Federal Practitioner

Disordered sleep is associated with a significantly increased risk for stroke, new research shows.

Results of a large international study show stroke risk was more than three times higher in those who slept too little, more than twice as high in those who sleep too much, and two to three times higher in those with symptoms of severe obstructive sleep apnea.

The study also showed that the greater the number of sleep disorder symptoms, the greater the stroke risk. The 11% of study participants with five or more symptoms of disordered sleep had a fivefold increased risk for stroke.

Jupiterimages/Thinkstock

More symptoms, more risk

Previous research shows severe OSA doubles the risk of stroke and increases the chance of recurrent stroke. A 2019 study showed that people with insomnia had a small increased risk of stroke.

“Both snoring and extremes of sleep duration have been previously associated with an increased risk of stroke in observational research, but less is known about other symptoms of sleep impairment, with less consistent findings,” Dr. McCarthy said.

Prior studies have also generally come from a single geographic region, which Dr. McCarthy noted could limit their generalizability.

For this effort, investigators used data from 4,496 participants in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. About half of the participants had a history of stroke.

Using information collected from a survey of sleep habits, researchers found an elevated stroke risk in those who received less than 5 hours of sleep per night (odds ratio, 3.15; 95% confidence interval, 2.09-4.76) or more than 9 hours of sleep per night (OR, 2.67; 95% CI, 1.89-3.78), compared with those who slept 7 hours a night.

Participants who took unplanned naps or naps lasting an hour or more (OR, 2.46; 95% CI, 1.69-3.57) and participants who reported poor quality sleep (OR,1.52; 95% CI, 1.32-1.75) were also at an increased risk for stroke.

Symptoms of OSA were also strongly associated with increased stroke risk, including snoring (OR, 1.91; 95% CI, 1.62-2.24), snorting (OR, 2.64; 95% CI, 2.17-3.20), and breathing cessation (OR, 2.87; 95% CI, 2.28-2.60).

Stroke risk increased as the number of sleep disturbance symptoms rose, with the greatest risk in the 11% of participants who had five or more symptoms (OR, 5.38; 95% CI, 4.03-7.18).

“This study finds an association between a broad range of sleep impairment symptoms and stroke, and a graded association with increasing symptoms, in an international setting,” Dr. McCarthy said.

Researchers aren’t sure what’s driving the higher stroke risk among people with sleep disturbances. Although the study did control for potential confounders, it wasn’t designed to get at what’s driving the association.

“Sleep disturbance may also have a bi-directional relationship with many stroke risk factors; for example, sleep disturbance may be a symptom of disease and exacerbate disease,” Dr. McCarthy said. “Future interventional studies are required to determine the true direction of the relationship.”
 

A marker of stroke risk

Daniel Lackland, DrPH, professor of neurology at the Medical University of South Carolina, Charleston, said the findings provide additional evidence of the link between sleep and stroke risk.

“The results confirm sleep disorders as a potential marker and part of the risk profile,” he said.

Collecting information about sleep using a validated assessment tool is an important piece of clinical care, Dr. Lackland said, especially among patients with other stroke risk factors.

One limitation of the study was that data on sleep was collected only at one point, and participants were not followed over time to see if changes in sleep affected stroke risk.

“This is an important point and should be a focus for future studies, as it is critical in the design of interventions,” Dr. Lackland said.

The INTERSTROKE study is funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, U.K. Chest, and U.K. Heart and Stroke. Dr. McCarthy and Lackland report no relevant financial relationships.

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

Disordered sleep is associated with a significantly increased risk for stroke, new research shows.

Results of a large international study show stroke risk was more than three times higher in those who slept too little, more than twice as high in those who sleep too much, and two to three times higher in those with symptoms of severe obstructive sleep apnea.

The study also showed that the greater the number of sleep disorder symptoms, the greater the stroke risk. The 11% of study participants with five or more symptoms of disordered sleep had a fivefold increased risk for stroke.

Jupiterimages/Thinkstock

More symptoms, more risk

Previous research shows severe OSA doubles the risk of stroke and increases the chance of recurrent stroke. A 2019 study showed that people with insomnia had a small increased risk of stroke.

“Both snoring and extremes of sleep duration have been previously associated with an increased risk of stroke in observational research, but less is known about other symptoms of sleep impairment, with less consistent findings,” Dr. McCarthy said.

Prior studies have also generally come from a single geographic region, which Dr. McCarthy noted could limit their generalizability.

For this effort, investigators used data from 4,496 participants in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. About half of the participants had a history of stroke.

Using information collected from a survey of sleep habits, researchers found an elevated stroke risk in those who received less than 5 hours of sleep per night (odds ratio, 3.15; 95% confidence interval, 2.09-4.76) or more than 9 hours of sleep per night (OR, 2.67; 95% CI, 1.89-3.78), compared with those who slept 7 hours a night.

Participants who took unplanned naps or naps lasting an hour or more (OR, 2.46; 95% CI, 1.69-3.57) and participants who reported poor quality sleep (OR,1.52; 95% CI, 1.32-1.75) were also at an increased risk for stroke.

Symptoms of OSA were also strongly associated with increased stroke risk, including snoring (OR, 1.91; 95% CI, 1.62-2.24), snorting (OR, 2.64; 95% CI, 2.17-3.20), and breathing cessation (OR, 2.87; 95% CI, 2.28-2.60).

Stroke risk increased as the number of sleep disturbance symptoms rose, with the greatest risk in the 11% of participants who had five or more symptoms (OR, 5.38; 95% CI, 4.03-7.18).

“This study finds an association between a broad range of sleep impairment symptoms and stroke, and a graded association with increasing symptoms, in an international setting,” Dr. McCarthy said.

Researchers aren’t sure what’s driving the higher stroke risk among people with sleep disturbances. Although the study did control for potential confounders, it wasn’t designed to get at what’s driving the association.

“Sleep disturbance may also have a bi-directional relationship with many stroke risk factors; for example, sleep disturbance may be a symptom of disease and exacerbate disease,” Dr. McCarthy said. “Future interventional studies are required to determine the true direction of the relationship.”
 

A marker of stroke risk

Daniel Lackland, DrPH, professor of neurology at the Medical University of South Carolina, Charleston, said the findings provide additional evidence of the link between sleep and stroke risk.

“The results confirm sleep disorders as a potential marker and part of the risk profile,” he said.

Collecting information about sleep using a validated assessment tool is an important piece of clinical care, Dr. Lackland said, especially among patients with other stroke risk factors.

One limitation of the study was that data on sleep was collected only at one point, and participants were not followed over time to see if changes in sleep affected stroke risk.

“This is an important point and should be a focus for future studies, as it is critical in the design of interventions,” Dr. Lackland said.

The INTERSTROKE study is funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, U.K. Chest, and U.K. Heart and Stroke. Dr. McCarthy and Lackland report no relevant financial relationships.

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

Disordered sleep is associated with a significantly increased risk for stroke, new research shows.

Results of a large international study show stroke risk was more than three times higher in those who slept too little, more than twice as high in those who sleep too much, and two to three times higher in those with symptoms of severe obstructive sleep apnea.

The study also showed that the greater the number of sleep disorder symptoms, the greater the stroke risk. The 11% of study participants with five or more symptoms of disordered sleep had a fivefold increased risk for stroke.

Jupiterimages/Thinkstock

More symptoms, more risk

Previous research shows severe OSA doubles the risk of stroke and increases the chance of recurrent stroke. A 2019 study showed that people with insomnia had a small increased risk of stroke.

“Both snoring and extremes of sleep duration have been previously associated with an increased risk of stroke in observational research, but less is known about other symptoms of sleep impairment, with less consistent findings,” Dr. McCarthy said.

Prior studies have also generally come from a single geographic region, which Dr. McCarthy noted could limit their generalizability.

For this effort, investigators used data from 4,496 participants in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. About half of the participants had a history of stroke.

Using information collected from a survey of sleep habits, researchers found an elevated stroke risk in those who received less than 5 hours of sleep per night (odds ratio, 3.15; 95% confidence interval, 2.09-4.76) or more than 9 hours of sleep per night (OR, 2.67; 95% CI, 1.89-3.78), compared with those who slept 7 hours a night.

Participants who took unplanned naps or naps lasting an hour or more (OR, 2.46; 95% CI, 1.69-3.57) and participants who reported poor quality sleep (OR,1.52; 95% CI, 1.32-1.75) were also at an increased risk for stroke.

Symptoms of OSA were also strongly associated with increased stroke risk, including snoring (OR, 1.91; 95% CI, 1.62-2.24), snorting (OR, 2.64; 95% CI, 2.17-3.20), and breathing cessation (OR, 2.87; 95% CI, 2.28-2.60).

Stroke risk increased as the number of sleep disturbance symptoms rose, with the greatest risk in the 11% of participants who had five or more symptoms (OR, 5.38; 95% CI, 4.03-7.18).

“This study finds an association between a broad range of sleep impairment symptoms and stroke, and a graded association with increasing symptoms, in an international setting,” Dr. McCarthy said.

Researchers aren’t sure what’s driving the higher stroke risk among people with sleep disturbances. Although the study did control for potential confounders, it wasn’t designed to get at what’s driving the association.

“Sleep disturbance may also have a bi-directional relationship with many stroke risk factors; for example, sleep disturbance may be a symptom of disease and exacerbate disease,” Dr. McCarthy said. “Future interventional studies are required to determine the true direction of the relationship.”
 

A marker of stroke risk

Daniel Lackland, DrPH, professor of neurology at the Medical University of South Carolina, Charleston, said the findings provide additional evidence of the link between sleep and stroke risk.

“The results confirm sleep disorders as a potential marker and part of the risk profile,” he said.

Collecting information about sleep using a validated assessment tool is an important piece of clinical care, Dr. Lackland said, especially among patients with other stroke risk factors.

One limitation of the study was that data on sleep was collected only at one point, and participants were not followed over time to see if changes in sleep affected stroke risk.

“This is an important point and should be a focus for future studies, as it is critical in the design of interventions,” Dr. Lackland said.

The INTERSTROKE study is funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, U.K. Chest, and U.K. Heart and Stroke. Dr. McCarthy and Lackland report no relevant financial relationships.

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

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.

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).

 

 

Discussion

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).

 

 

Discussion

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.