Neurology

Combining four of five healthy lifestyle choices has been linked to up to a 60% reduced risk for Alzheimer’s dementia in new research that strengthens ties between healthy behaviors and lower dementia risk. “I hope this study will motivate people to engage in a healthy lifestyle by not smoking, being physically and cognitively active, and having a high-quality diet,” lead investigator Klodian Dhana, MD, PhD, department of internal medicine, Rush University Medical Center, Chicago, said in an interview.

The study was published online June 17 in Neurology.
 

Risk-modifying behaviors

To help quantify the impact of a healthy life on risk for Alzheimer’s dementia, Dr. Dhana and colleagues reviewed data from two longitudinal study populations: the Chicago Health and Aging Project (CHAP), with 1,845 participants, and the Memory and Aging Project (MAP), with 920 participants.

They defined a healthy lifestyle score on the basis of the following factors: not smoking; engaging in 150 min/wk or more of physical exercise of moderate to vigorous intensity; light to moderate alcohol consumption (between 1 and less than 15 g/day for women and between 1 and less than 30 g/day for men); consuming a high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%); and engaging in late-life cognitive activities (upper 40%). The overall score ranged from 0 to 5.

At baseline, the mean age of participants was 73.2 years in the CHAP study and 81.1 years in the MAP study; 62.4% of the CHAP participants and 75.2% of the MAP participants were women.

During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, a total of 379 and 229 participants, respectively, developed Alzheimer’s dementia. Rates of dementia decreased with an increasing number of healthy lifestyle behaviors.

In multivariable-adjusted models across the two cohorts, the risk for Alzheimer’s dementia was 27% lower with each additional healthy lifestyle factor (pooled hazard ratio, 0.73; 95% confidence interval, 0.66-0.80).

Compared with individuals with a healthy lifestyle score of 0-1, the risk was 37% lower (pooled HR, 0.63; 95% CI, 0.47-0.84) for those with two or three healthy lifestyle factors and 60% lower (pooled HR, 0.40; 95% CI, 0.28-0.56) for those with four or five healthy lifestyle factors.

“From these findings and the fact that the lifestyle factors we studied are modifiable and in direct control of the individual, it is imperative to promote them concurrently among older adults as a strategy to delay or prevent Alzheimer’s dementia,” Dr. Dhana and colleagues concluded.

In a statement, Dallas Anderson, PhD, program director, division of neuroscience, National Institute on Aging, said the findings help “paint the picture of how multiple factors are likely playing parts in Alzheimer’s disease risk.”

“It’s not a clear cause-and-effect result, but a strong finding because of the dual data sets and combination of modifiable lifestyle factors that appear to lead to risk reduction,” Dr. Anderson added.

Essential questions remain

Commenting on the new study, Luca Giliberto, MD, PhD, neurologist with the Litwin-Zucker Research Center for Alzheimer’s Disease and Memory Disorders at the Feinstein Institutes for Medical Research in Manhasset, N.Y., said this analysis is “further demonstration that a healthy lifestyle is essential to overcome or curb” the risk for Alzheimer’s disease.

“What needs to be determined is how early should we start ‘behaving.’ We should all aim to score four to five factors across our entire lifespan, but this is not always feasible. So, when is the time to behave? Also, what is the relative weight of each of these factors?” said Dr. Giliberto.

Of note, he added, although addressing vascular risk factors such as hypertension, hyperlipidemia, and diabetes “may require an extensive mindful and logistic effort, a healthy diet is effortlessly achieved in some countries, where both the DASH and MIND diets do not need to be ‘prescribed’ but are rather culturally engraved in the population.

“This is, in part, related to the wide availability of high-quality food in these countries, which is not the same in the U.S. This work is one more demonstration of the need to revisit our take on quality of food in the U.S.,” said Dr. Giliberto.

Numerous clinical trials testing lifestyle interventions for dementia prevention are currently underway. The MIND Diet Intervention to Prevent Alzheimer’s Disease, for example, is an interventional clinical trial comparing parallel groups with two different diets. MIND has enrolled more than 600 participants and is ongoing. The anticipated completion date is 2021. Another is the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), a multisite randomized clinical trial evaluating whether lifestyle interventions – including exercise, cognitively stimulating activities, and the MIND diet – may protect cognitive function in older adults who are at increased risk for cognitive decline.

Funding for the current study was provided by the National Institutes of Health and the National Institute on Aging. Dr. Dhana and Dr. Giliberto have disclosed no relevant financial relationships.

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

Combining four of five healthy lifestyle choices has been linked to up to a 60% reduced risk for Alzheimer’s dementia in new research that strengthens ties between healthy behaviors and lower dementia risk. “I hope this study will motivate people to engage in a healthy lifestyle by not smoking, being physically and cognitively active, and having a high-quality diet,” lead investigator Klodian Dhana, MD, PhD, department of internal medicine, Rush University Medical Center, Chicago, said in an interview.

The study was published online June 17 in Neurology.
 

Risk-modifying behaviors

To help quantify the impact of a healthy life on risk for Alzheimer’s dementia, Dr. Dhana and colleagues reviewed data from two longitudinal study populations: the Chicago Health and Aging Project (CHAP), with 1,845 participants, and the Memory and Aging Project (MAP), with 920 participants.

They defined a healthy lifestyle score on the basis of the following factors: not smoking; engaging in 150 min/wk or more of physical exercise of moderate to vigorous intensity; light to moderate alcohol consumption (between 1 and less than 15 g/day for women and between 1 and less than 30 g/day for men); consuming a high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%); and engaging in late-life cognitive activities (upper 40%). The overall score ranged from 0 to 5.

At baseline, the mean age of participants was 73.2 years in the CHAP study and 81.1 years in the MAP study; 62.4% of the CHAP participants and 75.2% of the MAP participants were women.

During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, a total of 379 and 229 participants, respectively, developed Alzheimer’s dementia. Rates of dementia decreased with an increasing number of healthy lifestyle behaviors.

In multivariable-adjusted models across the two cohorts, the risk for Alzheimer’s dementia was 27% lower with each additional healthy lifestyle factor (pooled hazard ratio, 0.73; 95% confidence interval, 0.66-0.80).

Compared with individuals with a healthy lifestyle score of 0-1, the risk was 37% lower (pooled HR, 0.63; 95% CI, 0.47-0.84) for those with two or three healthy lifestyle factors and 60% lower (pooled HR, 0.40; 95% CI, 0.28-0.56) for those with four or five healthy lifestyle factors.

“From these findings and the fact that the lifestyle factors we studied are modifiable and in direct control of the individual, it is imperative to promote them concurrently among older adults as a strategy to delay or prevent Alzheimer’s dementia,” Dr. Dhana and colleagues concluded.

In a statement, Dallas Anderson, PhD, program director, division of neuroscience, National Institute on Aging, said the findings help “paint the picture of how multiple factors are likely playing parts in Alzheimer’s disease risk.”

“It’s not a clear cause-and-effect result, but a strong finding because of the dual data sets and combination of modifiable lifestyle factors that appear to lead to risk reduction,” Dr. Anderson added.

Essential questions remain

Commenting on the new study, Luca Giliberto, MD, PhD, neurologist with the Litwin-Zucker Research Center for Alzheimer’s Disease and Memory Disorders at the Feinstein Institutes for Medical Research in Manhasset, N.Y., said this analysis is “further demonstration that a healthy lifestyle is essential to overcome or curb” the risk for Alzheimer’s disease.

“What needs to be determined is how early should we start ‘behaving.’ We should all aim to score four to five factors across our entire lifespan, but this is not always feasible. So, when is the time to behave? Also, what is the relative weight of each of these factors?” said Dr. Giliberto.

Of note, he added, although addressing vascular risk factors such as hypertension, hyperlipidemia, and diabetes “may require an extensive mindful and logistic effort, a healthy diet is effortlessly achieved in some countries, where both the DASH and MIND diets do not need to be ‘prescribed’ but are rather culturally engraved in the population.

“This is, in part, related to the wide availability of high-quality food in these countries, which is not the same in the U.S. This work is one more demonstration of the need to revisit our take on quality of food in the U.S.,” said Dr. Giliberto.

Numerous clinical trials testing lifestyle interventions for dementia prevention are currently underway. The MIND Diet Intervention to Prevent Alzheimer’s Disease, for example, is an interventional clinical trial comparing parallel groups with two different diets. MIND has enrolled more than 600 participants and is ongoing. The anticipated completion date is 2021. Another is the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), a multisite randomized clinical trial evaluating whether lifestyle interventions – including exercise, cognitively stimulating activities, and the MIND diet – may protect cognitive function in older adults who are at increased risk for cognitive decline.

Funding for the current study was provided by the National Institutes of Health and the National Institute on Aging. Dr. Dhana and Dr. Giliberto have disclosed no relevant financial relationships.

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

Combining four of five healthy lifestyle choices has been linked to up to a 60% reduced risk for Alzheimer’s dementia in new research that strengthens ties between healthy behaviors and lower dementia risk. “I hope this study will motivate people to engage in a healthy lifestyle by not smoking, being physically and cognitively active, and having a high-quality diet,” lead investigator Klodian Dhana, MD, PhD, department of internal medicine, Rush University Medical Center, Chicago, said in an interview.

The study was published online June 17 in Neurology.
 

Risk-modifying behaviors

To help quantify the impact of a healthy life on risk for Alzheimer’s dementia, Dr. Dhana and colleagues reviewed data from two longitudinal study populations: the Chicago Health and Aging Project (CHAP), with 1,845 participants, and the Memory and Aging Project (MAP), with 920 participants.

They defined a healthy lifestyle score on the basis of the following factors: not smoking; engaging in 150 min/wk or more of physical exercise of moderate to vigorous intensity; light to moderate alcohol consumption (between 1 and less than 15 g/day for women and between 1 and less than 30 g/day for men); consuming a high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%); and engaging in late-life cognitive activities (upper 40%). The overall score ranged from 0 to 5.

At baseline, the mean age of participants was 73.2 years in the CHAP study and 81.1 years in the MAP study; 62.4% of the CHAP participants and 75.2% of the MAP participants were women.

During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, a total of 379 and 229 participants, respectively, developed Alzheimer’s dementia. Rates of dementia decreased with an increasing number of healthy lifestyle behaviors.

In multivariable-adjusted models across the two cohorts, the risk for Alzheimer’s dementia was 27% lower with each additional healthy lifestyle factor (pooled hazard ratio, 0.73; 95% confidence interval, 0.66-0.80).

Compared with individuals with a healthy lifestyle score of 0-1, the risk was 37% lower (pooled HR, 0.63; 95% CI, 0.47-0.84) for those with two or three healthy lifestyle factors and 60% lower (pooled HR, 0.40; 95% CI, 0.28-0.56) for those with four or five healthy lifestyle factors.

“From these findings and the fact that the lifestyle factors we studied are modifiable and in direct control of the individual, it is imperative to promote them concurrently among older adults as a strategy to delay or prevent Alzheimer’s dementia,” Dr. Dhana and colleagues concluded.

In a statement, Dallas Anderson, PhD, program director, division of neuroscience, National Institute on Aging, said the findings help “paint the picture of how multiple factors are likely playing parts in Alzheimer’s disease risk.”

“It’s not a clear cause-and-effect result, but a strong finding because of the dual data sets and combination of modifiable lifestyle factors that appear to lead to risk reduction,” Dr. Anderson added.

Essential questions remain

Commenting on the new study, Luca Giliberto, MD, PhD, neurologist with the Litwin-Zucker Research Center for Alzheimer’s Disease and Memory Disorders at the Feinstein Institutes for Medical Research in Manhasset, N.Y., said this analysis is “further demonstration that a healthy lifestyle is essential to overcome or curb” the risk for Alzheimer’s disease.

“What needs to be determined is how early should we start ‘behaving.’ We should all aim to score four to five factors across our entire lifespan, but this is not always feasible. So, when is the time to behave? Also, what is the relative weight of each of these factors?” said Dr. Giliberto.

Of note, he added, although addressing vascular risk factors such as hypertension, hyperlipidemia, and diabetes “may require an extensive mindful and logistic effort, a healthy diet is effortlessly achieved in some countries, where both the DASH and MIND diets do not need to be ‘prescribed’ but are rather culturally engraved in the population.

“This is, in part, related to the wide availability of high-quality food in these countries, which is not the same in the U.S. This work is one more demonstration of the need to revisit our take on quality of food in the U.S.,” said Dr. Giliberto.

Numerous clinical trials testing lifestyle interventions for dementia prevention are currently underway. The MIND Diet Intervention to Prevent Alzheimer’s Disease, for example, is an interventional clinical trial comparing parallel groups with two different diets. MIND has enrolled more than 600 participants and is ongoing. The anticipated completion date is 2021. Another is the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), a multisite randomized clinical trial evaluating whether lifestyle interventions – including exercise, cognitively stimulating activities, and the MIND diet – may protect cognitive function in older adults who are at increased risk for cognitive decline.

Funding for the current study was provided by the National Institutes of Health and the National Institute on Aging. Dr. Dhana and Dr. Giliberto have disclosed no relevant financial relationships.

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

ED visits for myocardial infarction, stroke, and hyperglycemic crisis dropped substantially in the 10 weeks after COVID-19 was declared a national emergency on March 13, according to the Centers for Disease Control and Prevention.

Compared with the 10-week period from Jan. 5 to March 14, ED visits were down by 23% for MI, 20% for stroke, and 10% for hyperglycemic crisis from March 15 to May 23, Samantha J. Lange, MPH, and associates at the CDC reported June 22 in the Morbidity and Mortality Weekly Report.

“A short-term decline of this magnitude … is biologically implausible for MI and stroke, especially for older adults, and unlikely for hyperglycemic crisis, and the finding suggests that patients with these conditions either could not access care or were delaying or avoiding seeking care during the early pandemic period,” they wrote.

The largest decreases in the actual number of visits for MI occurred among both men (down by 2,114, –24%) and women (down by 1,459, –25%) aged 65-74 years. For stroke, men aged 65-74 years had 1,406 (–19%) fewer visits to the ED and women 75-84 years had 1,642 (–23%) fewer visits, the CDC researchers said.

For hypoglycemic crisis, the largest declines during the early pandemic period occurred among younger adults: ED visits for men and women aged 18-44 years were down, respectively, by 419 (–8%) and 775 (–16%), they reported based on data from the National Syndromic Surveillance Program.

“Decreases in ED visits for hyperglycemic crisis might be less striking because patient recognition of this crisis is typically augmented by home glucose monitoring and not reliant upon symptoms alone, as is the case for MI and stroke,” Ms. Lange and her associates noted.

Charting weekly visit numbers showed that the drop for all three conditions actually started the week before the emergency was declared and reached its nadir the week after (March 22) for MI and 2 weeks later (March 29) for stroke and hypoglycemic crisis.

Visits for hypoglycemic crisis have largely returned to normal since those low points, but MI and stroke visits “remain below prepandemic levels” despite gradual increases through April and May, they said.

It has been reported that “deaths not associated with confirmed or probable COVID-19 might have been directly or indirectly attributed to the pandemic. The striking decline in ED visits for acute life-threatening conditions might partially explain observed excess mortality not associated with COVID-19,” the investigators wrote.

[email protected]

ED visits for myocardial infarction, stroke, and hyperglycemic crisis dropped substantially in the 10 weeks after COVID-19 was declared a national emergency on March 13, according to the Centers for Disease Control and Prevention.

Compared with the 10-week period from Jan. 5 to March 14, ED visits were down by 23% for MI, 20% for stroke, and 10% for hyperglycemic crisis from March 15 to May 23, Samantha J. Lange, MPH, and associates at the CDC reported June 22 in the Morbidity and Mortality Weekly Report.

“A short-term decline of this magnitude … is biologically implausible for MI and stroke, especially for older adults, and unlikely for hyperglycemic crisis, and the finding suggests that patients with these conditions either could not access care or were delaying or avoiding seeking care during the early pandemic period,” they wrote.

The largest decreases in the actual number of visits for MI occurred among both men (down by 2,114, –24%) and women (down by 1,459, –25%) aged 65-74 years. For stroke, men aged 65-74 years had 1,406 (–19%) fewer visits to the ED and women 75-84 years had 1,642 (–23%) fewer visits, the CDC researchers said.

For hypoglycemic crisis, the largest declines during the early pandemic period occurred among younger adults: ED visits for men and women aged 18-44 years were down, respectively, by 419 (–8%) and 775 (–16%), they reported based on data from the National Syndromic Surveillance Program.

“Decreases in ED visits for hyperglycemic crisis might be less striking because patient recognition of this crisis is typically augmented by home glucose monitoring and not reliant upon symptoms alone, as is the case for MI and stroke,” Ms. Lange and her associates noted.

Charting weekly visit numbers showed that the drop for all three conditions actually started the week before the emergency was declared and reached its nadir the week after (March 22) for MI and 2 weeks later (March 29) for stroke and hypoglycemic crisis.

Visits for hypoglycemic crisis have largely returned to normal since those low points, but MI and stroke visits “remain below prepandemic levels” despite gradual increases through April and May, they said.

It has been reported that “deaths not associated with confirmed or probable COVID-19 might have been directly or indirectly attributed to the pandemic. The striking decline in ED visits for acute life-threatening conditions might partially explain observed excess mortality not associated with COVID-19,” the investigators wrote.

[email protected]

ED visits for myocardial infarction, stroke, and hyperglycemic crisis dropped substantially in the 10 weeks after COVID-19 was declared a national emergency on March 13, according to the Centers for Disease Control and Prevention.

Compared with the 10-week period from Jan. 5 to March 14, ED visits were down by 23% for MI, 20% for stroke, and 10% for hyperglycemic crisis from March 15 to May 23, Samantha J. Lange, MPH, and associates at the CDC reported June 22 in the Morbidity and Mortality Weekly Report.

“A short-term decline of this magnitude … is biologically implausible for MI and stroke, especially for older adults, and unlikely for hyperglycemic crisis, and the finding suggests that patients with these conditions either could not access care or were delaying or avoiding seeking care during the early pandemic period,” they wrote.

The largest decreases in the actual number of visits for MI occurred among both men (down by 2,114, –24%) and women (down by 1,459, –25%) aged 65-74 years. For stroke, men aged 65-74 years had 1,406 (–19%) fewer visits to the ED and women 75-84 years had 1,642 (–23%) fewer visits, the CDC researchers said.

For hypoglycemic crisis, the largest declines during the early pandemic period occurred among younger adults: ED visits for men and women aged 18-44 years were down, respectively, by 419 (–8%) and 775 (–16%), they reported based on data from the National Syndromic Surveillance Program.

“Decreases in ED visits for hyperglycemic crisis might be less striking because patient recognition of this crisis is typically augmented by home glucose monitoring and not reliant upon symptoms alone, as is the case for MI and stroke,” Ms. Lange and her associates noted.

Charting weekly visit numbers showed that the drop for all three conditions actually started the week before the emergency was declared and reached its nadir the week after (March 22) for MI and 2 weeks later (March 29) for stroke and hypoglycemic crisis.

Visits for hypoglycemic crisis have largely returned to normal since those low points, but MI and stroke visits “remain below prepandemic levels” despite gradual increases through April and May, they said.

It has been reported that “deaths not associated with confirmed or probable COVID-19 might have been directly or indirectly attributed to the pandemic. The striking decline in ED visits for acute life-threatening conditions might partially explain observed excess mortality not associated with COVID-19,” the investigators wrote.

[email protected]

Abnormalities in circadian rhythm may represent an important feature in the very early stages of Parkinson’s disease before symptoms develop, a new study suggests. “We found that men with abnormal circadian rhythms had three times the risk of developing Parkinson’s disease over an 11-year follow-up period,” lead author, Yue Leng, MD, University of California, San Francisco, said in an interview.

“If confirmed to be a risk factor for Parkinson’s disease, then circadian rhythmicity could be a promising intervention target and will open new opportunities for the prevention and management of Parkinson’s disease,” the researchers concluded.

The study was published online in JAMA Neurology on June 15.

Circadian disruption is very common in neurodegenerative diseases such as Parkinson’s disease, but there isn’t much information on how it may predict the disease, Dr. Leng explained. “We wanted to see whether circadian abnormalities may predict Parkinson’s disease,” she said. “Parkinson’s disease has a long prodromal phase where brain changes have started to occur but no clinical symptoms have become evident. It would be useful to be able to identify these patients, and maybe changes in circadian rhythms may help us to do that,” she added.

For the study, the researchers analyzed data from 2,930 community-dwelling men aged 65 years or older (mean age, 76 years) who participated in the Osteoporotic Fractures in Men Study, in which they underwent comprehensive sleep and rest-activity rhythms assessment. “Patterns of rest and activity were measured with an actigraph device, which is worn on the wrist like a watch and captures movements which are translated into a rest-activity rhythm model – one of the most commonly used and evidence-based measures of circadian rhythm,” Dr. Leng said. Men were asked to wear the actigraphs continuously for a minimum of three 24-hour periods.

Results showed that 78 men (2.7%) developed Parkinson’s disease during the 11-year follow-up. After accounting for all covariates, the risk of Parkinson’s disease increased with decreasing circadian amplitude (strength of the rhythm) with an odds ratio of 1.77 per each decrease by one standard deviation; mesor (mean level of activity) with an odds ratio of 1.64; or robustness (how closely activity follows a 24-hour pattern) with an odds ratio of 1.54.

Those in the lowest quartile of amplitude, mesor, or robustness had approximately three times the risk of developing Parkinson’s disease compared with those in the highest quartile of amplitude. The association remained after further adjustment for nighttime sleep disturbances.

“It has previously been shown that daytime napping has been linked to risk of developing Parkinson’s disease. Now we have shown that abnormalities in the overall 24-hour circadian rest activity rhythm are also present in the prodromal phase of Parkinson’s disease, and this association was independent of several confounders, including nighttime sleep disturbances,” Dr. Leng said.

“This raises awareness of the importance of circadian rhythm in older individuals and changes in their 24-hour pattern of behavior could be an early signal of Parkinson’s disease,” she said.

“This study does not tell us whether these circadian changes are causal for Parkinson’s or not,” Dr. Leng noted.

Future studies are needed to explore underlying mechanisms and to determine whether circadian disruption itself might contribute to the development of Parkinson’s disease, the researchers said.

“If there is a causal link, then using techniques to improve circadian rhythm could help to prevent or slow the onset of Parkinson’s disease,” Dr. Leng suggested. There are many established therapies that act on circadian rhythm including bright light therapy, melatonin, and chronotherapy, she added.

Support for this study was provided by the National Institute on Aging (NIA); the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and the Weill Pilot Award. Dr. Leng reported grants from the NIA and the University of California, San Francisco, Weill Institute for Neurosciences during the conduct of the study; and grants from Global Brain Health Institute, the Alzheimer’s Association, and the Alzheimer’s Society outside the submitted work.

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

Abnormalities in circadian rhythm may represent an important feature in the very early stages of Parkinson’s disease before symptoms develop, a new study suggests. “We found that men with abnormal circadian rhythms had three times the risk of developing Parkinson’s disease over an 11-year follow-up period,” lead author, Yue Leng, MD, University of California, San Francisco, said in an interview.

“If confirmed to be a risk factor for Parkinson’s disease, then circadian rhythmicity could be a promising intervention target and will open new opportunities for the prevention and management of Parkinson’s disease,” the researchers concluded.

The study was published online in JAMA Neurology on June 15.

Circadian disruption is very common in neurodegenerative diseases such as Parkinson’s disease, but there isn’t much information on how it may predict the disease, Dr. Leng explained. “We wanted to see whether circadian abnormalities may predict Parkinson’s disease,” she said. “Parkinson’s disease has a long prodromal phase where brain changes have started to occur but no clinical symptoms have become evident. It would be useful to be able to identify these patients, and maybe changes in circadian rhythms may help us to do that,” she added.

For the study, the researchers analyzed data from 2,930 community-dwelling men aged 65 years or older (mean age, 76 years) who participated in the Osteoporotic Fractures in Men Study, in which they underwent comprehensive sleep and rest-activity rhythms assessment. “Patterns of rest and activity were measured with an actigraph device, which is worn on the wrist like a watch and captures movements which are translated into a rest-activity rhythm model – one of the most commonly used and evidence-based measures of circadian rhythm,” Dr. Leng said. Men were asked to wear the actigraphs continuously for a minimum of three 24-hour periods.

Results showed that 78 men (2.7%) developed Parkinson’s disease during the 11-year follow-up. After accounting for all covariates, the risk of Parkinson’s disease increased with decreasing circadian amplitude (strength of the rhythm) with an odds ratio of 1.77 per each decrease by one standard deviation; mesor (mean level of activity) with an odds ratio of 1.64; or robustness (how closely activity follows a 24-hour pattern) with an odds ratio of 1.54.

Those in the lowest quartile of amplitude, mesor, or robustness had approximately three times the risk of developing Parkinson’s disease compared with those in the highest quartile of amplitude. The association remained after further adjustment for nighttime sleep disturbances.

“It has previously been shown that daytime napping has been linked to risk of developing Parkinson’s disease. Now we have shown that abnormalities in the overall 24-hour circadian rest activity rhythm are also present in the prodromal phase of Parkinson’s disease, and this association was independent of several confounders, including nighttime sleep disturbances,” Dr. Leng said.

“This raises awareness of the importance of circadian rhythm in older individuals and changes in their 24-hour pattern of behavior could be an early signal of Parkinson’s disease,” she said.

“This study does not tell us whether these circadian changes are causal for Parkinson’s or not,” Dr. Leng noted.

Future studies are needed to explore underlying mechanisms and to determine whether circadian disruption itself might contribute to the development of Parkinson’s disease, the researchers said.

“If there is a causal link, then using techniques to improve circadian rhythm could help to prevent or slow the onset of Parkinson’s disease,” Dr. Leng suggested. There are many established therapies that act on circadian rhythm including bright light therapy, melatonin, and chronotherapy, she added.

Support for this study was provided by the National Institute on Aging (NIA); the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and the Weill Pilot Award. Dr. Leng reported grants from the NIA and the University of California, San Francisco, Weill Institute for Neurosciences during the conduct of the study; and grants from Global Brain Health Institute, the Alzheimer’s Association, and the Alzheimer’s Society outside the submitted work.

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

Abnormalities in circadian rhythm may represent an important feature in the very early stages of Parkinson’s disease before symptoms develop, a new study suggests. “We found that men with abnormal circadian rhythms had three times the risk of developing Parkinson’s disease over an 11-year follow-up period,” lead author, Yue Leng, MD, University of California, San Francisco, said in an interview.

“If confirmed to be a risk factor for Parkinson’s disease, then circadian rhythmicity could be a promising intervention target and will open new opportunities for the prevention and management of Parkinson’s disease,” the researchers concluded.

The study was published online in JAMA Neurology on June 15.

Circadian disruption is very common in neurodegenerative diseases such as Parkinson’s disease, but there isn’t much information on how it may predict the disease, Dr. Leng explained. “We wanted to see whether circadian abnormalities may predict Parkinson’s disease,” she said. “Parkinson’s disease has a long prodromal phase where brain changes have started to occur but no clinical symptoms have become evident. It would be useful to be able to identify these patients, and maybe changes in circadian rhythms may help us to do that,” she added.

For the study, the researchers analyzed data from 2,930 community-dwelling men aged 65 years or older (mean age, 76 years) who participated in the Osteoporotic Fractures in Men Study, in which they underwent comprehensive sleep and rest-activity rhythms assessment. “Patterns of rest and activity were measured with an actigraph device, which is worn on the wrist like a watch and captures movements which are translated into a rest-activity rhythm model – one of the most commonly used and evidence-based measures of circadian rhythm,” Dr. Leng said. Men were asked to wear the actigraphs continuously for a minimum of three 24-hour periods.

Results showed that 78 men (2.7%) developed Parkinson’s disease during the 11-year follow-up. After accounting for all covariates, the risk of Parkinson’s disease increased with decreasing circadian amplitude (strength of the rhythm) with an odds ratio of 1.77 per each decrease by one standard deviation; mesor (mean level of activity) with an odds ratio of 1.64; or robustness (how closely activity follows a 24-hour pattern) with an odds ratio of 1.54.

Those in the lowest quartile of amplitude, mesor, or robustness had approximately three times the risk of developing Parkinson’s disease compared with those in the highest quartile of amplitude. The association remained after further adjustment for nighttime sleep disturbances.

“It has previously been shown that daytime napping has been linked to risk of developing Parkinson’s disease. Now we have shown that abnormalities in the overall 24-hour circadian rest activity rhythm are also present in the prodromal phase of Parkinson’s disease, and this association was independent of several confounders, including nighttime sleep disturbances,” Dr. Leng said.

“This raises awareness of the importance of circadian rhythm in older individuals and changes in their 24-hour pattern of behavior could be an early signal of Parkinson’s disease,” she said.

“This study does not tell us whether these circadian changes are causal for Parkinson’s or not,” Dr. Leng noted.

Future studies are needed to explore underlying mechanisms and to determine whether circadian disruption itself might contribute to the development of Parkinson’s disease, the researchers said.

“If there is a causal link, then using techniques to improve circadian rhythm could help to prevent or slow the onset of Parkinson’s disease,” Dr. Leng suggested. There are many established therapies that act on circadian rhythm including bright light therapy, melatonin, and chronotherapy, she added.

Support for this study was provided by the National Institute on Aging (NIA); the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and the Weill Pilot Award. Dr. Leng reported grants from the NIA and the University of California, San Francisco, Weill Institute for Neurosciences during the conduct of the study; and grants from Global Brain Health Institute, the Alzheimer’s Association, and the Alzheimer’s Society outside the submitted work.

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

Headache may be a key symptom of COVID-19 that predicts the disease’s clinical evolution in individual patients, new research suggests. An observational study of more than 100 patients showed that headache onset could occur during the presymptomatic or symptomatic phase of COVID-19 and could resemble tension-type or migraine headache.

Headache itself was associated with a shorter symptomatic period, while headache and anosmia were associated with a shorter hospitalization period. In a subgroup of participants, headache persisted even after the symptoms of COVID-19 had been resolved.

Investigators noted that understanding the pathophysiology of headache in COVID-19 could improve understanding of migraine and other headache disorders. “It seems that those patients who start early on, during the asymptomatic or early symptomatic period of COVID-19, with headache have a more localized inflammatory response that may reflect the ability of the body to better control and respond to the infection by SARS-CoV-2,” lead investigator Patricia Pozo-Rosich, MD, PhD, head of the headache and craniofacial pain unit at Vall d’Hebron University Hospital, Barcelona, said in an interview.

She presented the findings at the virtual annual meeting of the American Headache Society.

Systemic inflammation

Headache is one of the main symptoms of COVID-19. A recent study of 214 patients with COVID-19 showed that approximately 13% of the participants had headache and 5% had anosmia.

SARS-CoV-2 penetrates the cells through the ACE2 receptor, which is present throughout the body. “SARS-CoV-2 enters the body through the nasal cavity and it probably penetrates the nervous system in the periphery through afferent branches of the olfactory and trigeminal nerve,” Dr. Pozo-Rosich said. It travels to the lungs and, later, the bloodstream. This generates systemic inflammation that may turn into a cytokine storm. Evidence has identified cortical hyperintensities and olfactory bulb hyperintensities in patients with COVID-19, suggesting that the virus directly infects the CNS.

Interleukin-6, one of the main inflammatory molecules, has been proven to be related to COVID-19 and has become a therapeutic target. Levels of IL-6 may be lower and tend to be more stable in patients with both COVID-19 and headache than in patients with COVID-19 only.

The researchers observed 130 patients (51% women; mean age, 54 years) with COVID-19 who were attended by neurologists at Vall d’Hebron. In this group, 74.4% had headache. Patients with headache tended to be younger than those without headache (mean age, 50 years vs. 63 years, respectively) and tended to be women (58.6% vs. 29.4%).

Approximately one-third of patients with headache had a history of migraine. Most reported mild to moderate pain that resembled tension-type headache. In participants with severe pain and migraine-like features, headache more often began during the asymptomatic phase of COVID-19.

Disease evolution predictor?

The investigators followed up on 100 of the 130 patients with COVID-19, of whom 74 had headache. About 38% of these patients had ongoing headache after 6 weeks, which suggests that some patients may develop a new daily persistent headache once a 3-month period has elapsed. Half of this group had no previous headache history. Headache had been the prodromal symptom of COVID-19 for 21.4% of these patients.

Results showed that headache predicted the clinical evolution of COVID-19. The symptomatic phase of COVID-19 was 7 days shorter for patients with headache than for those without headache. In addition, the period of hospitalization was 7 days shorter for patients with headache and anosmia, compared with patients who had neither headache nor anosmia.

Most therapies, including ibuprofen, candesartan, and anti–calcitonin gene–related peptide (CGRP) monoclonal antibodies, are safe for treating headache in COVID-19, the investigators noted. “We should just try to initially avoid steroids to avoid interference with the body’s reaction to SARS-CoV-2,” Dr. Pozo-Rosich said.

Researchers at Sidney Kimmel Medical College, Philadelphia, are currently studying intranasal vazegepant, an anti-CGRP therapy, as a way to potentially blunt the severe inflammatory response in the lungs of patients with COVID-19, she noted, adding that this peptide may have a future role not only in headache, but also in COVID-19.

Historical link to viral infections

Commenting on the study, Matthew S. Robbins, MD, associate professor of neurology at Weill Cornell Medicine, New York, said the findings associating headache with a shorter symptomatic phase of COVID-19 were “interesting.”

“Headache is common with mild viral infections. More severe viral infections may simply feature more overwhelming respiratory symptoms and fever that lead to underreporting or underascertainment of headache,” said Dr. Robbins, who was not involved with the research.

He noted that the finding showing an association of headache and COVID-19 with a younger age and in women “may be related to a higher prevalence of migraine biology in such patients, and being triggered by the virus or the psychological stress associated with it.”

Dr. Robbins added that viral illnesses have long been associated with new daily persistent headache, “dating back to the early 1980s,” when it was first described in association with Epstein-Barr virus. These infections have also been implicated in the progression of migraine to chronic migraine in adolescents.

“In my view, treatment should be aimed at the symptomatic headache type for which new daily persistent headache resembles, regardless of the potential inciting factor,” Dr. Robbins said.

Dr. Pozo-Rosich has received consulting fees from Allergan, Amgen, Almirall, Biohaven, Chiesi, Eli Lilly, Medscape, Novartis, and Teva Pharmaceuticals. Dr. Robbins has disclosed no relevant financial relationships.

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

Headache may be a key symptom of COVID-19 that predicts the disease’s clinical evolution in individual patients, new research suggests. An observational study of more than 100 patients showed that headache onset could occur during the presymptomatic or symptomatic phase of COVID-19 and could resemble tension-type or migraine headache.

Headache itself was associated with a shorter symptomatic period, while headache and anosmia were associated with a shorter hospitalization period. In a subgroup of participants, headache persisted even after the symptoms of COVID-19 had been resolved.

Investigators noted that understanding the pathophysiology of headache in COVID-19 could improve understanding of migraine and other headache disorders. “It seems that those patients who start early on, during the asymptomatic or early symptomatic period of COVID-19, with headache have a more localized inflammatory response that may reflect the ability of the body to better control and respond to the infection by SARS-CoV-2,” lead investigator Patricia Pozo-Rosich, MD, PhD, head of the headache and craniofacial pain unit at Vall d’Hebron University Hospital, Barcelona, said in an interview.

She presented the findings at the virtual annual meeting of the American Headache Society.

Systemic inflammation

Headache is one of the main symptoms of COVID-19. A recent study of 214 patients with COVID-19 showed that approximately 13% of the participants had headache and 5% had anosmia.

SARS-CoV-2 penetrates the cells through the ACE2 receptor, which is present throughout the body. “SARS-CoV-2 enters the body through the nasal cavity and it probably penetrates the nervous system in the periphery through afferent branches of the olfactory and trigeminal nerve,” Dr. Pozo-Rosich said. It travels to the lungs and, later, the bloodstream. This generates systemic inflammation that may turn into a cytokine storm. Evidence has identified cortical hyperintensities and olfactory bulb hyperintensities in patients with COVID-19, suggesting that the virus directly infects the CNS.

Interleukin-6, one of the main inflammatory molecules, has been proven to be related to COVID-19 and has become a therapeutic target. Levels of IL-6 may be lower and tend to be more stable in patients with both COVID-19 and headache than in patients with COVID-19 only.

The researchers observed 130 patients (51% women; mean age, 54 years) with COVID-19 who were attended by neurologists at Vall d’Hebron. In this group, 74.4% had headache. Patients with headache tended to be younger than those without headache (mean age, 50 years vs. 63 years, respectively) and tended to be women (58.6% vs. 29.4%).

Approximately one-third of patients with headache had a history of migraine. Most reported mild to moderate pain that resembled tension-type headache. In participants with severe pain and migraine-like features, headache more often began during the asymptomatic phase of COVID-19.

Disease evolution predictor?

The investigators followed up on 100 of the 130 patients with COVID-19, of whom 74 had headache. About 38% of these patients had ongoing headache after 6 weeks, which suggests that some patients may develop a new daily persistent headache once a 3-month period has elapsed. Half of this group had no previous headache history. Headache had been the prodromal symptom of COVID-19 for 21.4% of these patients.

Results showed that headache predicted the clinical evolution of COVID-19. The symptomatic phase of COVID-19 was 7 days shorter for patients with headache than for those without headache. In addition, the period of hospitalization was 7 days shorter for patients with headache and anosmia, compared with patients who had neither headache nor anosmia.

Most therapies, including ibuprofen, candesartan, and anti–calcitonin gene–related peptide (CGRP) monoclonal antibodies, are safe for treating headache in COVID-19, the investigators noted. “We should just try to initially avoid steroids to avoid interference with the body’s reaction to SARS-CoV-2,” Dr. Pozo-Rosich said.

Researchers at Sidney Kimmel Medical College, Philadelphia, are currently studying intranasal vazegepant, an anti-CGRP therapy, as a way to potentially blunt the severe inflammatory response in the lungs of patients with COVID-19, she noted, adding that this peptide may have a future role not only in headache, but also in COVID-19.

Historical link to viral infections

Commenting on the study, Matthew S. Robbins, MD, associate professor of neurology at Weill Cornell Medicine, New York, said the findings associating headache with a shorter symptomatic phase of COVID-19 were “interesting.”

“Headache is common with mild viral infections. More severe viral infections may simply feature more overwhelming respiratory symptoms and fever that lead to underreporting or underascertainment of headache,” said Dr. Robbins, who was not involved with the research.

He noted that the finding showing an association of headache and COVID-19 with a younger age and in women “may be related to a higher prevalence of migraine biology in such patients, and being triggered by the virus or the psychological stress associated with it.”

Dr. Robbins added that viral illnesses have long been associated with new daily persistent headache, “dating back to the early 1980s,” when it was first described in association with Epstein-Barr virus. These infections have also been implicated in the progression of migraine to chronic migraine in adolescents.

“In my view, treatment should be aimed at the symptomatic headache type for which new daily persistent headache resembles, regardless of the potential inciting factor,” Dr. Robbins said.

Dr. Pozo-Rosich has received consulting fees from Allergan, Amgen, Almirall, Biohaven, Chiesi, Eli Lilly, Medscape, Novartis, and Teva Pharmaceuticals. Dr. Robbins has disclosed no relevant financial relationships.

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

Headache may be a key symptom of COVID-19 that predicts the disease’s clinical evolution in individual patients, new research suggests. An observational study of more than 100 patients showed that headache onset could occur during the presymptomatic or symptomatic phase of COVID-19 and could resemble tension-type or migraine headache.

Headache itself was associated with a shorter symptomatic period, while headache and anosmia were associated with a shorter hospitalization period. In a subgroup of participants, headache persisted even after the symptoms of COVID-19 had been resolved.

Investigators noted that understanding the pathophysiology of headache in COVID-19 could improve understanding of migraine and other headache disorders. “It seems that those patients who start early on, during the asymptomatic or early symptomatic period of COVID-19, with headache have a more localized inflammatory response that may reflect the ability of the body to better control and respond to the infection by SARS-CoV-2,” lead investigator Patricia Pozo-Rosich, MD, PhD, head of the headache and craniofacial pain unit at Vall d’Hebron University Hospital, Barcelona, said in an interview.

She presented the findings at the virtual annual meeting of the American Headache Society.

Systemic inflammation

Headache is one of the main symptoms of COVID-19. A recent study of 214 patients with COVID-19 showed that approximately 13% of the participants had headache and 5% had anosmia.

SARS-CoV-2 penetrates the cells through the ACE2 receptor, which is present throughout the body. “SARS-CoV-2 enters the body through the nasal cavity and it probably penetrates the nervous system in the periphery through afferent branches of the olfactory and trigeminal nerve,” Dr. Pozo-Rosich said. It travels to the lungs and, later, the bloodstream. This generates systemic inflammation that may turn into a cytokine storm. Evidence has identified cortical hyperintensities and olfactory bulb hyperintensities in patients with COVID-19, suggesting that the virus directly infects the CNS.

Interleukin-6, one of the main inflammatory molecules, has been proven to be related to COVID-19 and has become a therapeutic target. Levels of IL-6 may be lower and tend to be more stable in patients with both COVID-19 and headache than in patients with COVID-19 only.

The researchers observed 130 patients (51% women; mean age, 54 years) with COVID-19 who were attended by neurologists at Vall d’Hebron. In this group, 74.4% had headache. Patients with headache tended to be younger than those without headache (mean age, 50 years vs. 63 years, respectively) and tended to be women (58.6% vs. 29.4%).

Approximately one-third of patients with headache had a history of migraine. Most reported mild to moderate pain that resembled tension-type headache. In participants with severe pain and migraine-like features, headache more often began during the asymptomatic phase of COVID-19.

Disease evolution predictor?

The investigators followed up on 100 of the 130 patients with COVID-19, of whom 74 had headache. About 38% of these patients had ongoing headache after 6 weeks, which suggests that some patients may develop a new daily persistent headache once a 3-month period has elapsed. Half of this group had no previous headache history. Headache had been the prodromal symptom of COVID-19 for 21.4% of these patients.

Results showed that headache predicted the clinical evolution of COVID-19. The symptomatic phase of COVID-19 was 7 days shorter for patients with headache than for those without headache. In addition, the period of hospitalization was 7 days shorter for patients with headache and anosmia, compared with patients who had neither headache nor anosmia.

Most therapies, including ibuprofen, candesartan, and anti–calcitonin gene–related peptide (CGRP) monoclonal antibodies, are safe for treating headache in COVID-19, the investigators noted. “We should just try to initially avoid steroids to avoid interference with the body’s reaction to SARS-CoV-2,” Dr. Pozo-Rosich said.

Researchers at Sidney Kimmel Medical College, Philadelphia, are currently studying intranasal vazegepant, an anti-CGRP therapy, as a way to potentially blunt the severe inflammatory response in the lungs of patients with COVID-19, she noted, adding that this peptide may have a future role not only in headache, but also in COVID-19.

Historical link to viral infections

Commenting on the study, Matthew S. Robbins, MD, associate professor of neurology at Weill Cornell Medicine, New York, said the findings associating headache with a shorter symptomatic phase of COVID-19 were “interesting.”

“Headache is common with mild viral infections. More severe viral infections may simply feature more overwhelming respiratory symptoms and fever that lead to underreporting or underascertainment of headache,” said Dr. Robbins, who was not involved with the research.

He noted that the finding showing an association of headache and COVID-19 with a younger age and in women “may be related to a higher prevalence of migraine biology in such patients, and being triggered by the virus or the psychological stress associated with it.”

Dr. Robbins added that viral illnesses have long been associated with new daily persistent headache, “dating back to the early 1980s,” when it was first described in association with Epstein-Barr virus. These infections have also been implicated in the progression of migraine to chronic migraine in adolescents.

“In my view, treatment should be aimed at the symptomatic headache type for which new daily persistent headache resembles, regardless of the potential inciting factor,” Dr. Robbins said.

Dr. Pozo-Rosich has received consulting fees from Allergan, Amgen, Almirall, Biohaven, Chiesi, Eli Lilly, Medscape, Novartis, and Teva Pharmaceuticals. Dr. Robbins has disclosed no relevant financial relationships.

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

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment. Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

“The addition of a CGRP monoclonal antibody provided statistically significantly fewer monthly headache days,” said study investigator Fred Cohen, MD, an internal medicine resident physician at Montefiore Health System, New York. “However, this was a retrospective chart review, which is hindered by elements such as recall bias. Therefore, future prospective studies are warranted for higher quality data.”

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

Fewer headache days

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed.

The CGRP-mAbs fremanezumab, galcanezumab, and erenumab, have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. However, patients treated with Botox were excluded from these trials and to date there are no data on combination treatment with Botox and CGRP-mAbs.

To determine whether adjunctive treatment with CGRP-mAbs augments Botox therapy in chronic migraine the investigators conducted a retrospective chart review of patients receiving Botox and prescribed a CGRP-mAb.

Eligible patients met the International Classification of Headache Disorders, 3rd edition, criteria for chronic migraine; were age 18 years or older; and presented at a single headache center between May 2018 and May 2019. Patients who received another new therapy during the study or those taking CGRP-mAb treatment for less than 2 months were excluded.

The study’s primary outcome was change in the number of reported monthly headache days, and change in pain severity was the secondary outcome.

The final analysis included data on 153 patients. The population’s mean age was 47.1 years, and 139 patients (90.8%) were women. In all, 89 patients (58.0%) received erenumab (35 received 70 mg and 54 received 140 mg), 51 (33.0%) received galcanezumab, and 13 (9.0%) received fremanezumab.

Overall, 114 (74.5%) patients reported a decrease in monthly headache days or pain severity. In the group of 66 patients for whom quantitative data were available, the average number of monthly headache days before Botox treatment was 25.7. After Botox treatment, patients had an average decrease of 10.9 monthly headache days, a 42.4% reduction, so on average study participants continued to have an average of 14.8 monthly headache days.

After treatment with a CGRP-mAb the number decreased by 5.6 additional days (37.8%). Patients receiving combined therapy had an average of 9.1 monthly headache days. The total decrease from baseline was 16.6 fewer monthly headache days, a 64.6% reduction.

The number of headache days per month was reduced to 9.3 for erenumab and galcanezumab and 5.8 for fremanezumab. However, few patients in the study took fremanezumab so this result had less statistical power than the results for the other CGRP-mAbs.

A total of 13 patients (8.5%) reported side effects associated with the CGRP-mAbs, which included constipation, injection-site reaction, and fatigue.
 

More evidence is needed

Commenting on the findings, Peter McAllister, MD, medical director of the New England Institute for Neurology and Headache in Stamford, Conn., said the study’s main limitation is that it is a retrospective chart review, which yields lower level evidence than a prospective, double-blind, placebo-controlled study. Dr. McAllister, who was not involved in the research, also noted that the sample size was small, particularly with respect to fremanezumab.

“This study, despite its limitations, shows that addition of a monoclonal antibody to onabotulinumtoxinA is safe and well tolerated, and may confer additional reduction in migraine or headache days. The authors correctly state that more evidence via prospective study is warranted,” said Dr. McAllister, who is also chief medical officer of the New England Institute for Clinical Research and was not involved in the investigation.

Dr. Cohen has reported no relevant financial relationships. Dr. McAllister was an investigator in the PREEMPT trial of onabotulinumtoxinA, as well as in all of the phase 3 monoclonal antibody studies.

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

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment. Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

“The addition of a CGRP monoclonal antibody provided statistically significantly fewer monthly headache days,” said study investigator Fred Cohen, MD, an internal medicine resident physician at Montefiore Health System, New York. “However, this was a retrospective chart review, which is hindered by elements such as recall bias. Therefore, future prospective studies are warranted for higher quality data.”

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

Fewer headache days

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed.

The CGRP-mAbs fremanezumab, galcanezumab, and erenumab, have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. However, patients treated with Botox were excluded from these trials and to date there are no data on combination treatment with Botox and CGRP-mAbs.

To determine whether adjunctive treatment with CGRP-mAbs augments Botox therapy in chronic migraine the investigators conducted a retrospective chart review of patients receiving Botox and prescribed a CGRP-mAb.

Eligible patients met the International Classification of Headache Disorders, 3rd edition, criteria for chronic migraine; were age 18 years or older; and presented at a single headache center between May 2018 and May 2019. Patients who received another new therapy during the study or those taking CGRP-mAb treatment for less than 2 months were excluded.

The study’s primary outcome was change in the number of reported monthly headache days, and change in pain severity was the secondary outcome.

The final analysis included data on 153 patients. The population’s mean age was 47.1 years, and 139 patients (90.8%) were women. In all, 89 patients (58.0%) received erenumab (35 received 70 mg and 54 received 140 mg), 51 (33.0%) received galcanezumab, and 13 (9.0%) received fremanezumab.

Overall, 114 (74.5%) patients reported a decrease in monthly headache days or pain severity. In the group of 66 patients for whom quantitative data were available, the average number of monthly headache days before Botox treatment was 25.7. After Botox treatment, patients had an average decrease of 10.9 monthly headache days, a 42.4% reduction, so on average study participants continued to have an average of 14.8 monthly headache days.

After treatment with a CGRP-mAb the number decreased by 5.6 additional days (37.8%). Patients receiving combined therapy had an average of 9.1 monthly headache days. The total decrease from baseline was 16.6 fewer monthly headache days, a 64.6% reduction.

The number of headache days per month was reduced to 9.3 for erenumab and galcanezumab and 5.8 for fremanezumab. However, few patients in the study took fremanezumab so this result had less statistical power than the results for the other CGRP-mAbs.

A total of 13 patients (8.5%) reported side effects associated with the CGRP-mAbs, which included constipation, injection-site reaction, and fatigue.
 

More evidence is needed

Commenting on the findings, Peter McAllister, MD, medical director of the New England Institute for Neurology and Headache in Stamford, Conn., said the study’s main limitation is that it is a retrospective chart review, which yields lower level evidence than a prospective, double-blind, placebo-controlled study. Dr. McAllister, who was not involved in the research, also noted that the sample size was small, particularly with respect to fremanezumab.

“This study, despite its limitations, shows that addition of a monoclonal antibody to onabotulinumtoxinA is safe and well tolerated, and may confer additional reduction in migraine or headache days. The authors correctly state that more evidence via prospective study is warranted,” said Dr. McAllister, who is also chief medical officer of the New England Institute for Clinical Research and was not involved in the investigation.

Dr. Cohen has reported no relevant financial relationships. Dr. McAllister was an investigator in the PREEMPT trial of onabotulinumtoxinA, as well as in all of the phase 3 monoclonal antibody studies.

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

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment. Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

“The addition of a CGRP monoclonal antibody provided statistically significantly fewer monthly headache days,” said study investigator Fred Cohen, MD, an internal medicine resident physician at Montefiore Health System, New York. “However, this was a retrospective chart review, which is hindered by elements such as recall bias. Therefore, future prospective studies are warranted for higher quality data.”

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

Fewer headache days

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed.

The CGRP-mAbs fremanezumab, galcanezumab, and erenumab, have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. However, patients treated with Botox were excluded from these trials and to date there are no data on combination treatment with Botox and CGRP-mAbs.

To determine whether adjunctive treatment with CGRP-mAbs augments Botox therapy in chronic migraine the investigators conducted a retrospective chart review of patients receiving Botox and prescribed a CGRP-mAb.

Eligible patients met the International Classification of Headache Disorders, 3rd edition, criteria for chronic migraine; were age 18 years or older; and presented at a single headache center between May 2018 and May 2019. Patients who received another new therapy during the study or those taking CGRP-mAb treatment for less than 2 months were excluded.

The study’s primary outcome was change in the number of reported monthly headache days, and change in pain severity was the secondary outcome.

The final analysis included data on 153 patients. The population’s mean age was 47.1 years, and 139 patients (90.8%) were women. In all, 89 patients (58.0%) received erenumab (35 received 70 mg and 54 received 140 mg), 51 (33.0%) received galcanezumab, and 13 (9.0%) received fremanezumab.

Overall, 114 (74.5%) patients reported a decrease in monthly headache days or pain severity. In the group of 66 patients for whom quantitative data were available, the average number of monthly headache days before Botox treatment was 25.7. After Botox treatment, patients had an average decrease of 10.9 monthly headache days, a 42.4% reduction, so on average study participants continued to have an average of 14.8 monthly headache days.

After treatment with a CGRP-mAb the number decreased by 5.6 additional days (37.8%). Patients receiving combined therapy had an average of 9.1 monthly headache days. The total decrease from baseline was 16.6 fewer monthly headache days, a 64.6% reduction.

The number of headache days per month was reduced to 9.3 for erenumab and galcanezumab and 5.8 for fremanezumab. However, few patients in the study took fremanezumab so this result had less statistical power than the results for the other CGRP-mAbs.

A total of 13 patients (8.5%) reported side effects associated with the CGRP-mAbs, which included constipation, injection-site reaction, and fatigue.
 

More evidence is needed

Commenting on the findings, Peter McAllister, MD, medical director of the New England Institute for Neurology and Headache in Stamford, Conn., said the study’s main limitation is that it is a retrospective chart review, which yields lower level evidence than a prospective, double-blind, placebo-controlled study. Dr. McAllister, who was not involved in the research, also noted that the sample size was small, particularly with respect to fremanezumab.

“This study, despite its limitations, shows that addition of a monoclonal antibody to onabotulinumtoxinA is safe and well tolerated, and may confer additional reduction in migraine or headache days. The authors correctly state that more evidence via prospective study is warranted,” said Dr. McAllister, who is also chief medical officer of the New England Institute for Clinical Research and was not involved in the investigation.

Dr. Cohen has reported no relevant financial relationships. Dr. McAllister was an investigator in the PREEMPT trial of onabotulinumtoxinA, as well as in all of the phase 3 monoclonal antibody studies.

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

A combination of rizatriptan and the nonsteroidal anti-inflammatory drug (NSAID) meloxicam formulated to improve oral absorption led to better pain control than did rizatriptan alone in a phase 3 clinical trial. The combination (AXS-07), in development by Axsome Therapeutics, was also safe and well tolerated, according to Cedric O’Gorman, MD, Axsome senior vice president for clinical development and medical affairs. It was tested in subjects who had inadequately responded to previous treatment and who had an average of 2-8 migraines per month.

The therapy combines 10-mg rizatriptan with 20-mg meloxicam delivered by the company’s MoSEIC technology. “Treatment with AXS-07 resulted in rapid, sustained, substantial, and statistically significant effect as compared with rizatriptan and placebo. The enhanced effect of AXS-07 may be especially relevant for patients with more difficult-to-treat migraine,” said Dr. O’Gorman during a presentation of the study at the virtual annual meeting of the American Headache Society.

Matthew Robbins, MD, said in an interview, “This combination may be particularly useful for patients who want to take an oral medication but still need rapid and sustained pain freedom.” Dr. Robbins is the neurology residency program director at New York Presbyterian Hospital and an associate professor of neurology at Weill Cornell Medicine, New York. He was not involved in the research.

The study randomized 1,594 patients 2:2:2:1 to AXS-07, rizatriptan alone, MoSEIC meloxicam alone, or placebo, which could be administered immediately after a migraine event. Between 35% and 40% of participants across the groups had previously used triptans. The mean migraine treatment optimization questionnaire (mTOQ4) score was 3.6, indicating that the population was made up of people with poor responses to medication. Among patients in the study group, 37%-43% had severe pain intensity, 41%-47% were obese, and 35%-37% had morning migraine.

At 2 hours, more patients in the AXS-07 group than in the placebo group were pain free (19.9% vs. 6.7%; P < 0.001). They were also more likely to experience freedom from the most bothersome symptom at 2 hours (36.9% vs. 24.4%; P = 0.002). Secondary outcome measures favored the AXS-07 group when compared with the rizatriptan-only group, including 1-hour pain relief (44% vs. 37%; P = 0.04), 2- to 24-hour sustained pain relief (53% vs. 44%; P = 0.006), 2- to 48-hour sustained pain relief (47% vs. 37%; P = 0.003), 2- to 24-hour sustained pain freedom (16% vs. 11%; P = 0.038), 2- to 48-hour sustained pain freedom (15% vs. 8.8%; P = 0.003), rescue medication use (23% vs. 35%; P < 0.001), a rating of much or very much improved on the Patient Global Impression of Change (PGI-C) scale (47% vs. 39%; P = 0.022), and functional improvement at 24 hours (64% vs. 56%; P = 0.027).

“The percentage of patients achieving pain relief with AXS-07 was numerically greater than with rizatriptan at every time point measure, starting at 15 minutes, and was statistically significant by 60 minutes. This is significant because rizatriptan is widely recognized as the fastest-acting and one of the most effective oral triptans,” said Dr. O’Gorman.

The frequency of adverse events was 11.0% in the AXS-07, 15.4% in the rizatriptan group, 11.5% in the meloxicam group, and 6.0% in the placebo group.

“The added benefit of this study was the demonstration of efficacy in patients who have previously failed other acute treatments. We know that ineffective acute treatments are a likely risk factor for the progression of episodic migraine to chronic migraine, and the more options that we have for our patients, the better,” Dr. Robbins commented.

He remains concerned about cost and access, however. A limited number of tablets per month for acute treatments prompt clinicians to prescribe the medications individually and advise patients to take them in combination. “Rizatriptan is generally available in 12 monthly tablets by many coverage plans, and I would hope that, if ultimately FDA approved, a similar allotment is made affordable and accessible,” he said.

The study was funded by Axsome Therapeutics. Dr. O’Gorman is an employee of Axsome. Dr. Robbins has no relevant financial disclosures.

SOURCE: O’Gorman C et al. AHS 2020, Abstract 840673.

A combination of rizatriptan and the nonsteroidal anti-inflammatory drug (NSAID) meloxicam formulated to improve oral absorption led to better pain control than did rizatriptan alone in a phase 3 clinical trial. The combination (AXS-07), in development by Axsome Therapeutics, was also safe and well tolerated, according to Cedric O’Gorman, MD, Axsome senior vice president for clinical development and medical affairs. It was tested in subjects who had inadequately responded to previous treatment and who had an average of 2-8 migraines per month.

The therapy combines 10-mg rizatriptan with 20-mg meloxicam delivered by the company’s MoSEIC technology. “Treatment with AXS-07 resulted in rapid, sustained, substantial, and statistically significant effect as compared with rizatriptan and placebo. The enhanced effect of AXS-07 may be especially relevant for patients with more difficult-to-treat migraine,” said Dr. O’Gorman during a presentation of the study at the virtual annual meeting of the American Headache Society.

Matthew Robbins, MD, said in an interview, “This combination may be particularly useful for patients who want to take an oral medication but still need rapid and sustained pain freedom.” Dr. Robbins is the neurology residency program director at New York Presbyterian Hospital and an associate professor of neurology at Weill Cornell Medicine, New York. He was not involved in the research.

The study randomized 1,594 patients 2:2:2:1 to AXS-07, rizatriptan alone, MoSEIC meloxicam alone, or placebo, which could be administered immediately after a migraine event. Between 35% and 40% of participants across the groups had previously used triptans. The mean migraine treatment optimization questionnaire (mTOQ4) score was 3.6, indicating that the population was made up of people with poor responses to medication. Among patients in the study group, 37%-43% had severe pain intensity, 41%-47% were obese, and 35%-37% had morning migraine.

At 2 hours, more patients in the AXS-07 group than in the placebo group were pain free (19.9% vs. 6.7%; P < 0.001). They were also more likely to experience freedom from the most bothersome symptom at 2 hours (36.9% vs. 24.4%; P = 0.002). Secondary outcome measures favored the AXS-07 group when compared with the rizatriptan-only group, including 1-hour pain relief (44% vs. 37%; P = 0.04), 2- to 24-hour sustained pain relief (53% vs. 44%; P = 0.006), 2- to 48-hour sustained pain relief (47% vs. 37%; P = 0.003), 2- to 24-hour sustained pain freedom (16% vs. 11%; P = 0.038), 2- to 48-hour sustained pain freedom (15% vs. 8.8%; P = 0.003), rescue medication use (23% vs. 35%; P < 0.001), a rating of much or very much improved on the Patient Global Impression of Change (PGI-C) scale (47% vs. 39%; P = 0.022), and functional improvement at 24 hours (64% vs. 56%; P = 0.027).

“The percentage of patients achieving pain relief with AXS-07 was numerically greater than with rizatriptan at every time point measure, starting at 15 minutes, and was statistically significant by 60 minutes. This is significant because rizatriptan is widely recognized as the fastest-acting and one of the most effective oral triptans,” said Dr. O’Gorman.

The frequency of adverse events was 11.0% in the AXS-07, 15.4% in the rizatriptan group, 11.5% in the meloxicam group, and 6.0% in the placebo group.

“The added benefit of this study was the demonstration of efficacy in patients who have previously failed other acute treatments. We know that ineffective acute treatments are a likely risk factor for the progression of episodic migraine to chronic migraine, and the more options that we have for our patients, the better,” Dr. Robbins commented.

He remains concerned about cost and access, however. A limited number of tablets per month for acute treatments prompt clinicians to prescribe the medications individually and advise patients to take them in combination. “Rizatriptan is generally available in 12 monthly tablets by many coverage plans, and I would hope that, if ultimately FDA approved, a similar allotment is made affordable and accessible,” he said.

The study was funded by Axsome Therapeutics. Dr. O’Gorman is an employee of Axsome. Dr. Robbins has no relevant financial disclosures.

SOURCE: O’Gorman C et al. AHS 2020, Abstract 840673.

A combination of rizatriptan and the nonsteroidal anti-inflammatory drug (NSAID) meloxicam formulated to improve oral absorption led to better pain control than did rizatriptan alone in a phase 3 clinical trial. The combination (AXS-07), in development by Axsome Therapeutics, was also safe and well tolerated, according to Cedric O’Gorman, MD, Axsome senior vice president for clinical development and medical affairs. It was tested in subjects who had inadequately responded to previous treatment and who had an average of 2-8 migraines per month.

The therapy combines 10-mg rizatriptan with 20-mg meloxicam delivered by the company’s MoSEIC technology. “Treatment with AXS-07 resulted in rapid, sustained, substantial, and statistically significant effect as compared with rizatriptan and placebo. The enhanced effect of AXS-07 may be especially relevant for patients with more difficult-to-treat migraine,” said Dr. O’Gorman during a presentation of the study at the virtual annual meeting of the American Headache Society.

Matthew Robbins, MD, said in an interview, “This combination may be particularly useful for patients who want to take an oral medication but still need rapid and sustained pain freedom.” Dr. Robbins is the neurology residency program director at New York Presbyterian Hospital and an associate professor of neurology at Weill Cornell Medicine, New York. He was not involved in the research.

The study randomized 1,594 patients 2:2:2:1 to AXS-07, rizatriptan alone, MoSEIC meloxicam alone, or placebo, which could be administered immediately after a migraine event. Between 35% and 40% of participants across the groups had previously used triptans. The mean migraine treatment optimization questionnaire (mTOQ4) score was 3.6, indicating that the population was made up of people with poor responses to medication. Among patients in the study group, 37%-43% had severe pain intensity, 41%-47% were obese, and 35%-37% had morning migraine.

At 2 hours, more patients in the AXS-07 group than in the placebo group were pain free (19.9% vs. 6.7%; P < 0.001). They were also more likely to experience freedom from the most bothersome symptom at 2 hours (36.9% vs. 24.4%; P = 0.002). Secondary outcome measures favored the AXS-07 group when compared with the rizatriptan-only group, including 1-hour pain relief (44% vs. 37%; P = 0.04), 2- to 24-hour sustained pain relief (53% vs. 44%; P = 0.006), 2- to 48-hour sustained pain relief (47% vs. 37%; P = 0.003), 2- to 24-hour sustained pain freedom (16% vs. 11%; P = 0.038), 2- to 48-hour sustained pain freedom (15% vs. 8.8%; P = 0.003), rescue medication use (23% vs. 35%; P < 0.001), a rating of much or very much improved on the Patient Global Impression of Change (PGI-C) scale (47% vs. 39%; P = 0.022), and functional improvement at 24 hours (64% vs. 56%; P = 0.027).

“The percentage of patients achieving pain relief with AXS-07 was numerically greater than with rizatriptan at every time point measure, starting at 15 minutes, and was statistically significant by 60 minutes. This is significant because rizatriptan is widely recognized as the fastest-acting and one of the most effective oral triptans,” said Dr. O’Gorman.

The frequency of adverse events was 11.0% in the AXS-07, 15.4% in the rizatriptan group, 11.5% in the meloxicam group, and 6.0% in the placebo group.

“The added benefit of this study was the demonstration of efficacy in patients who have previously failed other acute treatments. We know that ineffective acute treatments are a likely risk factor for the progression of episodic migraine to chronic migraine, and the more options that we have for our patients, the better,” Dr. Robbins commented.

He remains concerned about cost and access, however. A limited number of tablets per month for acute treatments prompt clinicians to prescribe the medications individually and advise patients to take them in combination. “Rizatriptan is generally available in 12 monthly tablets by many coverage plans, and I would hope that, if ultimately FDA approved, a similar allotment is made affordable and accessible,” he said.

The study was funded by Axsome Therapeutics. Dr. O’Gorman is an employee of Axsome. Dr. Robbins has no relevant financial disclosures.

SOURCE: O’Gorman C et al. AHS 2020, Abstract 840673.

The calcitonin gene–related peptide receptor monoclonal antibodies (CGRP mAbs)for treatment of migraine have gained wide acceptance since their approval in 2018, but a real-world study has reported adverse event rates higher than those the preapproval clinical trials reported and has found that patients who fail on one of the treatments are likely to fail again if they’re switched to another.

At the virtual annual meeting of the American Headache Society, Larry Robbins, MD, assistant professor of neurology at Chicago Medical School, North Chicago, reported on the results of his postapproval study of 369 migraine patients taking one of the three approved CGRP mAbs. “If patients do not do well on one mAb, it is sometimes worthwhile to switch, but most patients do not do well from the second or third mAb as well,” Dr. Robbins said in an interview. “In addition, there are numerous adverse effects that were not captured in the official phase 3 studies. Efficacy has held up well, but for a number of reasons, the true adverse event profile is often missed.”
 

Assessing efficacy and adverse events

In evaluating the efficacy of the three approved CGRP mAbs, Dr. Robbins used measures of degree of relief based on percentage decrease of symptoms versus baseline and the number of migraine days, combined with the number of moderate or severe headache days. Most of the patients kept calendars and were interviewed by two headache specialists. The study also utilized a 10-point visual analog scale and averaged relief over 3 months.

Of the patients on erenumab (n = 220), 10% described 95%-100% relief of symptoms, 24% reported 71%-100% relief, 34% described 31%-70% relief, and 43% experienced 0%-30% relief. Adverse events among this group included constipation (20%), nausea (7%), increased headache and fatigue (5% for each), and joint pain and depression (3% for each). Three patients on erenumab experienced unspecified serious adverse reactions.

In the fremanezumab group (n = 79), 8% described 95%-100% relief, 18% had 71%-100% relief, 33% experienced 31%-70% improvement, and 50% had 30% improvement or less. Adverse events in these patients included nausea, constipation, and depression (6% each); increased headache and muscle pain or cramps (5% each); rash, joint pain, anxiety, fatigue, or weight gain (4% for each ); and injection-site reactions, irritability, or alopecia (3% combined).

Patients taking galcanezumab (n = 70) reported the following outcomes: 3% had 95%-100% relief of symptoms, 14% had 71%-100% relief, 46% with 31%-70% relief, and 40% had 0%-30% relief. This group’s adverse events included constipation (10%); depression and increased headache (6% for each); nausea, fatigue, or injection-site reactions (4% each ); and muscle pain or cramps, rash, anxiety, weight gain, or alopecia (3% each).

Dr. Robbins also assessed switching from one CGRP mAb to another for various reasons. “When the reason for switching was poor efficacy, only 27% of patients did well,” he stated in the presentation. “If the reason was adverse events, 33% did well. When insurance/financial reasons alone were the reason, but efficacy was adequate, 58% did well after switching.”

Overall, postapproval efficacy of the medications “held up well,” Dr. Robbins noted. “Efficacy after 2 months somewhat predicted how patients would do after 6 months.” Among the predictors of poor response his study identified were opioid use and moderate or severe refractory chronic migraine at baseline.

However, the rates of adverse events he reported were significantly greater than those reported in the clinical trials, Dr. Robbins said. He noted four reasons to explain this discrepancy: the trials did not use an 18-item supplemental checklist that he has advocated to identify patients at risk of side effects, the trials weren’t powered for adverse events, patients in the trials tended to be less refractory than those in the clinic, and that adverse events tend to be underreported in trials.

“Adverse events become disaggregated, with the same descriptors used for an adverse event,” Dr. Robbins said. “Examples include fatigue, somnolence, and tiredness; all may be 1%, while different patients are describing the same adverse event. It is possible to reaggregate the adverse events after the study, but this is fraught with error.”
 

Uncovering shortcomings in clinical trials

Emily Rubenstein Engel, MD, director of the Dalessio Headache Center at the Scripps Clinic in La Jolla, Calif., noted that Dr. Robbins’ findings are significant for two reasons. “Dr. Robbins has uncovered a general flaw in clinical trials, whereby the lack of consistency of adverse event terminology as well as the lack of a standardized questionnaire format for adverse events can result in significant under-reporting of adverse events,” she said.

“Specifically for the CGRPs,” Dr. Engel continued, “he has raised awareness that this new class of medication, however promising from an efficacy standpoint, has side effects that are much more frequent and severe than seen in the initial clinical trials.”

Dr. Robbins reported financial relationships with Allergan, Amgen and Teva. Dr. Engel has no financial relationships to disclose.

The calcitonin gene–related peptide receptor monoclonal antibodies (CGRP mAbs)for treatment of migraine have gained wide acceptance since their approval in 2018, but a real-world study has reported adverse event rates higher than those the preapproval clinical trials reported and has found that patients who fail on one of the treatments are likely to fail again if they’re switched to another.

At the virtual annual meeting of the American Headache Society, Larry Robbins, MD, assistant professor of neurology at Chicago Medical School, North Chicago, reported on the results of his postapproval study of 369 migraine patients taking one of the three approved CGRP mAbs. “If patients do not do well on one mAb, it is sometimes worthwhile to switch, but most patients do not do well from the second or third mAb as well,” Dr. Robbins said in an interview. “In addition, there are numerous adverse effects that were not captured in the official phase 3 studies. Efficacy has held up well, but for a number of reasons, the true adverse event profile is often missed.”
 

Assessing efficacy and adverse events

In evaluating the efficacy of the three approved CGRP mAbs, Dr. Robbins used measures of degree of relief based on percentage decrease of symptoms versus baseline and the number of migraine days, combined with the number of moderate or severe headache days. Most of the patients kept calendars and were interviewed by two headache specialists. The study also utilized a 10-point visual analog scale and averaged relief over 3 months.

Of the patients on erenumab (n = 220), 10% described 95%-100% relief of symptoms, 24% reported 71%-100% relief, 34% described 31%-70% relief, and 43% experienced 0%-30% relief. Adverse events among this group included constipation (20%), nausea (7%), increased headache and fatigue (5% for each), and joint pain and depression (3% for each). Three patients on erenumab experienced unspecified serious adverse reactions.

In the fremanezumab group (n = 79), 8% described 95%-100% relief, 18% had 71%-100% relief, 33% experienced 31%-70% improvement, and 50% had 30% improvement or less. Adverse events in these patients included nausea, constipation, and depression (6% each); increased headache and muscle pain or cramps (5% each); rash, joint pain, anxiety, fatigue, or weight gain (4% for each ); and injection-site reactions, irritability, or alopecia (3% combined).

Patients taking galcanezumab (n = 70) reported the following outcomes: 3% had 95%-100% relief of symptoms, 14% had 71%-100% relief, 46% with 31%-70% relief, and 40% had 0%-30% relief. This group’s adverse events included constipation (10%); depression and increased headache (6% for each); nausea, fatigue, or injection-site reactions (4% each ); and muscle pain or cramps, rash, anxiety, weight gain, or alopecia (3% each).

Dr. Robbins also assessed switching from one CGRP mAb to another for various reasons. “When the reason for switching was poor efficacy, only 27% of patients did well,” he stated in the presentation. “If the reason was adverse events, 33% did well. When insurance/financial reasons alone were the reason, but efficacy was adequate, 58% did well after switching.”

Overall, postapproval efficacy of the medications “held up well,” Dr. Robbins noted. “Efficacy after 2 months somewhat predicted how patients would do after 6 months.” Among the predictors of poor response his study identified were opioid use and moderate or severe refractory chronic migraine at baseline.

However, the rates of adverse events he reported were significantly greater than those reported in the clinical trials, Dr. Robbins said. He noted four reasons to explain this discrepancy: the trials did not use an 18-item supplemental checklist that he has advocated to identify patients at risk of side effects, the trials weren’t powered for adverse events, patients in the trials tended to be less refractory than those in the clinic, and that adverse events tend to be underreported in trials.

“Adverse events become disaggregated, with the same descriptors used for an adverse event,” Dr. Robbins said. “Examples include fatigue, somnolence, and tiredness; all may be 1%, while different patients are describing the same adverse event. It is possible to reaggregate the adverse events after the study, but this is fraught with error.”
 

Uncovering shortcomings in clinical trials

Emily Rubenstein Engel, MD, director of the Dalessio Headache Center at the Scripps Clinic in La Jolla, Calif., noted that Dr. Robbins’ findings are significant for two reasons. “Dr. Robbins has uncovered a general flaw in clinical trials, whereby the lack of consistency of adverse event terminology as well as the lack of a standardized questionnaire format for adverse events can result in significant under-reporting of adverse events,” she said.

“Specifically for the CGRPs,” Dr. Engel continued, “he has raised awareness that this new class of medication, however promising from an efficacy standpoint, has side effects that are much more frequent and severe than seen in the initial clinical trials.”

Dr. Robbins reported financial relationships with Allergan, Amgen and Teva. Dr. Engel has no financial relationships to disclose.

The calcitonin gene–related peptide receptor monoclonal antibodies (CGRP mAbs)for treatment of migraine have gained wide acceptance since their approval in 2018, but a real-world study has reported adverse event rates higher than those the preapproval clinical trials reported and has found that patients who fail on one of the treatments are likely to fail again if they’re switched to another.

At the virtual annual meeting of the American Headache Society, Larry Robbins, MD, assistant professor of neurology at Chicago Medical School, North Chicago, reported on the results of his postapproval study of 369 migraine patients taking one of the three approved CGRP mAbs. “If patients do not do well on one mAb, it is sometimes worthwhile to switch, but most patients do not do well from the second or third mAb as well,” Dr. Robbins said in an interview. “In addition, there are numerous adverse effects that were not captured in the official phase 3 studies. Efficacy has held up well, but for a number of reasons, the true adverse event profile is often missed.”
 

Assessing efficacy and adverse events

In evaluating the efficacy of the three approved CGRP mAbs, Dr. Robbins used measures of degree of relief based on percentage decrease of symptoms versus baseline and the number of migraine days, combined with the number of moderate or severe headache days. Most of the patients kept calendars and were interviewed by two headache specialists. The study also utilized a 10-point visual analog scale and averaged relief over 3 months.

Of the patients on erenumab (n = 220), 10% described 95%-100% relief of symptoms, 24% reported 71%-100% relief, 34% described 31%-70% relief, and 43% experienced 0%-30% relief. Adverse events among this group included constipation (20%), nausea (7%), increased headache and fatigue (5% for each), and joint pain and depression (3% for each). Three patients on erenumab experienced unspecified serious adverse reactions.

In the fremanezumab group (n = 79), 8% described 95%-100% relief, 18% had 71%-100% relief, 33% experienced 31%-70% improvement, and 50% had 30% improvement or less. Adverse events in these patients included nausea, constipation, and depression (6% each); increased headache and muscle pain or cramps (5% each); rash, joint pain, anxiety, fatigue, or weight gain (4% for each ); and injection-site reactions, irritability, or alopecia (3% combined).

Patients taking galcanezumab (n = 70) reported the following outcomes: 3% had 95%-100% relief of symptoms, 14% had 71%-100% relief, 46% with 31%-70% relief, and 40% had 0%-30% relief. This group’s adverse events included constipation (10%); depression and increased headache (6% for each); nausea, fatigue, or injection-site reactions (4% each ); and muscle pain or cramps, rash, anxiety, weight gain, or alopecia (3% each).

Dr. Robbins also assessed switching from one CGRP mAb to another for various reasons. “When the reason for switching was poor efficacy, only 27% of patients did well,” he stated in the presentation. “If the reason was adverse events, 33% did well. When insurance/financial reasons alone were the reason, but efficacy was adequate, 58% did well after switching.”

Overall, postapproval efficacy of the medications “held up well,” Dr. Robbins noted. “Efficacy after 2 months somewhat predicted how patients would do after 6 months.” Among the predictors of poor response his study identified were opioid use and moderate or severe refractory chronic migraine at baseline.

However, the rates of adverse events he reported were significantly greater than those reported in the clinical trials, Dr. Robbins said. He noted four reasons to explain this discrepancy: the trials did not use an 18-item supplemental checklist that he has advocated to identify patients at risk of side effects, the trials weren’t powered for adverse events, patients in the trials tended to be less refractory than those in the clinic, and that adverse events tend to be underreported in trials.

“Adverse events become disaggregated, with the same descriptors used for an adverse event,” Dr. Robbins said. “Examples include fatigue, somnolence, and tiredness; all may be 1%, while different patients are describing the same adverse event. It is possible to reaggregate the adverse events after the study, but this is fraught with error.”
 

Uncovering shortcomings in clinical trials

Emily Rubenstein Engel, MD, director of the Dalessio Headache Center at the Scripps Clinic in La Jolla, Calif., noted that Dr. Robbins’ findings are significant for two reasons. “Dr. Robbins has uncovered a general flaw in clinical trials, whereby the lack of consistency of adverse event terminology as well as the lack of a standardized questionnaire format for adverse events can result in significant under-reporting of adverse events,” she said.

“Specifically for the CGRPs,” Dr. Engel continued, “he has raised awareness that this new class of medication, however promising from an efficacy standpoint, has side effects that are much more frequent and severe than seen in the initial clinical trials.”

Dr. Robbins reported financial relationships with Allergan, Amgen and Teva. Dr. Engel has no financial relationships to disclose.

An intranasal form of dihydroergotamine (DHE) targeting the upper nasal region is safe and effective for the treatment of migraine, and ranks high in patient satisfaction, according to results from a phase 3 clinical trial. In development by Impel NeuroPharma, the new formulation could offer patients an at-home alternative to intramuscular infusions or intravenous injections currently used to deliver DHE.

“Our analysis of the data suggests that nothing new or untoward seemed to be happening as a result of delivering DHE to the upper nasal space,” Stephen Shrewsbury, MD, chief medical officer of Impel NeuroPharma, said in an interview. The company released key results from its phase 3 clinical trial, while a poster examining patient satisfaction was presented by Dr. Shrewsbury at the virtual annual meeting of the American Headache Society.
 

An improved intranasal formulation

The product isn’t the first effort to develop an inhaled form of DHE. An inhaled version called Migranal, marketed by Bausch Health, delivers DHE to the front part of the nose, where it may be lost to the upper lip or down the throat, according to Dr. Shrewsbury. Impel’s formulation (INP104) delivers the drug to the upper nasal space, where an earlier phase 1 trial demonstrated it could achieve higher serum concentrations compared with Migranal.

In 2018, MAP Pharmaceuticals came close to a product, but it was ultimately rejected by the Food and Drug Administration because DHE was not stable in the propellant used in the formulation. This time is different, said Dr. Shrewsbury, who was chief medical officer at MAP before joining Impel. The new device holds DHE and the propellant in separate compartments until they are combined right before use, which should circumvent stability problems.

Dr. Shrewsbury believes that patients will welcome an inhaled version of DHE. “People with migraines don’t want to have to go into hospital or even an infusion center if they can help it,” he said.

The study was one of a number of presentations at the AHS meeting that focused on novel delivery methods for established drugs. “The idea of taking things that we know work and improving upon them, both in terms of formulation and then delivery, that’s a common theme. My impression is that this will be an interesting arrow to have in our sling,” said Andrew Charles, MD, professor of neurology and director of the UCLA Goldberg Migraine Program, who was not involved in the study.
 

Open-label trial results

The STOP 301 phase 3 open-label safety and tolerability trial treated over 5,650 migraine attacks in 354 patients who self-administered INP104 for up to 52 weeks. They were provided up to three doses per week (1.45 mg in a dose of two puffs, one per nostril). Maximum doses included two per day and three per week.

There were no new safety signals or concern trends in nasal safety findings. 15.0% of patients experienced nasal congestion, 6.8% nausea, 5.1% nasal discomfort, and 5.1% unpleasant taste.

A total of 66.3% of participants reported pain relief by 2 hours (severe or moderate pain reduced to mild or none, or mild pain reduced to none) following a dose, and 38% had freedom from pain. 16.3% reported pain relief onset at 15 minutes, with continued improvement over time. During weeks 21-24 of the study, 98.4% and 95% of patients reporting no recurrence of their migraine or use of rescue medications during the 24- and 48-hour periods after using INP104. “Once they got rid of the pain, it didn’t come back, and that’s been one of the shortcomings of many of the available oral therapies – although some of them can be quite effective, that effect can wear off and people can find their migraine comes back within a 24- or 48-hour period,” said Dr. Shrewsbury.

The drug was also rated as convenient, with 83.6% of participants strongly agreeing (50%) or agreeing (33.6%) that it is easy to use.

“It certainly looks like compliance will be good. The possibility is that this will be quite useful,” said Dr. Charles, who is also enthusiastic about some of the other drug formulations announced at the meeting. “It really is just fun times for us as clinicians to be able to have so many different options for patients,” he said.

Dr. Shrewsbury is an employee of Impel NeuroPharma, which funded the study.* Dr. Charles consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

SOURCE: Shrewsbury S, et al. AHS 2020. Abstract 832509.

*Correction, 6/19/20: An earlier version of this article misstated the name of Impel NeuroPharma.

An intranasal form of dihydroergotamine (DHE) targeting the upper nasal region is safe and effective for the treatment of migraine, and ranks high in patient satisfaction, according to results from a phase 3 clinical trial. In development by Impel NeuroPharma, the new formulation could offer patients an at-home alternative to intramuscular infusions or intravenous injections currently used to deliver DHE.

“Our analysis of the data suggests that nothing new or untoward seemed to be happening as a result of delivering DHE to the upper nasal space,” Stephen Shrewsbury, MD, chief medical officer of Impel NeuroPharma, said in an interview. The company released key results from its phase 3 clinical trial, while a poster examining patient satisfaction was presented by Dr. Shrewsbury at the virtual annual meeting of the American Headache Society.
 

An improved intranasal formulation

The product isn’t the first effort to develop an inhaled form of DHE. An inhaled version called Migranal, marketed by Bausch Health, delivers DHE to the front part of the nose, where it may be lost to the upper lip or down the throat, according to Dr. Shrewsbury. Impel’s formulation (INP104) delivers the drug to the upper nasal space, where an earlier phase 1 trial demonstrated it could achieve higher serum concentrations compared with Migranal.

In 2018, MAP Pharmaceuticals came close to a product, but it was ultimately rejected by the Food and Drug Administration because DHE was not stable in the propellant used in the formulation. This time is different, said Dr. Shrewsbury, who was chief medical officer at MAP before joining Impel. The new device holds DHE and the propellant in separate compartments until they are combined right before use, which should circumvent stability problems.

Dr. Shrewsbury believes that patients will welcome an inhaled version of DHE. “People with migraines don’t want to have to go into hospital or even an infusion center if they can help it,” he said.

The study was one of a number of presentations at the AHS meeting that focused on novel delivery methods for established drugs. “The idea of taking things that we know work and improving upon them, both in terms of formulation and then delivery, that’s a common theme. My impression is that this will be an interesting arrow to have in our sling,” said Andrew Charles, MD, professor of neurology and director of the UCLA Goldberg Migraine Program, who was not involved in the study.
 

Open-label trial results

The STOP 301 phase 3 open-label safety and tolerability trial treated over 5,650 migraine attacks in 354 patients who self-administered INP104 for up to 52 weeks. They were provided up to three doses per week (1.45 mg in a dose of two puffs, one per nostril). Maximum doses included two per day and three per week.

There were no new safety signals or concern trends in nasal safety findings. 15.0% of patients experienced nasal congestion, 6.8% nausea, 5.1% nasal discomfort, and 5.1% unpleasant taste.

A total of 66.3% of participants reported pain relief by 2 hours (severe or moderate pain reduced to mild or none, or mild pain reduced to none) following a dose, and 38% had freedom from pain. 16.3% reported pain relief onset at 15 minutes, with continued improvement over time. During weeks 21-24 of the study, 98.4% and 95% of patients reporting no recurrence of their migraine or use of rescue medications during the 24- and 48-hour periods after using INP104. “Once they got rid of the pain, it didn’t come back, and that’s been one of the shortcomings of many of the available oral therapies – although some of them can be quite effective, that effect can wear off and people can find their migraine comes back within a 24- or 48-hour period,” said Dr. Shrewsbury.

The drug was also rated as convenient, with 83.6% of participants strongly agreeing (50%) or agreeing (33.6%) that it is easy to use.

“It certainly looks like compliance will be good. The possibility is that this will be quite useful,” said Dr. Charles, who is also enthusiastic about some of the other drug formulations announced at the meeting. “It really is just fun times for us as clinicians to be able to have so many different options for patients,” he said.

Dr. Shrewsbury is an employee of Impel NeuroPharma, which funded the study.* Dr. Charles consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

SOURCE: Shrewsbury S, et al. AHS 2020. Abstract 832509.

*Correction, 6/19/20: An earlier version of this article misstated the name of Impel NeuroPharma.

An intranasal form of dihydroergotamine (DHE) targeting the upper nasal region is safe and effective for the treatment of migraine, and ranks high in patient satisfaction, according to results from a phase 3 clinical trial. In development by Impel NeuroPharma, the new formulation could offer patients an at-home alternative to intramuscular infusions or intravenous injections currently used to deliver DHE.

“Our analysis of the data suggests that nothing new or untoward seemed to be happening as a result of delivering DHE to the upper nasal space,” Stephen Shrewsbury, MD, chief medical officer of Impel NeuroPharma, said in an interview. The company released key results from its phase 3 clinical trial, while a poster examining patient satisfaction was presented by Dr. Shrewsbury at the virtual annual meeting of the American Headache Society.
 

An improved intranasal formulation

The product isn’t the first effort to develop an inhaled form of DHE. An inhaled version called Migranal, marketed by Bausch Health, delivers DHE to the front part of the nose, where it may be lost to the upper lip or down the throat, according to Dr. Shrewsbury. Impel’s formulation (INP104) delivers the drug to the upper nasal space, where an earlier phase 1 trial demonstrated it could achieve higher serum concentrations compared with Migranal.

In 2018, MAP Pharmaceuticals came close to a product, but it was ultimately rejected by the Food and Drug Administration because DHE was not stable in the propellant used in the formulation. This time is different, said Dr. Shrewsbury, who was chief medical officer at MAP before joining Impel. The new device holds DHE and the propellant in separate compartments until they are combined right before use, which should circumvent stability problems.

Dr. Shrewsbury believes that patients will welcome an inhaled version of DHE. “People with migraines don’t want to have to go into hospital or even an infusion center if they can help it,” he said.

The study was one of a number of presentations at the AHS meeting that focused on novel delivery methods for established drugs. “The idea of taking things that we know work and improving upon them, both in terms of formulation and then delivery, that’s a common theme. My impression is that this will be an interesting arrow to have in our sling,” said Andrew Charles, MD, professor of neurology and director of the UCLA Goldberg Migraine Program, who was not involved in the study.
 

Open-label trial results

The STOP 301 phase 3 open-label safety and tolerability trial treated over 5,650 migraine attacks in 354 patients who self-administered INP104 for up to 52 weeks. They were provided up to three doses per week (1.45 mg in a dose of two puffs, one per nostril). Maximum doses included two per day and three per week.

There were no new safety signals or concern trends in nasal safety findings. 15.0% of patients experienced nasal congestion, 6.8% nausea, 5.1% nasal discomfort, and 5.1% unpleasant taste.

A total of 66.3% of participants reported pain relief by 2 hours (severe or moderate pain reduced to mild or none, or mild pain reduced to none) following a dose, and 38% had freedom from pain. 16.3% reported pain relief onset at 15 minutes, with continued improvement over time. During weeks 21-24 of the study, 98.4% and 95% of patients reporting no recurrence of their migraine or use of rescue medications during the 24- and 48-hour periods after using INP104. “Once they got rid of the pain, it didn’t come back, and that’s been one of the shortcomings of many of the available oral therapies – although some of them can be quite effective, that effect can wear off and people can find their migraine comes back within a 24- or 48-hour period,” said Dr. Shrewsbury.

The drug was also rated as convenient, with 83.6% of participants strongly agreeing (50%) or agreeing (33.6%) that it is easy to use.

“It certainly looks like compliance will be good. The possibility is that this will be quite useful,” said Dr. Charles, who is also enthusiastic about some of the other drug formulations announced at the meeting. “It really is just fun times for us as clinicians to be able to have so many different options for patients,” he said.

Dr. Shrewsbury is an employee of Impel NeuroPharma, which funded the study.* Dr. Charles consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

SOURCE: Shrewsbury S, et al. AHS 2020. Abstract 832509.

*Correction, 6/19/20: An earlier version of this article misstated the name of Impel NeuroPharma.

A new analysis of 300 patients with posttraumatic headache confirmed some long-suspected risk factors for persistent headache, including history of medication overuse or psychological symptoms, new parathyroid hormone–associated comorbidities, and history of migraine. It also revealed a surprisingly high frequency of misdiagnosis. The original sample included 500 patients drawn from the Stanford Research Repository Cohort Discovery Tool, but a review found 200 records that were misdiagnosed and had to be excluded.

“It’s very easy to label someone who suffered a head injury and say this is the reason why they have this (headache),” said lead author Tommy Chan, MBBS, a headache fellow in the department of neurology at Stanford (Calif.) University, in an interview. Such patients are often seen by ED or primary care physicians who do not have a lot of experience with posttraumatic headache, and that can lead to negative consequences if a low-pressure headache is mistaken as stemming from a skull fracture. “It’s a very different treatment plan for one versus the other,” said Dr. Chan in an interview.

He noted that it can help to take a patient history that includes the preaccident headache frequency and determine if there was a change in frequency post injury.

Dr. Chan presented the results at the virtual annual meeting of the American Headache Society.

“The results are what one might expect, although we haven’t studied it enough to really know. We haven’t systematically characterized these risk factors for chronic posttraumatic headache very well, [so] it’s useful to have this information,” said Andrew Charles, MD, professor neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program, who was not involved in the study. However, Dr. Charles emphasized the need to confirm the results prospectively.
 

Defining risk factors

The analysis found that a history of migraines, medication overuse, psychological disorders, and new posttraumatic headache–associated comorbidities were all associated with a greater risk for persistent posttraumatic headache. None of those came as a surprise, “but we live in a world where medicine is practiced based on evidence, and providers want to see data to support that. I think that this will help with resource allocation. It’s important to address [a patient’s] overuse of medications, or if they’re having psychological symptoms,” said Dr. Chan.

A total of 150 patients in the analysis had acute posttraumatic headache (mean duration, 0.7 months) while 150 had persistent posttraumatic headache (mean duration, 24 months; P < .00001). Clinical factors associated with risk of persistent headache included a history migraine (relative risk, 2.4; P < .0001), a previous head injury (odds ratio, 5.8; P < .0001), medication overuse (RR, 2.6; P < .0001), preexisting psychological history (OR, 5; P < .0001), and new posttraumatic headache–associated comorbidities, such as vertigo or posttraumatic stress disorder (RR, 9.8; P < .0001).
 

Identifying patient subgroups

The researchers also identified four subcategories of patients with persistent posttraumatic headache, each with differing risk factors and clinical characteristics. It’s too soon to use these identifiers to make clinical recommendations, but Dr. Chan hopes that further study of these groups will be informative. “It might point us toward (the idea) that each patient population is actually different, even within the chronic persistent posttraumatic headache population, we can’t group them all under the same umbrella term. If we can tease out that a patient has truly had a head injury, but no history of migraine, no overuse of medication, no psychological history, and no other associated symptoms, this would be a very interesting population to study because they would help us understand the pathophysiology [of persistent posttraumatic headache].”

Although the study was conducted by defining persistent posttraumatic headache as lasting at least 3 months, Dr. Chan took issue with that commonly held definition. That choice is arbitrary, with no pathophysiological basis or data to support it, and is based more on clinical trials testing preventative treatments. But when it is used in clinical practice, it can muddy communication with patients. “When this timeline is told to a patient, and when it’s not achieved, they might become disappointed. We should not put too much emphasis on time. Everybody is different,” he said.

The study did not receive any funding. Dr. Chan had no relevant financial disclosures. Dr. Charles consults for consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

A new analysis of 300 patients with posttraumatic headache confirmed some long-suspected risk factors for persistent headache, including history of medication overuse or psychological symptoms, new parathyroid hormone–associated comorbidities, and history of migraine. It also revealed a surprisingly high frequency of misdiagnosis. The original sample included 500 patients drawn from the Stanford Research Repository Cohort Discovery Tool, but a review found 200 records that were misdiagnosed and had to be excluded.

“It’s very easy to label someone who suffered a head injury and say this is the reason why they have this (headache),” said lead author Tommy Chan, MBBS, a headache fellow in the department of neurology at Stanford (Calif.) University, in an interview. Such patients are often seen by ED or primary care physicians who do not have a lot of experience with posttraumatic headache, and that can lead to negative consequences if a low-pressure headache is mistaken as stemming from a skull fracture. “It’s a very different treatment plan for one versus the other,” said Dr. Chan in an interview.

He noted that it can help to take a patient history that includes the preaccident headache frequency and determine if there was a change in frequency post injury.

Dr. Chan presented the results at the virtual annual meeting of the American Headache Society.

“The results are what one might expect, although we haven’t studied it enough to really know. We haven’t systematically characterized these risk factors for chronic posttraumatic headache very well, [so] it’s useful to have this information,” said Andrew Charles, MD, professor neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program, who was not involved in the study. However, Dr. Charles emphasized the need to confirm the results prospectively.
 

Defining risk factors

The analysis found that a history of migraines, medication overuse, psychological disorders, and new posttraumatic headache–associated comorbidities were all associated with a greater risk for persistent posttraumatic headache. None of those came as a surprise, “but we live in a world where medicine is practiced based on evidence, and providers want to see data to support that. I think that this will help with resource allocation. It’s important to address [a patient’s] overuse of medications, or if they’re having psychological symptoms,” said Dr. Chan.

A total of 150 patients in the analysis had acute posttraumatic headache (mean duration, 0.7 months) while 150 had persistent posttraumatic headache (mean duration, 24 months; P < .00001). Clinical factors associated with risk of persistent headache included a history migraine (relative risk, 2.4; P < .0001), a previous head injury (odds ratio, 5.8; P < .0001), medication overuse (RR, 2.6; P < .0001), preexisting psychological history (OR, 5; P < .0001), and new posttraumatic headache–associated comorbidities, such as vertigo or posttraumatic stress disorder (RR, 9.8; P < .0001).
 

Identifying patient subgroups

The researchers also identified four subcategories of patients with persistent posttraumatic headache, each with differing risk factors and clinical characteristics. It’s too soon to use these identifiers to make clinical recommendations, but Dr. Chan hopes that further study of these groups will be informative. “It might point us toward (the idea) that each patient population is actually different, even within the chronic persistent posttraumatic headache population, we can’t group them all under the same umbrella term. If we can tease out that a patient has truly had a head injury, but no history of migraine, no overuse of medication, no psychological history, and no other associated symptoms, this would be a very interesting population to study because they would help us understand the pathophysiology [of persistent posttraumatic headache].”

Although the study was conducted by defining persistent posttraumatic headache as lasting at least 3 months, Dr. Chan took issue with that commonly held definition. That choice is arbitrary, with no pathophysiological basis or data to support it, and is based more on clinical trials testing preventative treatments. But when it is used in clinical practice, it can muddy communication with patients. “When this timeline is told to a patient, and when it’s not achieved, they might become disappointed. We should not put too much emphasis on time. Everybody is different,” he said.

The study did not receive any funding. Dr. Chan had no relevant financial disclosures. Dr. Charles consults for consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

A new analysis of 300 patients with posttraumatic headache confirmed some long-suspected risk factors for persistent headache, including history of medication overuse or psychological symptoms, new parathyroid hormone–associated comorbidities, and history of migraine. It also revealed a surprisingly high frequency of misdiagnosis. The original sample included 500 patients drawn from the Stanford Research Repository Cohort Discovery Tool, but a review found 200 records that were misdiagnosed and had to be excluded.

“It’s very easy to label someone who suffered a head injury and say this is the reason why they have this (headache),” said lead author Tommy Chan, MBBS, a headache fellow in the department of neurology at Stanford (Calif.) University, in an interview. Such patients are often seen by ED or primary care physicians who do not have a lot of experience with posttraumatic headache, and that can lead to negative consequences if a low-pressure headache is mistaken as stemming from a skull fracture. “It’s a very different treatment plan for one versus the other,” said Dr. Chan in an interview.

He noted that it can help to take a patient history that includes the preaccident headache frequency and determine if there was a change in frequency post injury.

Dr. Chan presented the results at the virtual annual meeting of the American Headache Society.

“The results are what one might expect, although we haven’t studied it enough to really know. We haven’t systematically characterized these risk factors for chronic posttraumatic headache very well, [so] it’s useful to have this information,” said Andrew Charles, MD, professor neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program, who was not involved in the study. However, Dr. Charles emphasized the need to confirm the results prospectively.
 

Defining risk factors

The analysis found that a history of migraines, medication overuse, psychological disorders, and new posttraumatic headache–associated comorbidities were all associated with a greater risk for persistent posttraumatic headache. None of those came as a surprise, “but we live in a world where medicine is practiced based on evidence, and providers want to see data to support that. I think that this will help with resource allocation. It’s important to address [a patient’s] overuse of medications, or if they’re having psychological symptoms,” said Dr. Chan.

A total of 150 patients in the analysis had acute posttraumatic headache (mean duration, 0.7 months) while 150 had persistent posttraumatic headache (mean duration, 24 months; P < .00001). Clinical factors associated with risk of persistent headache included a history migraine (relative risk, 2.4; P < .0001), a previous head injury (odds ratio, 5.8; P < .0001), medication overuse (RR, 2.6; P < .0001), preexisting psychological history (OR, 5; P < .0001), and new posttraumatic headache–associated comorbidities, such as vertigo or posttraumatic stress disorder (RR, 9.8; P < .0001).
 

Identifying patient subgroups

The researchers also identified four subcategories of patients with persistent posttraumatic headache, each with differing risk factors and clinical characteristics. It’s too soon to use these identifiers to make clinical recommendations, but Dr. Chan hopes that further study of these groups will be informative. “It might point us toward (the idea) that each patient population is actually different, even within the chronic persistent posttraumatic headache population, we can’t group them all under the same umbrella term. If we can tease out that a patient has truly had a head injury, but no history of migraine, no overuse of medication, no psychological history, and no other associated symptoms, this would be a very interesting population to study because they would help us understand the pathophysiology [of persistent posttraumatic headache].”

Although the study was conducted by defining persistent posttraumatic headache as lasting at least 3 months, Dr. Chan took issue with that commonly held definition. That choice is arbitrary, with no pathophysiological basis or data to support it, and is based more on clinical trials testing preventative treatments. But when it is used in clinical practice, it can muddy communication with patients. “When this timeline is told to a patient, and when it’s not achieved, they might become disappointed. We should not put too much emphasis on time. Everybody is different,” he said.

The study did not receive any funding. Dr. Chan had no relevant financial disclosures. Dr. Charles consults for consults for Amgen, BioHaven, Eli Lilly, Novartis, and Lundbeck.

Few patients with episodic migraine, and even fewer with chronic migraine, receive optimal treatment, new research shows.

Results from a survey study showed less than 8% of patients with episodic migraine and less than 2% of patients with chronic migraine were able to overcome four key treatment barriers associated with optimal migraine management. These included current medical consultation, appropriate diagnosis, minimally adequate acute and preventive pharmacologic treatment (if indicated), and absence of acute medication overdose.

The researchers also evaluated any potential impact of race, ethnicity, and sociodemographic factors on these barriers.

“While chronic migraine was associated with higher rates of consulting, only 1.8% of respondents with chronic migraine traversed all four barriers compared with 8.5% of those with episodic migraine,” the investigators, led by Dawn C. Buse, PhD, clinical professor of neurology at Albert Einstein College of Medicine of Yeshiva University in New York City, noted.

The study was presented at the virtual annual meeting of the American Headache Society.

Ongoing challenges

Migraineurs’ challenges include receiving an appropriate diagnosis and finding effective acute and preventive treatments, the researchers noted. Many patients do not receive optimal care. Previous research by Dr. Buse and colleagues showed that general clinicians were less likely to provide an appropriate diagnosis of migraine compared with headache specialists.

Among patients with chronic migraine who consulted headache specialists, most did not receive an accurate diagnosis of chronic migraine. Data also indicate that a minority, approximately 34%, of patients with chronic migraine used preventive pharmacologic treatments.

The investigators analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study to determine the proportion of patients who overcame four prespecified barriers to good outcomes.

Eligible participants met modified International Classification of Headache Disorders (3rd edition) criteria for migraine, had Migraine Disability Assessment Scores (MIDAS) of grade II or higher, and provided data on health insurance status. In addition, all eligible participants had to be receiving appropriate treatment for either episodic or chronic migraine.

In all, 16,789 participants met criteria for migraine. Of this group, 9,184 patients had a MIDAS score of grade II or higher and reported health insurance status. In this subgroup, 7,930 (86.3%) patients had episodic migraine and 1,254 (13.7%) had chronic migraine.

A total of 2,187 (27.6%) patients with episodic migraine and 512 (40.8%) patients with chronic migraine were under the care of a healthcare professional. Of this group, 1,655 patients with episodic migraine (75.7%) and 168 with chronic migraine (32.8%) reported receiving an appropriate diagnosis.

Of participants who successfully overcame the first two optimal management barriers—a consultation with a healthcare professional and an appropriate diagnosis—1,133 (68.5%) episodic migraineurs and 113 (67.3%) chronic migraineurs reported receiving minimally adequate acute treatment.

Furthermore, 1,430 (86.4%) episodic migraineurs and 127 (75.6%) chronic migraineurs reported receiving minimally adequate preventive medication treatment. In addition, 982 (59.3%) episodic migraineurs and 88 (52.4%) chronic migraineurs received minimally adequate acute and preventive treatment.

Acute medication overuse was relatively common, the investigators reported. A total of 310 (31.6%) patients with episodic migraine and 66 (75%) patients with chronic migraine met criteria for acute medication overuse.

“Overuse of acute medication for migraine in people with chronic migraine is a serious concern and is associated with increased risks of migraine progression, headache-related disability, and anxiety and depression. Active patient management and education is important to reduce the likelihood of medication overuse,” said Dr. Buse.

Among all eligible respondents, only 672 (8.5%) patients with episodic migraine and 22 (1.8%) with chronic migraine overcame all four barriers to optimal care.

The researchers found no significant effect of ethnicity or race on the likelihood of overcoming any barrier, but they acknowledged that participation bias might have contributed to this lack of difference. Higher annual household income was significantly associated with high likelihood of surmounting all four barriers.

“The analysis of sociodemographics revealed that female sex and higher annual household income showed a strong relationship with likelihood of obtaining an accurate episodic migraine or chronic migraine diagnosis,” said Dr. Buse.

“Although the reasons for this are not clear, it may be that women are more likely to convey the full scope of their symptoms during consultation. Additionally, the known prevalence of migraine in women may influence healthcare providers by reducing suspicion of chronic migraine in men,” she added.

The CaMEO Study was funded by Allergan (now AbbVie). Dr. Buse reports receiving grant support and honoraria from Allergan, Amgen, Biohaven, Eli Lilly and Co, and Promius. She also receives compensation for work on the editorial board of Current Pain and Headache Reports.

This article first appeared on Medscape.com.

Few patients with episodic migraine, and even fewer with chronic migraine, receive optimal treatment, new research shows.

Results from a survey study showed less than 8% of patients with episodic migraine and less than 2% of patients with chronic migraine were able to overcome four key treatment barriers associated with optimal migraine management. These included current medical consultation, appropriate diagnosis, minimally adequate acute and preventive pharmacologic treatment (if indicated), and absence of acute medication overdose.

The researchers also evaluated any potential impact of race, ethnicity, and sociodemographic factors on these barriers.

“While chronic migraine was associated with higher rates of consulting, only 1.8% of respondents with chronic migraine traversed all four barriers compared with 8.5% of those with episodic migraine,” the investigators, led by Dawn C. Buse, PhD, clinical professor of neurology at Albert Einstein College of Medicine of Yeshiva University in New York City, noted.

The study was presented at the virtual annual meeting of the American Headache Society.

Ongoing challenges

Migraineurs’ challenges include receiving an appropriate diagnosis and finding effective acute and preventive treatments, the researchers noted. Many patients do not receive optimal care. Previous research by Dr. Buse and colleagues showed that general clinicians were less likely to provide an appropriate diagnosis of migraine compared with headache specialists.

Among patients with chronic migraine who consulted headache specialists, most did not receive an accurate diagnosis of chronic migraine. Data also indicate that a minority, approximately 34%, of patients with chronic migraine used preventive pharmacologic treatments.

The investigators analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study to determine the proportion of patients who overcame four prespecified barriers to good outcomes.

Eligible participants met modified International Classification of Headache Disorders (3rd edition) criteria for migraine, had Migraine Disability Assessment Scores (MIDAS) of grade II or higher, and provided data on health insurance status. In addition, all eligible participants had to be receiving appropriate treatment for either episodic or chronic migraine.

In all, 16,789 participants met criteria for migraine. Of this group, 9,184 patients had a MIDAS score of grade II or higher and reported health insurance status. In this subgroup, 7,930 (86.3%) patients had episodic migraine and 1,254 (13.7%) had chronic migraine.

A total of 2,187 (27.6%) patients with episodic migraine and 512 (40.8%) patients with chronic migraine were under the care of a healthcare professional. Of this group, 1,655 patients with episodic migraine (75.7%) and 168 with chronic migraine (32.8%) reported receiving an appropriate diagnosis.

Of participants who successfully overcame the first two optimal management barriers—a consultation with a healthcare professional and an appropriate diagnosis—1,133 (68.5%) episodic migraineurs and 113 (67.3%) chronic migraineurs reported receiving minimally adequate acute treatment.

Furthermore, 1,430 (86.4%) episodic migraineurs and 127 (75.6%) chronic migraineurs reported receiving minimally adequate preventive medication treatment. In addition, 982 (59.3%) episodic migraineurs and 88 (52.4%) chronic migraineurs received minimally adequate acute and preventive treatment.

Acute medication overuse was relatively common, the investigators reported. A total of 310 (31.6%) patients with episodic migraine and 66 (75%) patients with chronic migraine met criteria for acute medication overuse.

“Overuse of acute medication for migraine in people with chronic migraine is a serious concern and is associated with increased risks of migraine progression, headache-related disability, and anxiety and depression. Active patient management and education is important to reduce the likelihood of medication overuse,” said Dr. Buse.

Among all eligible respondents, only 672 (8.5%) patients with episodic migraine and 22 (1.8%) with chronic migraine overcame all four barriers to optimal care.

The researchers found no significant effect of ethnicity or race on the likelihood of overcoming any barrier, but they acknowledged that participation bias might have contributed to this lack of difference. Higher annual household income was significantly associated with high likelihood of surmounting all four barriers.

“The analysis of sociodemographics revealed that female sex and higher annual household income showed a strong relationship with likelihood of obtaining an accurate episodic migraine or chronic migraine diagnosis,” said Dr. Buse.

“Although the reasons for this are not clear, it may be that women are more likely to convey the full scope of their symptoms during consultation. Additionally, the known prevalence of migraine in women may influence healthcare providers by reducing suspicion of chronic migraine in men,” she added.

The CaMEO Study was funded by Allergan (now AbbVie). Dr. Buse reports receiving grant support and honoraria from Allergan, Amgen, Biohaven, Eli Lilly and Co, and Promius. She also receives compensation for work on the editorial board of Current Pain and Headache Reports.

This article first appeared on Medscape.com.

Few patients with episodic migraine, and even fewer with chronic migraine, receive optimal treatment, new research shows.

Results from a survey study showed less than 8% of patients with episodic migraine and less than 2% of patients with chronic migraine were able to overcome four key treatment barriers associated with optimal migraine management. These included current medical consultation, appropriate diagnosis, minimally adequate acute and preventive pharmacologic treatment (if indicated), and absence of acute medication overdose.

The researchers also evaluated any potential impact of race, ethnicity, and sociodemographic factors on these barriers.

“While chronic migraine was associated with higher rates of consulting, only 1.8% of respondents with chronic migraine traversed all four barriers compared with 8.5% of those with episodic migraine,” the investigators, led by Dawn C. Buse, PhD, clinical professor of neurology at Albert Einstein College of Medicine of Yeshiva University in New York City, noted.

The study was presented at the virtual annual meeting of the American Headache Society.

Ongoing challenges

Migraineurs’ challenges include receiving an appropriate diagnosis and finding effective acute and preventive treatments, the researchers noted. Many patients do not receive optimal care. Previous research by Dr. Buse and colleagues showed that general clinicians were less likely to provide an appropriate diagnosis of migraine compared with headache specialists.

Among patients with chronic migraine who consulted headache specialists, most did not receive an accurate diagnosis of chronic migraine. Data also indicate that a minority, approximately 34%, of patients with chronic migraine used preventive pharmacologic treatments.

The investigators analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study to determine the proportion of patients who overcame four prespecified barriers to good outcomes.

Eligible participants met modified International Classification of Headache Disorders (3rd edition) criteria for migraine, had Migraine Disability Assessment Scores (MIDAS) of grade II or higher, and provided data on health insurance status. In addition, all eligible participants had to be receiving appropriate treatment for either episodic or chronic migraine.

In all, 16,789 participants met criteria for migraine. Of this group, 9,184 patients had a MIDAS score of grade II or higher and reported health insurance status. In this subgroup, 7,930 (86.3%) patients had episodic migraine and 1,254 (13.7%) had chronic migraine.

A total of 2,187 (27.6%) patients with episodic migraine and 512 (40.8%) patients with chronic migraine were under the care of a healthcare professional. Of this group, 1,655 patients with episodic migraine (75.7%) and 168 with chronic migraine (32.8%) reported receiving an appropriate diagnosis.

Of participants who successfully overcame the first two optimal management barriers—a consultation with a healthcare professional and an appropriate diagnosis—1,133 (68.5%) episodic migraineurs and 113 (67.3%) chronic migraineurs reported receiving minimally adequate acute treatment.

Furthermore, 1,430 (86.4%) episodic migraineurs and 127 (75.6%) chronic migraineurs reported receiving minimally adequate preventive medication treatment. In addition, 982 (59.3%) episodic migraineurs and 88 (52.4%) chronic migraineurs received minimally adequate acute and preventive treatment.

Acute medication overuse was relatively common, the investigators reported. A total of 310 (31.6%) patients with episodic migraine and 66 (75%) patients with chronic migraine met criteria for acute medication overuse.

“Overuse of acute medication for migraine in people with chronic migraine is a serious concern and is associated with increased risks of migraine progression, headache-related disability, and anxiety and depression. Active patient management and education is important to reduce the likelihood of medication overuse,” said Dr. Buse.

Among all eligible respondents, only 672 (8.5%) patients with episodic migraine and 22 (1.8%) with chronic migraine overcame all four barriers to optimal care.

The researchers found no significant effect of ethnicity or race on the likelihood of overcoming any barrier, but they acknowledged that participation bias might have contributed to this lack of difference. Higher annual household income was significantly associated with high likelihood of surmounting all four barriers.

“The analysis of sociodemographics revealed that female sex and higher annual household income showed a strong relationship with likelihood of obtaining an accurate episodic migraine or chronic migraine diagnosis,” said Dr. Buse.

“Although the reasons for this are not clear, it may be that women are more likely to convey the full scope of their symptoms during consultation. Additionally, the known prevalence of migraine in women may influence healthcare providers by reducing suspicion of chronic migraine in men,” she added.

The CaMEO Study was funded by Allergan (now AbbVie). Dr. Buse reports receiving grant support and honoraria from Allergan, Amgen, Biohaven, Eli Lilly and Co, and Promius. She also receives compensation for work on the editorial board of Current Pain and Headache Reports.

This article first appeared on Medscape.com.