarding standard care, which was not defined by the study’s authors.

The Jesse Brown Veterans Affairs Medical Center (JBVAMC) in Chicago, Illinois, offers several CAM modalities, such as exercise/movement therapy, chiropractic, art/music therapy, and relaxation workshops, which are widely used by veterans. Recent evidence suggests BFA could reduce pain scores as an adjunct or an alternative to pharmacologic therapy. We are interested in how CAM therapies, such as BFA, can help avoid AEs associated with opioid or NSAID therapy.

At the JBVAMC ED, ketorolac 15 mg is the preferred first-line treatment of acute, noncancer pain, based on the results of previous studies. In 2018 BFA was offered first to veterans presenting with acute or acute-on-chronic pain to the ED; however, its effectiveness for pain reduction vs ketorolac has not been evaluated in this patient population. Limited literature is available on BFA and its use in the ED. To our knowledge, this was the first observational study assessing the difference between a single session of BFA vs a single dose of ketorolac in treating noncancer acute or acute-on-chronic pain in the ED.

Methods

This study was a retrospective chart review of patients who presented to the JBVAMC ED with acute pain or acute-on-chronic pain, who received ketorolac or BFA. The study population was generated from a list of all IV and intramuscular (IM) ketorolac unit dose orders verified from June 1, 2018, through August 30, 2019, and a list of all BFA procedure notes signed from June 1, 2018, through August 30, 2019. Patients were included in the study if they had documented administration of IV or IM ketorolac or BFA between June 1, 2018, and August 30, 2019. Patients who received ketorolac doses other than 15 mg, the intervention was administered outside of the ED, received adjunct treatment in addition to the treatment intervention in the ED, had no baseline NRS pain score documented before the intervention, had an NRS pain score of < 4, had no postintervention NRS pain score documented within 6 hours, had a treatment indication other than pain, or had active cancer were excluded. As in previous JBVAMC studies, we used NRS pain score cutoffs (mild, moderate, severe, and very severe) based on Woo and colleagues’ meta-analysis and excluded scores < 4.¹⁵

Endpoints

The primary endpoint was the mean difference in NRS pain score before and after the intervention, determined by comparing the NRS pain score documented at triage to the ED with the first documented NRS pain score at least 30 minutes to 6 hours after treatment administration. The secondary endpoints included the number of patients prescribed pain medication at discharge, the number of patients who were discharged with no medications, and the number of patients admitted to the hospital. The safety endpoint included any AEs of the intervention. Subgroup analyses were performed comparing the mean difference in NRS pain score among subgroups classified by severity of baseline NRS pain score and pain location.

Statistical Analysis

Baseline characteristics and endpoints were analyzed using descriptive statistics. Categorical data were analyzed using Fisher exact test and z test for proportions, and continuous data were compared using t test and paired t test. An 80% power calculation determined that 84 patients per group were needed to detect a statistically significant difference in pain score reduction of 1.3 at a type-1 error rate of 0.05. The sample size was based on a calculation performed in a previously published study that compared IV ketorolac at 3 single-dose regimens for treating acute pain in the ED.¹⁶ The 1.3 pain score reduction is considered the minimum clinically significant difference in pain that could be detected with the NRS.¹⁷

Results

Sixty-one patients received BFA during the study period: 31 were excluded (26 received adjunct treatment in the ED, 2 had active cancer documented, 2 had an indication other than pain, and 1 received BFA outside of the ED), leaving 30 patients in the BFA cohort. During the study period, 1299 patients received ketorolac. These patients were selected using a random number generator and then screened to determine inclusion or exclusion in the study. We continued to randomly select patients for the ketorolac group until we had a similar number in each treatment group. Of these 148 patients who were randomly selected to be reviewed, 116 were excluded: 48 received adjunct treatment in the ED, 24 had no postintervention NRS pain score documented within 6 hours, 18 received ketorolac doses other than 15 mg, 12 received ketorolac outside the ED, 9 had no baseline NRS pain score documented, 3 presented with a NRS pain score of ≤ 3, and 2 had active cancer documented. The ketorolac cohort comprised 31 patients.

Baseline characteristics were similar between the 2 groups except for the average baseline NRS pain score, which was statistically significantly higher in the BFA vs ketorolac group (8.7 vs 7.7, respectively; P = .02). The mean age was 51 years in the BFA group and 48 years in the ketorolac group. Most patients in each cohort were male: 80% in the BFA group and 71% in the ketorolac group. The most common types of pain documented as the chief ED presentation included back, lower extremity, and head.

Endpoints

The mean difference in NRS pain score was 3.9 for the BFA group and 5.1 for the ketorolac group. Both were clinically and statistically significant reductions (P = .03 and P < .01), but the difference between the intervention groups in NRS score reduction was not statistically significant (P = .07).

For the secondary endpoint of outpatient prescriptions written at discharge, there was no significant difference between the groups except for oral NSAIDs, which were more likely to be prescribed to patients who received ketorolac (P = .01).

Subgroup Analysis

An analysis was performed for subgroups classified by baseline NRS pain score (mild: 4; moderate, 5 - 6; severe, 7 - 9; and very severe, 10). Data for mild pain was limited because a small number of patients received interventions. For moderate pain, the mean difference in NRS pain score for BFA and ketorolac was 3.5 and 3.8, respectively; for severe pain, 3.4 and 5.3; and for very severe pain, 4.6 and 6.4. There was a larger difference in the preintervention and postintervention NRS pain scores within severe pain and very severe pain groups.

Discussion

Both interventions resulted in a significant reduction in the mean NRS pain score of about 4 to 5 points within their group, and BFA resulted in a similar NRS pain score reduction compared with ketorolac 15 mg. Because the baseline NRS pain scores were significantly different between the BFA and ketorolac groups, a subgroup analysis revealed that BFA reduced mean NRS pain score in patients with severe and very severe pain but appears to be less beneficial for moderate pain, unlike the ketorolac results that showed a large reduction in all pain groups except for the small sample of patients with mild pain.

In this study, more patients in the BFA group presented to the ED with lower extremity pain, such as gout or neuropathy, compared with the ketorolac group; however, BFA did not result in a significantly different pain score reduction in this subgroup compared with ketorolac. Patients receiving BFA were more likely to receive topical analgesics or muscle relaxants at discharge; whereas those receiving ketorolac were significantly more likely to receive oral NSAIDs. Patients in this study also were more likely to be admitted to the hospital if they received ketorolac; however, for these patients, pain was secondary to their chief presentation, and the admitting physician’s familiarity with ketorolac might have been the reason for choosing this intervention. Reasons for the admissions were surgical observation, psychiatric stabilization, kidney/gallstones, rule out of acute coronary syndrome, pneumonia, and proctitis in the ketorolac group, and suicidal ideations in the BFA group.

Limitations

As a limited number of patients received BFA at JBVAMC, the study was not sufficiently powered to detect a difference in the primary outcome. Because BFA required a consultation to be entered in the electronic health record, in addition to time needed to perform the procedure, practitioners might have preferred IV/IM ketorolac during busy times in the ED, potentially leading to underrepresentation in the BFA group. Prescribing preferences might have differed among the rotating physicians, timing of the documentation of the NRS pain score could have differed based on the treatment intervention, and the investigators were unable to control or accurately assess whether patients had taken an analgesic medication before presenting to the ED. Because pain and the treating physician are subjective, patients who reported a higher baseline pain severity might have been more likely to be discharged with topical analgesics or muscle relaxants. One way to correct for this subjectivity would be to conduct a larger prospective trial with a single treating physician. Finally, ED encounters in this study were short, and there was no follow-up permitting identification of AEs.

Conclusions

NRS pain score reduction with BFA did not differ compared with ketorolac 15 mg for treating acute and acute-on-chronic pain in the ED. Although this study was underpowered, these results add to the limited existing literature, suggesting that both interventions could result in clinically significant pain score reductions for patients presenting to the ED with severe and very severe pain, making BFA a viable nonpharmacologic option. Future studies could include investigating the benefit of BFA in the veteran population by studying larger samples in the ED, surveying patients after their interventions to identify rates AEs, and exploring the use of BFA for chronic pain in the outpatient setting.

Acute pain is a primary symptom for many patients who present to the emergency department (ED). The ED team is challenged with relieving pain while limiting harm from medications.¹ A 2017 National Health Interview Survey showed that compared with nonveterans, more veterans reported pain in the previous 3 months, and the rate of severe pain was 40% higher in the veteran group especially among those who served during the era of wars in Afghanistan and Iraq.²

The American College of Emergency Physicians guidelines pain management guidelines recommend patient-centered shared decision making that includes patient education about treatment goals and expectations, and short- and long-term risks, as well as a preference toward pharmacologic treatment with nonopioid analgesics except for patients with severe pain or pain refractory to other drug and treatment modalities.³ There is a lack of evidence regarding superior efficacy of either opioid or nonopioid analgesics; therefore, the use of nonopioid analgesics, such as oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) or central analgesics, such as acetaminophen, is preferred for treating acute pain to mitigate adverse effects (AEs) and risks associated with opioid use.^1,3,4 The US Department of Veterans Affairs (VA) and Department of Defense (DoD) guideline on managing opioid therapy for chronic pain, updated in 2017 and 2022, similarly recommends alternatives to opioids for mild-to-moderate acute pain and encourages multimodal pain care.⁵ However, use of other pharmacologic treatments, such as NSAIDs, is limited by AE profiles, patient contraindications, and severity of acute pain etiologies. There is a need for the expanded use of nonpharmacologic treatments for addressing pain in the veteran population.

The American College of Emergency Physicians guidelines recommend nonpharmacologic modalities, such as applying heat or cold, physical therapy, cognitive behavioral therapy, and acupuncture.³ A 2014 study reported that 37% to 46% of active duty and reserve military personnel use complementary and alternative medicine (CAM) for a variety of ailments, and there is increasing interest in the use of CAM as adjuncts to traditional therapies.⁶ According to one study, some CAM therapies are used significantly more by military personnel than used by civilians.⁷ However, the percentage of the veteran population using acupuncture in this study was small, and more information is needed to assess its use.

Auricular acupuncture originated in traditional Chinese medicine.⁸ Contemporary auricular acupuncture experts view this modality as a self-contained microsystem mapping portions of the ear to specific parts of the body and internal organs. The analgesic effects may be mediated through the central nervous system by local release of endorphins through nerve fiber activation and neurotransmitters—including serotonin, dopamine, and norepinephrine—leading to pre- and postsynaptic suppression of pain transmission.

Battlefield acupuncture (BFA) uses 5 set points anatomically located on each ear.⁹ Practitioners use small semipermanent, dartlike acupuncture needles. Patients could experience pain relief in a few minutes, which can last minutes, hours, days, weeks, or months depending on the pathology of the pain. This procedure developed in 2001 has been studied for different pain types and has shown benefit when used for postsurgical pain, chronic spinal cord injury−related neuropathic pain, and general chronic pain, as well as for other indications, such as insomnia, depression, and weight loss.^8,10-13 In 2018, a randomized controlled trial compared postintervention numeric rating scale (NRS) pain scores in patients presenting to the ED with acute or acute-on-chronic lower back pain who received BFA as an adjunct to standard care vs standard care alone.¹⁴ Patients receiving BFA as an adjunct to standard care were found to have mean postintervention pain scores 1.7 points lower than those receiving standard care alone. This study demonstrated that BFA was feasible and well tolerated for lower back pain in the ED as an adjunct to standard care. The study was limited by the adjunct use of BFA rather than as monotherapy and by the practitioners’ discretion regarding standard care, which was not defined by the study’s authors.

The Jesse Brown Veterans Affairs Medical Center (JBVAMC) in Chicago, Illinois, offers several CAM modalities, such as exercise/movement therapy, chiropractic, art/music therapy, and relaxation workshops, which are widely used by veterans. Recent evidence suggests BFA could reduce pain scores as an adjunct or an alternative to pharmacologic therapy. We are interested in how CAM therapies, such as BFA, can help avoid AEs associated with opioid or NSAID therapy.

At the JBVAMC ED, ketorolac 15 mg is the preferred first-line treatment of acute, noncancer pain, based on the results of previous studies. In 2018 BFA was offered first to veterans presenting with acute or acute-on-chronic pain to the ED; however, its effectiveness for pain reduction vs ketorolac has not been evaluated in this patient population. Limited literature is available on BFA and its use in the ED. To our knowledge, this was the first observational study assessing the difference between a single session of BFA vs a single dose of ketorolac in treating noncancer acute or acute-on-chronic pain in the ED.

Methods

This study was a retrospective chart review of patients who presented to the JBVAMC ED with acute pain or acute-on-chronic pain, who received ketorolac or BFA. The study population was generated from a list of all IV and intramuscular (IM) ketorolac unit dose orders verified from June 1, 2018, through August 30, 2019, and a list of all BFA procedure notes signed from June 1, 2018, through August 30, 2019. Patients were included in the study if they had documented administration of IV or IM ketorolac or BFA between June 1, 2018, and August 30, 2019. Patients who received ketorolac doses other than 15 mg, the intervention was administered outside of the ED, received adjunct treatment in addition to the treatment intervention in the ED, had no baseline NRS pain score documented before the intervention, had an NRS pain score of < 4, had no postintervention NRS pain score documented within 6 hours, had a treatment indication other than pain, or had active cancer were excluded. As in previous JBVAMC studies, we used NRS pain score cutoffs (mild, moderate, severe, and very severe) based on Woo and colleagues’ meta-analysis and excluded scores < 4.¹⁵

Endpoints

The primary endpoint was the mean difference in NRS pain score before and after the intervention, determined by comparing the NRS pain score documented at triage to the ED with the first documented NRS pain score at least 30 minutes to 6 hours after treatment administration. The secondary endpoints included the number of patients prescribed pain medication at discharge, the number of patients who were discharged with no medications, and the number of patients admitted to the hospital. The safety endpoint included any AEs of the intervention. Subgroup analyses were performed comparing the mean difference in NRS pain score among subgroups classified by severity of baseline NRS pain score and pain location.

Statistical Analysis

Baseline characteristics and endpoints were analyzed using descriptive statistics. Categorical data were analyzed using Fisher exact test and z test for proportions, and continuous data were compared using t test and paired t test. An 80% power calculation determined that 84 patients per group were needed to detect a statistically significant difference in pain score reduction of 1.3 at a type-1 error rate of 0.05. The sample size was based on a calculation performed in a previously published study that compared IV ketorolac at 3 single-dose regimens for treating acute pain in the ED.¹⁶ The 1.3 pain score reduction is considered the minimum clinically significant difference in pain that could be detected with the NRS.¹⁷

Results

Sixty-one patients received BFA during the study period: 31 were excluded (26 received adjunct treatment in the ED, 2 had active cancer documented, 2 had an indication other than pain, and 1 received BFA outside of the ED), leaving 30 patients in the BFA cohort. During the study period, 1299 patients received ketorolac. These patients were selected using a random number generator and then screened to determine inclusion or exclusion in the study. We continued to randomly select patients for the ketorolac group until we had a similar number in each treatment group. Of these 148 patients who were randomly selected to be reviewed, 116 were excluded: 48 received adjunct treatment in the ED, 24 had no postintervention NRS pain score documented within 6 hours, 18 received ketorolac doses other than 15 mg, 12 received ketorolac outside the ED, 9 had no baseline NRS pain score documented, 3 presented with a NRS pain score of ≤ 3, and 2 had active cancer documented. The ketorolac cohort comprised 31 patients.

Baseline characteristics were similar between the 2 groups except for the average baseline NRS pain score, which was statistically significantly higher in the BFA vs ketorolac group (8.7 vs 7.7, respectively; P = .02). The mean age was 51 years in the BFA group and 48 years in the ketorolac group. Most patients in each cohort were male: 80% in the BFA group and 71% in the ketorolac group. The most common types of pain documented as the chief ED presentation included back, lower extremity, and head.

Endpoints

The mean difference in NRS pain score was 3.9 for the BFA group and 5.1 for the ketorolac group. Both were clinically and statistically significant reductions (P = .03 and P < .01), but the difference between the intervention groups in NRS score reduction was not statistically significant (P = .07).

For the secondary endpoint of outpatient prescriptions written at discharge, there was no significant difference between the groups except for oral NSAIDs, which were more likely to be prescribed to patients who received ketorolac (P = .01).

Subgroup Analysis

An analysis was performed for subgroups classified by baseline NRS pain score (mild: 4; moderate, 5 - 6; severe, 7 - 9; and very severe, 10). Data for mild pain was limited because a small number of patients received interventions. For moderate pain, the mean difference in NRS pain score for BFA and ketorolac was 3.5 and 3.8, respectively; for severe pain, 3.4 and 5.3; and for very severe pain, 4.6 and 6.4. There was a larger difference in the preintervention and postintervention NRS pain scores within severe pain and very severe pain groups.

Discussion

Both interventions resulted in a significant reduction in the mean NRS pain score of about 4 to 5 points within their group, and BFA resulted in a similar NRS pain score reduction compared with ketorolac 15 mg. Because the baseline NRS pain scores were significantly different between the BFA and ketorolac groups, a subgroup analysis revealed that BFA reduced mean NRS pain score in patients with severe and very severe pain but appears to be less beneficial for moderate pain, unlike the ketorolac results that showed a large reduction in all pain groups except for the small sample of patients with mild pain.

In this study, more patients in the BFA group presented to the ED with lower extremity pain, such as gout or neuropathy, compared with the ketorolac group; however, BFA did not result in a significantly different pain score reduction in this subgroup compared with ketorolac. Patients receiving BFA were more likely to receive topical analgesics or muscle relaxants at discharge; whereas those receiving ketorolac were significantly more likely to receive oral NSAIDs. Patients in this study also were more likely to be admitted to the hospital if they received ketorolac; however, for these patients, pain was secondary to their chief presentation, and the admitting physician’s familiarity with ketorolac might have been the reason for choosing this intervention. Reasons for the admissions were surgical observation, psychiatric stabilization, kidney/gallstones, rule out of acute coronary syndrome, pneumonia, and proctitis in the ketorolac group, and suicidal ideations in the BFA group.

Limitations

As a limited number of patients received BFA at JBVAMC, the study was not sufficiently powered to detect a difference in the primary outcome. Because BFA required a consultation to be entered in the electronic health record, in addition to time needed to perform the procedure, practitioners might have preferred IV/IM ketorolac during busy times in the ED, potentially leading to underrepresentation in the BFA group. Prescribing preferences might have differed among the rotating physicians, timing of the documentation of the NRS pain score could have differed based on the treatment intervention, and the investigators were unable to control or accurately assess whether patients had taken an analgesic medication before presenting to the ED. Because pain and the treating physician are subjective, patients who reported a higher baseline pain severity might have been more likely to be discharged with topical analgesics or muscle relaxants. One way to correct for this subjectivity would be to conduct a larger prospective trial with a single treating physician. Finally, ED encounters in this study were short, and there was no follow-up permitting identification of AEs.

Conclusions

NRS pain score reduction with BFA did not differ compared with ketorolac 15 mg for treating acute and acute-on-chronic pain in the ED. Although this study was underpowered, these results add to the limited existing literature, suggesting that both interventions could result in clinically significant pain score reductions for patients presenting to the ED with severe and very severe pain, making BFA a viable nonpharmacologic option. Future studies could include investigating the benefit of BFA in the veteran population by studying larger samples in the ED, surveying patients after their interventions to identify rates AEs, and exploring the use of BFA for chronic pain in the outpatient setting.

Acute pain is a primary symptom for many patients who present to the emergency department (ED). The ED team is challenged with relieving pain while limiting harm from medications.¹ A 2017 National Health Interview Survey showed that compared with nonveterans, more veterans reported pain in the previous 3 months, and the rate of severe pain was 40% higher in the veteran group especially among those who served during the era of wars in Afghanistan and Iraq.²

The American College of Emergency Physicians guidelines pain management guidelines recommend patient-centered shared decision making that includes patient education about treatment goals and expectations, and short- and long-term risks, as well as a preference toward pharmacologic treatment with nonopioid analgesics except for patients with severe pain or pain refractory to other drug and treatment modalities.³ There is a lack of evidence regarding superior efficacy of either opioid or nonopioid analgesics; therefore, the use of nonopioid analgesics, such as oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) or central analgesics, such as acetaminophen, is preferred for treating acute pain to mitigate adverse effects (AEs) and risks associated with opioid use.^1,3,4 The US Department of Veterans Affairs (VA) and Department of Defense (DoD) guideline on managing opioid therapy for chronic pain, updated in 2017 and 2022, similarly recommends alternatives to opioids for mild-to-moderate acute pain and encourages multimodal pain care.⁵ However, use of other pharmacologic treatments, such as NSAIDs, is limited by AE profiles, patient contraindications, and severity of acute pain etiologies. There is a need for the expanded use of nonpharmacologic treatments for addressing pain in the veteran population.

The American College of Emergency Physicians guidelines recommend nonpharmacologic modalities, such as applying heat or cold, physical therapy, cognitive behavioral therapy, and acupuncture.³ A 2014 study reported that 37% to 46% of active duty and reserve military personnel use complementary and alternative medicine (CAM) for a variety of ailments, and there is increasing interest in the use of CAM as adjuncts to traditional therapies.⁶ According to one study, some CAM therapies are used significantly more by military personnel than used by civilians.⁷ However, the percentage of the veteran population using acupuncture in this study was small, and more information is needed to assess its use.

Auricular acupuncture originated in traditional Chinese medicine.⁸ Contemporary auricular acupuncture experts view this modality as a self-contained microsystem mapping portions of the ear to specific parts of the body and internal organs. The analgesic effects may be mediated through the central nervous system by local release of endorphins through nerve fiber activation and neurotransmitters—including serotonin, dopamine, and norepinephrine—leading to pre- and postsynaptic suppression of pain transmission.

Battlefield acupuncture (BFA) uses 5 set points anatomically located on each ear.⁹ Practitioners use small semipermanent, dartlike acupuncture needles. Patients could experience pain relief in a few minutes, which can last minutes, hours, days, weeks, or months depending on the pathology of the pain. This procedure developed in 2001 has been studied for different pain types and has shown benefit when used for postsurgical pain, chronic spinal cord injury−related neuropathic pain, and general chronic pain, as well as for other indications, such as insomnia, depression, and weight loss.^8,10-13 In 2018, a randomized controlled trial compared postintervention numeric rating scale (NRS) pain scores in patients presenting to the ED with acute or acute-on-chronic lower back pain who received BFA as an adjunct to standard care vs standard care alone.¹⁴ Patients receiving BFA as an adjunct to standard care were found to have mean postintervention pain scores 1.7 points lower than those receiving standard care alone. This study demonstrated that BFA was feasible and well tolerated for lower back pain in the ED as an adjunct to standard care. The study was limited by the adjunct use of BFA rather than as monotherapy and by the practitioners’ discretion regarding standard care, which was not defined by the study’s authors.

The Jesse Brown Veterans Affairs Medical Center (JBVAMC) in Chicago, Illinois, offers several CAM modalities, such as exercise/movement therapy, chiropractic, art/music therapy, and relaxation workshops, which are widely used by veterans. Recent evidence suggests BFA could reduce pain scores as an adjunct or an alternative to pharmacologic therapy. We are interested in how CAM therapies, such as BFA, can help avoid AEs associated with opioid or NSAID therapy.

At the JBVAMC ED, ketorolac 15 mg is the preferred first-line treatment of acute, noncancer pain, based on the results of previous studies. In 2018 BFA was offered first to veterans presenting with acute or acute-on-chronic pain to the ED; however, its effectiveness for pain reduction vs ketorolac has not been evaluated in this patient population. Limited literature is available on BFA and its use in the ED. To our knowledge, this was the first observational study assessing the difference between a single session of BFA vs a single dose of ketorolac in treating noncancer acute or acute-on-chronic pain in the ED.

Methods

This study was a retrospective chart review of patients who presented to the JBVAMC ED with acute pain or acute-on-chronic pain, who received ketorolac or BFA. The study population was generated from a list of all IV and intramuscular (IM) ketorolac unit dose orders verified from June 1, 2018, through August 30, 2019, and a list of all BFA procedure notes signed from June 1, 2018, through August 30, 2019. Patients were included in the study if they had documented administration of IV or IM ketorolac or BFA between June 1, 2018, and August 30, 2019. Patients who received ketorolac doses other than 15 mg, the intervention was administered outside of the ED, received adjunct treatment in addition to the treatment intervention in the ED, had no baseline NRS pain score documented before the intervention, had an NRS pain score of < 4, had no postintervention NRS pain score documented within 6 hours, had a treatment indication other than pain, or had active cancer were excluded. As in previous JBVAMC studies, we used NRS pain score cutoffs (mild, moderate, severe, and very severe) based on Woo and colleagues’ meta-analysis and excluded scores < 4.¹⁵

Endpoints

The primary endpoint was the mean difference in NRS pain score before and after the intervention, determined by comparing the NRS pain score documented at triage to the ED with the first documented NRS pain score at least 30 minutes to 6 hours after treatment administration. The secondary endpoints included the number of patients prescribed pain medication at discharge, the number of patients who were discharged with no medications, and the number of patients admitted to the hospital. The safety endpoint included any AEs of the intervention. Subgroup analyses were performed comparing the mean difference in NRS pain score among subgroups classified by severity of baseline NRS pain score and pain location.

Statistical Analysis

Baseline characteristics and endpoints were analyzed using descriptive statistics. Categorical data were analyzed using Fisher exact test and z test for proportions, and continuous data were compared using t test and paired t test. An 80% power calculation determined that 84 patients per group were needed to detect a statistically significant difference in pain score reduction of 1.3 at a type-1 error rate of 0.05. The sample size was based on a calculation performed in a previously published study that compared IV ketorolac at 3 single-dose regimens for treating acute pain in the ED.¹⁶ The 1.3 pain score reduction is considered the minimum clinically significant difference in pain that could be detected with the NRS.¹⁷

Results

Sixty-one patients received BFA during the study period: 31 were excluded (26 received adjunct treatment in the ED, 2 had active cancer documented, 2 had an indication other than pain, and 1 received BFA outside of the ED), leaving 30 patients in the BFA cohort. During the study period, 1299 patients received ketorolac. These patients were selected using a random number generator and then screened to determine inclusion or exclusion in the study. We continued to randomly select patients for the ketorolac group until we had a similar number in each treatment group. Of these 148 patients who were randomly selected to be reviewed, 116 were excluded: 48 received adjunct treatment in the ED, 24 had no postintervention NRS pain score documented within 6 hours, 18 received ketorolac doses other than 15 mg, 12 received ketorolac outside the ED, 9 had no baseline NRS pain score documented, 3 presented with a NRS pain score of ≤ 3, and 2 had active cancer documented. The ketorolac cohort comprised 31 patients.

Baseline characteristics were similar between the 2 groups except for the average baseline NRS pain score, which was statistically significantly higher in the BFA vs ketorolac group (8.7 vs 7.7, respectively; P = .02). The mean age was 51 years in the BFA group and 48 years in the ketorolac group. Most patients in each cohort were male: 80% in the BFA group and 71% in the ketorolac group. The most common types of pain documented as the chief ED presentation included back, lower extremity, and head.

Endpoints

The mean difference in NRS pain score was 3.9 for the BFA group and 5.1 for the ketorolac group. Both were clinically and statistically significant reductions (P = .03 and P < .01), but the difference between the intervention groups in NRS score reduction was not statistically significant (P = .07).

For the secondary endpoint of outpatient prescriptions written at discharge, there was no significant difference between the groups except for oral NSAIDs, which were more likely to be prescribed to patients who received ketorolac (P = .01).

Subgroup Analysis

An analysis was performed for subgroups classified by baseline NRS pain score (mild: 4; moderate, 5 - 6; severe, 7 - 9; and very severe, 10). Data for mild pain was limited because a small number of patients received interventions. For moderate pain, the mean difference in NRS pain score for BFA and ketorolac was 3.5 and 3.8, respectively; for severe pain, 3.4 and 5.3; and for very severe pain, 4.6 and 6.4. There was a larger difference in the preintervention and postintervention NRS pain scores within severe pain and very severe pain groups.

Discussion

Both interventions resulted in a significant reduction in the mean NRS pain score of about 4 to 5 points within their group, and BFA resulted in a similar NRS pain score reduction compared with ketorolac 15 mg. Because the baseline NRS pain scores were significantly different between the BFA and ketorolac groups, a subgroup analysis revealed that BFA reduced mean NRS pain score in patients with severe and very severe pain but appears to be less beneficial for moderate pain, unlike the ketorolac results that showed a large reduction in all pain groups except for the small sample of patients with mild pain.

In this study, more patients in the BFA group presented to the ED with lower extremity pain, such as gout or neuropathy, compared with the ketorolac group; however, BFA did not result in a significantly different pain score reduction in this subgroup compared with ketorolac. Patients receiving BFA were more likely to receive topical analgesics or muscle relaxants at discharge; whereas those receiving ketorolac were significantly more likely to receive oral NSAIDs. Patients in this study also were more likely to be admitted to the hospital if they received ketorolac; however, for these patients, pain was secondary to their chief presentation, and the admitting physician’s familiarity with ketorolac might have been the reason for choosing this intervention. Reasons for the admissions were surgical observation, psychiatric stabilization, kidney/gallstones, rule out of acute coronary syndrome, pneumonia, and proctitis in the ketorolac group, and suicidal ideations in the BFA group.

Limitations

As a limited number of patients received BFA at JBVAMC, the study was not sufficiently powered to detect a difference in the primary outcome. Because BFA required a consultation to be entered in the electronic health record, in addition to time needed to perform the procedure, practitioners might have preferred IV/IM ketorolac during busy times in the ED, potentially leading to underrepresentation in the BFA group. Prescribing preferences might have differed among the rotating physicians, timing of the documentation of the NRS pain score could have differed based on the treatment intervention, and the investigators were unable to control or accurately assess whether patients had taken an analgesic medication before presenting to the ED. Because pain and the treating physician are subjective, patients who reported a higher baseline pain severity might have been more likely to be discharged with topical analgesics or muscle relaxants. One way to correct for this subjectivity would be to conduct a larger prospective trial with a single treating physician. Finally, ED encounters in this study were short, and there was no follow-up permitting identification of AEs.

Conclusions

NRS pain score reduction with BFA did not differ compared with ketorolac 15 mg for treating acute and acute-on-chronic pain in the ED. Although this study was underpowered, these results add to the limited existing literature, suggesting that both interventions could result in clinically significant pain score reductions for patients presenting to the ED with severe and very severe pain, making BFA a viable nonpharmacologic option. Future studies could include investigating the benefit of BFA in the veteran population by studying larger samples in the ED, surveying patients after their interventions to identify rates AEs, and exploring the use of BFA for chronic pain in the outpatient setting.

Staphylococcus lugdunensis (S lugdunensis) is a species of coagulase-negative Staphylococcus (CoNS) and a constituent of human skin flora. Unlike other strains of CoNS, however, S lugdunensis has gained notoriety for virulence that resembles Staphylococcus aureus (S aureus). S lugdunensis is now recognized as an important nosocomial pathogen and cause of prosthetic device infections, including vascular catheter infections. We present a case of persistent S lugdunensis bacteremia occurring in a patient on hemodialysis (HD) without any implanted prosthetic materials.

Case Presentation

A 60-year-old man with a history of uncontrolled type 2 diabetes mellitus (T2DM) and end-stage renal disease on home HD via arteriovenous fistula (AVF) presented to the emergency department (ED) for evaluation of subacute progressive low back pain. His symptoms began abruptly 2 weeks prior to presentation without any identifiable trigger or trauma. His pain localized to the lower thoracic spine, radiating anteriorly into his abdomen. He reported tactile fever for several days before presentation but no chills, night sweats, paresthesia, weakness, or bowel/bladder incontinence. He had no recent surgeries, implanted hardware, or invasive procedures involving the spine. HD was performed 5 times a week at home with a family member cannulating his AVF via buttonhole technique. He initially sought evaluation in a community hospital several days prior, where he underwent magnetic resonance imaging (MRI) of the thoracic spine. He was discharged from the community ED with oral opioids prior to the MRI results. He presented to West Los Angeles Veterans Affairs Medical Center (WLAVAMC) ED when MRI results came back indicating abnormalities and he reported recalcitrant pain.

On arrival at WLAVAMC, the patient was afebrile with a heart rate of 107 bpm and blood pressure of 152/97 mm Hg. The remainder of his vital signs were normal. The physical examination revealed midline tenderness on palpation of the distal thoracic and proximal lumbar spine. Muscle strength was 4 of 5 in the bilateral hip flexors, though this was limited by pain. The remainder of his neurologic examination was nonfocal. The cardiac examination was unremarkable with no murmurs auscultated. His left upper extremity AVF had an audible bruit and palpable thrill. The skin examination was notable for acanthosis nigricans but no areas of skin erythema or induration and no obvious stigmata of infective endocarditis.

The initial laboratory workup was remarkable for a white blood cell (WBC) count of 10.0 × 10³/µL with left shift, blood urea nitrogen level of 59 mg/dL, and creatinine level of 9.3 mg/dL. The patient’s erythrocyte sedimentation rate (ESR) was 45 mm/h (reference range, ≤ 20 mm/h) and C-reactive protein level was > 8.0 mg/L (reference range, ≤ 0.74 mg/L). Two months prior the hemoglobin A_1c had been recorded at 9.9%.

Given his intractable low back pain and elevated inflammatory markers, the patient underwent an MRI of the thoracic and lumbar spine with contrast while in the ED. This MRI revealed abnormal marrow edema in the T11-T12 vertebrae with abnormal fluid signal in the T11-T12 disc space. Subjacent paravertebral edema also was noted. There was no well-defined fluid collection or abnormal signal in the spinal cord. Taken together, these findings were concerning for T11-T12 discitis with osteomyelitis.

Discussion

CoNS are a major contributor to human skin flora, a common contaminant of blood cultures, and an important cause of nosocomial bloodstream infections.^1,2 These species have a predilection for forming biofilms, making CoNS a major cause of prosthetic device infections.³S lugdunensis is a CoNS species that was first described in 1988.⁴ In addition to foreign body–related infections, S lugdunensis has been implicated in bone/joint infections, native valve endocarditis, toxic shock syndrome, and brain abscesses.^5-8 Infections due to S lugdunensis are notorious for their aggressive and fulminant courses. With its increased virulence that is atypical of other CoNS, S lugdunensis has understandably been likened more to S aureus.

Prior cases have been reported of S lugdunensis bacteremia in patients using HD. However, the suspected source of bacteremia in these cases has generally been central venous catheters.^9-12

Conclusions

S lugdunensis is an increasingly recognized cause of nosocomial bloodstream infections. Given the commonalities in virulence that S lugdunensis shares with S aureus, treatment of bacteremia caused by either species should follow similar management principles: prompt initiation of IV antistaphylococcal therapy, a thorough evaluation for the source(s) of bacteremia as well as metastatic complications, and consultation with an infectious disease specialist. This case report also highlights the importance of considering a patient’s AVF as a potential source for infection even in the absence of localized signs of infection. The buttonhole method of AVF cannulation was thought to be a major contributor to the development and persistence of our patient’s bacteremia. This risk should be discussed with patients using a shared decision-making approach when developing a dialysis treatment plan.

Staphylococcus lugdunensis (S lugdunensis) is a species of coagulase-negative Staphylococcus (CoNS) and a constituent of human skin flora. Unlike other strains of CoNS, however, S lugdunensis has gained notoriety for virulence that resembles Staphylococcus aureus (S aureus). S lugdunensis is now recognized as an important nosocomial pathogen and cause of prosthetic device infections, including vascular catheter infections. We present a case of persistent S lugdunensis bacteremia occurring in a patient on hemodialysis (HD) without any implanted prosthetic materials.

Case Presentation

A 60-year-old man with a history of uncontrolled type 2 diabetes mellitus (T2DM) and end-stage renal disease on home HD via arteriovenous fistula (AVF) presented to the emergency department (ED) for evaluation of subacute progressive low back pain. His symptoms began abruptly 2 weeks prior to presentation without any identifiable trigger or trauma. His pain localized to the lower thoracic spine, radiating anteriorly into his abdomen. He reported tactile fever for several days before presentation but no chills, night sweats, paresthesia, weakness, or bowel/bladder incontinence. He had no recent surgeries, implanted hardware, or invasive procedures involving the spine. HD was performed 5 times a week at home with a family member cannulating his AVF via buttonhole technique. He initially sought evaluation in a community hospital several days prior, where he underwent magnetic resonance imaging (MRI) of the thoracic spine. He was discharged from the community ED with oral opioids prior to the MRI results. He presented to West Los Angeles Veterans Affairs Medical Center (WLAVAMC) ED when MRI results came back indicating abnormalities and he reported recalcitrant pain.

On arrival at WLAVAMC, the patient was afebrile with a heart rate of 107 bpm and blood pressure of 152/97 mm Hg. The remainder of his vital signs were normal. The physical examination revealed midline tenderness on palpation of the distal thoracic and proximal lumbar spine. Muscle strength was 4 of 5 in the bilateral hip flexors, though this was limited by pain. The remainder of his neurologic examination was nonfocal. The cardiac examination was unremarkable with no murmurs auscultated. His left upper extremity AVF had an audible bruit and palpable thrill. The skin examination was notable for acanthosis nigricans but no areas of skin erythema or induration and no obvious stigmata of infective endocarditis.

The initial laboratory workup was remarkable for a white blood cell (WBC) count of 10.0 × 10³/µL with left shift, blood urea nitrogen level of 59 mg/dL, and creatinine level of 9.3 mg/dL. The patient’s erythrocyte sedimentation rate (ESR) was 45 mm/h (reference range, ≤ 20 mm/h) and C-reactive protein level was > 8.0 mg/L (reference range, ≤ 0.74 mg/L). Two months prior the hemoglobin A_1c had been recorded at 9.9%.

Given his intractable low back pain and elevated inflammatory markers, the patient underwent an MRI of the thoracic and lumbar spine with contrast while in the ED. This MRI revealed abnormal marrow edema in the T11-T12 vertebrae with abnormal fluid signal in the T11-T12 disc space. Subjacent paravertebral edema also was noted. There was no well-defined fluid collection or abnormal signal in the spinal cord. Taken together, these findings were concerning for T11-T12 discitis with osteomyelitis.

Discussion

CoNS are a major contributor to human skin flora, a common contaminant of blood cultures, and an important cause of nosocomial bloodstream infections.^1,2 These species have a predilection for forming biofilms, making CoNS a major cause of prosthetic device infections.³S lugdunensis is a CoNS species that was first described in 1988.⁴ In addition to foreign body–related infections, S lugdunensis has been implicated in bone/joint infections, native valve endocarditis, toxic shock syndrome, and brain abscesses.^5-8 Infections due to S lugdunensis are notorious for their aggressive and fulminant courses. With its increased virulence that is atypical of other CoNS, S lugdunensis has understandably been likened more to S aureus.

Prior cases have been reported of S lugdunensis bacteremia in patients using HD. However, the suspected source of bacteremia in these cases has generally been central venous catheters.^9-12

Conclusions

S lugdunensis is an increasingly recognized cause of nosocomial bloodstream infections. Given the commonalities in virulence that S lugdunensis shares with S aureus, treatment of bacteremia caused by either species should follow similar management principles: prompt initiation of IV antistaphylococcal therapy, a thorough evaluation for the source(s) of bacteremia as well as metastatic complications, and consultation with an infectious disease specialist. This case report also highlights the importance of considering a patient’s AVF as a potential source for infection even in the absence of localized signs of infection. The buttonhole method of AVF cannulation was thought to be a major contributor to the development and persistence of our patient’s bacteremia. This risk should be discussed with patients using a shared decision-making approach when developing a dialysis treatment plan.

Staphylococcus lugdunensis (S lugdunensis) is a species of coagulase-negative Staphylococcus (CoNS) and a constituent of human skin flora. Unlike other strains of CoNS, however, S lugdunensis has gained notoriety for virulence that resembles Staphylococcus aureus (S aureus). S lugdunensis is now recognized as an important nosocomial pathogen and cause of prosthetic device infections, including vascular catheter infections. We present a case of persistent S lugdunensis bacteremia occurring in a patient on hemodialysis (HD) without any implanted prosthetic materials.

Case Presentation

A 60-year-old man with a history of uncontrolled type 2 diabetes mellitus (T2DM) and end-stage renal disease on home HD via arteriovenous fistula (AVF) presented to the emergency department (ED) for evaluation of subacute progressive low back pain. His symptoms began abruptly 2 weeks prior to presentation without any identifiable trigger or trauma. His pain localized to the lower thoracic spine, radiating anteriorly into his abdomen. He reported tactile fever for several days before presentation but no chills, night sweats, paresthesia, weakness, or bowel/bladder incontinence. He had no recent surgeries, implanted hardware, or invasive procedures involving the spine. HD was performed 5 times a week at home with a family member cannulating his AVF via buttonhole technique. He initially sought evaluation in a community hospital several days prior, where he underwent magnetic resonance imaging (MRI) of the thoracic spine. He was discharged from the community ED with oral opioids prior to the MRI results. He presented to West Los Angeles Veterans Affairs Medical Center (WLAVAMC) ED when MRI results came back indicating abnormalities and he reported recalcitrant pain.

On arrival at WLAVAMC, the patient was afebrile with a heart rate of 107 bpm and blood pressure of 152/97 mm Hg. The remainder of his vital signs were normal. The physical examination revealed midline tenderness on palpation of the distal thoracic and proximal lumbar spine. Muscle strength was 4 of 5 in the bilateral hip flexors, though this was limited by pain. The remainder of his neurologic examination was nonfocal. The cardiac examination was unremarkable with no murmurs auscultated. His left upper extremity AVF had an audible bruit and palpable thrill. The skin examination was notable for acanthosis nigricans but no areas of skin erythema or induration and no obvious stigmata of infective endocarditis.

The initial laboratory workup was remarkable for a white blood cell (WBC) count of 10.0 × 10³/µL with left shift, blood urea nitrogen level of 59 mg/dL, and creatinine level of 9.3 mg/dL. The patient’s erythrocyte sedimentation rate (ESR) was 45 mm/h (reference range, ≤ 20 mm/h) and C-reactive protein level was > 8.0 mg/L (reference range, ≤ 0.74 mg/L). Two months prior the hemoglobin A_1c had been recorded at 9.9%.

Given his intractable low back pain and elevated inflammatory markers, the patient underwent an MRI of the thoracic and lumbar spine with contrast while in the ED. This MRI revealed abnormal marrow edema in the T11-T12 vertebrae with abnormal fluid signal in the T11-T12 disc space. Subjacent paravertebral edema also was noted. There was no well-defined fluid collection or abnormal signal in the spinal cord. Taken together, these findings were concerning for T11-T12 discitis with osteomyelitis.

Discussion

CoNS are a major contributor to human skin flora, a common contaminant of blood cultures, and an important cause of nosocomial bloodstream infections.^1,2 These species have a predilection for forming biofilms, making CoNS a major cause of prosthetic device infections.³S lugdunensis is a CoNS species that was first described in 1988.⁴ In addition to foreign body–related infections, S lugdunensis has been implicated in bone/joint infections, native valve endocarditis, toxic shock syndrome, and brain abscesses.^5-8 Infections due to S lugdunensis are notorious for their aggressive and fulminant courses. With its increased virulence that is atypical of other CoNS, S lugdunensis has understandably been likened more to S aureus.

Prior cases have been reported of S lugdunensis bacteremia in patients using HD. However, the suspected source of bacteremia in these cases has generally been central venous catheters.^9-12

Conclusions

S lugdunensis is an increasingly recognized cause of nosocomial bloodstream infections. Given the commonalities in virulence that S lugdunensis shares with S aureus, treatment of bacteremia caused by either species should follow similar management principles: prompt initiation of IV antistaphylococcal therapy, a thorough evaluation for the source(s) of bacteremia as well as metastatic complications, and consultation with an infectious disease specialist. This case report also highlights the importance of considering a patient’s AVF as a potential source for infection even in the absence of localized signs of infection. The buttonhole method of AVF cannulation was thought to be a major contributor to the development and persistence of our patient’s bacteremia. This risk should be discussed with patients using a shared decision-making approach when developing a dialysis treatment plan.