Migraine ICYMI

The results of a recent study are consistent with an additive increase in stroke risk with combined hormonal contraceptives (CHC) use in women who have migraine with aura. Since the absolute risk of stroke is low even in the presence of these risk factors, use of CHCs in women who have migraine with aura should be based on an individualized assessment of harms and benefits. Researchers conducted a literature search of PubMed, the Cochrane Library, and EMBASE from inception through January 2016 for relevant studies. They included studies that examined exposure to CHCs and reported outcomes of ischemic or hemorrhagic stroke. They found:

• Of 2480 records, 15 studies met inclusion criteria.
• No studies reported odds ratios for stroke risk as a function of estrogen dose in women with migraine, largely due to insufficient sample sizes.
• No interaction effect between migraine and CHCs was seen in the 7 studies that assessed this.
• One study differentiated risk by presence or absence of migraine aura and found an increased risk in the migraine with aura population.

Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: A systematic review. [Published online ahead of print November 15, 2017]. Headache. doi:10.1111/head.13229.

The results of a recent study are consistent with an additive increase in stroke risk with combined hormonal contraceptives (CHC) use in women who have migraine with aura. Since the absolute risk of stroke is low even in the presence of these risk factors, use of CHCs in women who have migraine with aura should be based on an individualized assessment of harms and benefits. Researchers conducted a literature search of PubMed, the Cochrane Library, and EMBASE from inception through January 2016 for relevant studies. They included studies that examined exposure to CHCs and reported outcomes of ischemic or hemorrhagic stroke. They found:

• Of 2480 records, 15 studies met inclusion criteria.
• No studies reported odds ratios for stroke risk as a function of estrogen dose in women with migraine, largely due to insufficient sample sizes.
• No interaction effect between migraine and CHCs was seen in the 7 studies that assessed this.
• One study differentiated risk by presence or absence of migraine aura and found an increased risk in the migraine with aura population.

Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: A systematic review. [Published online ahead of print November 15, 2017]. Headache. doi:10.1111/head.13229.

The results of a recent study are consistent with an additive increase in stroke risk with combined hormonal contraceptives (CHC) use in women who have migraine with aura. Since the absolute risk of stroke is low even in the presence of these risk factors, use of CHCs in women who have migraine with aura should be based on an individualized assessment of harms and benefits. Researchers conducted a literature search of PubMed, the Cochrane Library, and EMBASE from inception through January 2016 for relevant studies. They included studies that examined exposure to CHCs and reported outcomes of ischemic or hemorrhagic stroke. They found:

• Of 2480 records, 15 studies met inclusion criteria.
• No studies reported odds ratios for stroke risk as a function of estrogen dose in women with migraine, largely due to insufficient sample sizes.
• No interaction effect between migraine and CHCs was seen in the 7 studies that assessed this.
• One study differentiated risk by presence or absence of migraine aura and found an increased risk in the migraine with aura population.

Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: A systematic review. [Published online ahead of print November 15, 2017]. Headache. doi:10.1111/head.13229.

More than a quarter of initial emergency department (ED) visits for migraine are followed by headache revisits in less than 6 months, a recent study found. Using the New York City Department of Health and Mental Hygiene Syndromic Surveillance database, researchers conducted a retrospective nested cohort study. They analyzed visits from 18 New York City EDs with discharge diagnoses in the first 6 months of 2015, and conducted descriptive analyses to determine the frequency of headache revisit within 6 months of an index ED visit for migraine and the elapsed time to revisit. They found:

• Of 1052 ED visits with an ED discharge diagnosis of migraine during the first 6 months of 2015, 277 patients (26.3%) had a headache revisit within 6 months of their initial migraine visit and 131 (12.5%) had 2 or more revisits at the same hospital.
• Of the revisits for headache, 9% occurred within 72 hours and 46% occurred within 90 days of the initial migraine visit.
• Sex, age, and poverty level were not associated with an ED revisit.

A retrospective nested cohort study of emergency department revisits for migraine in New York City. [Published online ahead of print November 2, 2017]. Headache. doi:10.1111/head.13216.

More than a quarter of initial emergency department (ED) visits for migraine are followed by headache revisits in less than 6 months, a recent study found. Using the New York City Department of Health and Mental Hygiene Syndromic Surveillance database, researchers conducted a retrospective nested cohort study. They analyzed visits from 18 New York City EDs with discharge diagnoses in the first 6 months of 2015, and conducted descriptive analyses to determine the frequency of headache revisit within 6 months of an index ED visit for migraine and the elapsed time to revisit. They found:

• Of 1052 ED visits with an ED discharge diagnosis of migraine during the first 6 months of 2015, 277 patients (26.3%) had a headache revisit within 6 months of their initial migraine visit and 131 (12.5%) had 2 or more revisits at the same hospital.
• Of the revisits for headache, 9% occurred within 72 hours and 46% occurred within 90 days of the initial migraine visit.
• Sex, age, and poverty level were not associated with an ED revisit.

A retrospective nested cohort study of emergency department revisits for migraine in New York City. [Published online ahead of print November 2, 2017]. Headache. doi:10.1111/head.13216.

More than a quarter of initial emergency department (ED) visits for migraine are followed by headache revisits in less than 6 months, a recent study found. Using the New York City Department of Health and Mental Hygiene Syndromic Surveillance database, researchers conducted a retrospective nested cohort study. They analyzed visits from 18 New York City EDs with discharge diagnoses in the first 6 months of 2015, and conducted descriptive analyses to determine the frequency of headache revisit within 6 months of an index ED visit for migraine and the elapsed time to revisit. They found:

• Of 1052 ED visits with an ED discharge diagnosis of migraine during the first 6 months of 2015, 277 patients (26.3%) had a headache revisit within 6 months of their initial migraine visit and 131 (12.5%) had 2 or more revisits at the same hospital.
• Of the revisits for headache, 9% occurred within 72 hours and 46% occurred within 90 days of the initial migraine visit.
• Sex, age, and poverty level were not associated with an ED revisit.

A retrospective nested cohort study of emergency department revisits for migraine in New York City. [Published online ahead of print November 2, 2017]. Headache. doi:10.1111/head.13216.

For a minority of women who are overweight or obese, physical activity consistently contributed to the worsening of migraine pain, according to a recent study. Furthermore, more frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity. Participants included 132 women, aged 18 to 50 years, with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women’s Health and Migraine trial. Researchers found:

• Subjects reported 5.5 ± 2.8 (mean ± standard deviation) migraine attacks over 28 days.
• The intraclass correlation indicated high consistency in participants’ reports of activity-related pain worsening or not.
• On average, activity worsened pain in 34.8 ± 35.6% of attacks, had no effect on pain in 61.8 ± 34.6% of attacks, and improved pain in 3.4 ± 12.7% of attacks.
• Few participants (9.8%) reported activity-related pain worsening in all attacks.
• A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia.

Pain worsening with physical activity during migraine attacks in women with overweight/obesity: A prospective evaluation of frequency, consistency, and correlates. [Published online ahead of print December 13, 2017]. Cephalalgia. doi:10.1177/0333102417747231.

For a minority of women who are overweight or obese, physical activity consistently contributed to the worsening of migraine pain, according to a recent study. Furthermore, more frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity. Participants included 132 women, aged 18 to 50 years, with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women’s Health and Migraine trial. Researchers found:

• Subjects reported 5.5 ± 2.8 (mean ± standard deviation) migraine attacks over 28 days.
• The intraclass correlation indicated high consistency in participants’ reports of activity-related pain worsening or not.
• On average, activity worsened pain in 34.8 ± 35.6% of attacks, had no effect on pain in 61.8 ± 34.6% of attacks, and improved pain in 3.4 ± 12.7% of attacks.
• Few participants (9.8%) reported activity-related pain worsening in all attacks.
• A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia.

Pain worsening with physical activity during migraine attacks in women with overweight/obesity: A prospective evaluation of frequency, consistency, and correlates. [Published online ahead of print December 13, 2017]. Cephalalgia. doi:10.1177/0333102417747231.

For a minority of women who are overweight or obese, physical activity consistently contributed to the worsening of migraine pain, according to a recent study. Furthermore, more frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity. Participants included 132 women, aged 18 to 50 years, with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women’s Health and Migraine trial. Researchers found:

• Subjects reported 5.5 ± 2.8 (mean ± standard deviation) migraine attacks over 28 days.
• The intraclass correlation indicated high consistency in participants’ reports of activity-related pain worsening or not.
• On average, activity worsened pain in 34.8 ± 35.6% of attacks, had no effect on pain in 61.8 ± 34.6% of attacks, and improved pain in 3.4 ± 12.7% of attacks.
• Few participants (9.8%) reported activity-related pain worsening in all attacks.
• A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia.

Pain worsening with physical activity during migraine attacks in women with overweight/obesity: A prospective evaluation of frequency, consistency, and correlates. [Published online ahead of print December 13, 2017]. Cephalalgia. doi:10.1177/0333102417747231.

Imaging Shows Youth Football’s Effects on the Brain

School-age football players with a history of concussion and high impact exposure undergo brain changes after one season of play, according to two studies conducted at the University of Texas Southwestern Medical Center in Dallas and Wake Forest University in Winston-Salem, North Carolina.

Both studies analyzed the default mode network (DMN), a system of brain regions that is active during wakeful rest. Changes in the DMN are observed in patients with mental disorders. Decreased connectivity within the network is also associated with traumatic brain injury.

“The DMN exists in the deep gray matter areas of the brain,” said Elizabeth M. Davenport, PhD, a postdoctoral researcher in the Advanced NeuroScience Imaging Research (ANSIR) lab at UT Southwestern’s O’Donnell Brain Institute. “It includes structures that activate when we are awake and engaging in introspection or processing emotions, which are activities that are important for brain health.”

In the first study, researchers studied youth football players without a history of concussion to identify the effect of repeated subconcussive impacts on the DMN.

“Over a season of football, players are exposed to numerous head impacts. The vast majority of these do not result in concussion,” said Gowtham Krishnan Murugesan, a PhD student in biomedical engineering and member of the ANSIR laboratory. “This work adds to a growing body of literature indicating that subconcussive head impacts can have an effect on the brain. This is a highly understudied area at the youth and high school level.”

For the study, 26 youth football players (ages 9–13) were outfitted with the Head Impact Telemetry System (HITS) for an entire football season. HITS helmets are lined with accelerometers that measure the magnitude, location, and direction of impacts to the head. Impact data from the helmets were used to calculate a risk of concussion exposure for each player.

Players were separated into high and low concussion exposure groups. Players with a history of concussion were excluded. A third group of 13 noncontact sport controls was established. Pre- and post-season resting functional MRI (fMRI) scans were performed on all players and controls, and connectivity within the DMN subcomponents was analyzed. The researchers used machine learning to analyze the fMRI data.

“Machine learning has a lot to add to our research because it gives us a fresh perspective and an ability to analyze the complex relationships within the data,” said Mr. Murugesan. “Our results suggest an increasing functional change in the brain with increasing head impact exposure.”

Five machine learning classification algorithms were used to predict whether players were in the high-exposure, low-exposure or noncontact groups, based on the fMRI results. The algorithm discriminated between high-impact exposure and noncontact controls with 82% accuracy, and between low-impact exposure and noncontact controls with 70% accuracy. The results suggest an increasing functional change with increasing head-impact exposure.

“The brains of these youth and adolescent athletes are undergoing rapid maturation in this age range. This study demonstrates that playing a season of contact sports at the youth level can produce neuroimaging brain changes, particularly for the DMN,” Mr. Murugesan said.

In the second study, 20 high school football players (median age, 16.9) wore helmets outfitted with HITS for a season. Of the 20 players, five had experienced at least one concussion, and 15 had no history of concussion.

Before and following the season, the players underwent an eight-minute magnetoencephalography (MEG) scan, which records and analyzes the magnetic fields produced by brain activity. Researchers then analyzed the MEG power associated with the eight brain regions of the DMN.

Post-season, the five players with a history of concussion had significantly lower connectivity between DMN regions. Players with no history of concussion had, on average, an increase in DMN connectivity.

The results demonstrate that concussions from previous years can influence the changes occurring in the brain during the current season, suggesting that longitudinal effects of concussion affect brain function.

“The brain’s DMN changes differently as a result of previous concussion,” said Dr. Davenport. “Previous concussion seems to prime the brain for additional changes. Concussion history may be affecting the brain’s ability to compensate for subconcussive impacts.”

Both researchers said that larger data sets, longitudinal studies that follow young football players, and research that combines MEG and fMRI are needed to better understand the complex factors involved in concussions.

Neurofeedback May Help Treat Tinnitus

Functional MRI (fMRI) suggests that neurofeedback training has the potential to reduce the severity of tinnitus or eliminate it.

Tinnitus affects approximately one in five people. As patients focus more on the noise, they become more frustrated and anxious, which in turn makes the noise seem worse. The primary auditory cortex has been implicated in tinnitus-related distress.

Researchers examined a potential way to treat tinnitus by having people use neurofeedback training to divert their focus from the sounds in their ears. Neurofeedback is a way of training the brain by allowing an individual to view an external indicator of brain activity and attempt to exert control over it.

“The idea is that in people with tinnitus, there is an overattention drawn to the auditory cortex, making it more active than in a healthy person,” said Matthew S. Sherwood, PhD, a research engineer in the Department of Biomedical, Industrial, and Human Factors Engineering at Wright State University in Fairborn, Ohio. “Our hope is that tinnitus sufferers could use neurofeedback to divert attention away from their tinnitus and possibly make it go away.”

To determine the potential efficacy of this approach, the researchers asked 18 healthy volunteers with normal hearing to undergo five fMRI-neurofeedback training sessions. Study participants were given earplugs through which white noise could be introduced. The earplugs also blocked out the scanner noise.

To obtain fMRI results, the researchers used single-shot echoplanar imaging, an MRI technique that is sensitive to blood oxygen levels, providing an indirect measure of brain activity.

“We started with alternating periods of sound and no sound in order to create a map of the brain and find areas that produced the highest activity during the sound phase,” said Dr. Sherwood. “Then we selected the voxels that were heavily activated when sound was being played.”

The subjects then participated in the fMRI-neurofeedback training phase while inside the MRI scanner. They received white noise through their earplugs and were able to view the activity in their primary auditory cortex as a bar on a screen. Each fMRI-neurofeedback training session contained eight blocks separated into a 30-second “relax” period, followed by a 30-second “lower” period. Participants were instructed to watch the bar during the relax period and attempt to lower it by decreasing primary auditory cortex activity during the lower phase. The researchers gave the participants techniques to help them do this, such as trying to divert attention from sound to other sensations like touch and sight.

“Many focused on breathing because it gave them a feeling of control,” said Dr. Sherwood. “By diverting their attention away from sound, the participants’ auditory cortex activity went down, and the signal we were measuring also went down.”

A control group of nine individuals was provided sham neurofeedback. They performed the same tasks as the other group, but the feedback came not from them, but from a random participant. By performing the exact same procedures with both groups using either real or sham neurofeedback, the researchers were able to distinguish the effect of real neurofeedback on control of the primary auditory cortex.

The study represents the first time that fMRI-neurofeedback training has been applied to demonstrate that there is a significant relationship between control of the primary auditory cortex and attentional processes. This result is important to therapeutic development, said Dr. Sherwood, because the neural mechanisms of tinnitus are unknown, but likely related to attention.

The results represent a promising avenue of research that could lead to improvements in other areas of health, like pain management, according to Dr. Sherwood. “Ultimately, we would like to take what we learned from MRI and develop a neurofeedback program that does not require MRI to use, such as an app or home-based therapy that could apply to tinnitus and other conditions,” he said.

Migraine Is Associated With High Sodium Levels in CSF

Migraineurs have significantly higher sodium concentrations in their CSF than people without migraine, according to the first study to use a technique called sodium MRI to examine patients with migraine.

Diagnosis of migraine is challenging, as the characteristics of migraines and the types of attacks vary widely among patients. Consequently, many patients with migraine are undiagnosed and untreated. Other patients, in contrast, are treated with medications for migraines even though they have a different type of headache, such as tension-type headache.

“It would be helpful to have a diagnostic tool supporting or even diagnosing migraine and differentiating migraine from all other types of headache,” said Melissa Meyer, MD, a radiology resident at the Institute of Clinical Radiology and Nuclear Medicine at University Hospital Mannheim and Heidelberg University in Heidelberg, Germany.

Dr. Meyer and colleagues explored a technique called cerebral sodium MRI as a possible means to help in the diagnosis and understanding of migraine. While MRI most often relies on protons to generate an image, sodium can be visualized as well. Research has shown that sodium plays an important role in brain chemistry.

The researchers recruited 12 women (mean age, 34) who had been clinically evaluated for migraine. The women filled out a questionnaire regarding the length, intensity, and frequency of their migraine attacks and accompanying auras. The researchers also enrolled 12 healthy women of similar age as a control group. Both groups underwent cerebral sodium MRI. Sodium concentrations of patients with migraine and healthy controls were compared and statistically analyzed.

The researchers found no significant differences between the two groups in sodium concentrations in the gray and white matter, brainstem, and cerebellum. Significant differences emerged, however, when the researchers looked at sodium concentrations in the CSF. Overall, sodium concentrations were significantly higher in the CSF of migraineurs than in healthy controls.

“These findings might facilitate the challenging diagnosis of a migraine,” said Dr. Meyer. The researchers hope to learn more about the connection between migraine and sodium in future studies. “As this was an exploratory study, we plan to examine more patients, preferably during or shortly after a migraine attack, for further validation.”

Gadolinium May Not Cause Neurologic Harm

There is no evidence that accumulation of gadolinium in the brain speeds cognitive decline, according to researchers.

“Approximately 400 million doses of gadolinium have been administered since 1988,” said Robert J. McDonald, MD, PhD, a neuroradiologist at the Mayo Clinic in Rochester, Minnesota. “Gadolinium contrast material is used in 40% to 50% of MRI scans performed today.”

Scientists previously believed that gadolinium contrast material could not cross the blood–brain barrier. Recent studies, however, including one by Dr. McDonald and colleagues, found that traces of gadolinium could be retained in the brain for years after MRI.

On September 8, 2017, the FDA recommended adding a warning about gadolinium retention in various organs, including the brain, to labels for gadolinium-based contrast agents used during MRI. The FDA highlighted several specific patient populations at greater risk, including children and pregnant women. Yet little is known about the health effects, if any, of gadolinium that is retained in the brain.

For this study, Dr. McDonald and colleagues set out to identify the neurotoxic potential of intracranial gadolinium deposition following IV administration of gadolinium-based contrast agents during MRI. The researchers used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychologic testing at baseline and 15-month follow-up intervals. Neurologic and neurocognitive scores were compared using standard methods between MCSA patients with no history of prior gadolinium exposure and those who had undergone prior MRI with gadolinium-based contrast agents. Progression from normal cognitive status to mild cognitive impairment and dementia was assessed using multistate Markov model analysis.

The study included 4,261 cognitively normal men and women between ages 50 and 90 (mean age, 72). Mean length of study participation was 3.7 years. Of the 4,261 participants, 1,092 (25.6%) had received one or more doses of gadolinium-based contrast agents, with at least one participant receiving as many as 28 prior doses. Median time since first gadolinium exposure was 5.6 years.

After adjusting for age, sex, education level, baseline neurocognitive performance, and other factors, gadolinium exposure was not a significant predictor of cognitive decline, dementia, diminished neuropsychologic performance, or diminished motor performance. No dose-related effects were observed among these metrics. Gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia in this study group.

“There is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” said Dr. McDonald. “This study provides useful data that at the reasonable doses [that] 95% of the population is likely to receive in their lifetime, there is no evidence at this point that gadolinium retention in the brain is associated with adverse clinical outcomes.”

Imaging Shows Youth Football’s Effects on the Brain

School-age football players with a history of concussion and high impact exposure undergo brain changes after one season of play, according to two studies conducted at the University of Texas Southwestern Medical Center in Dallas and Wake Forest University in Winston-Salem, North Carolina.

Both studies analyzed the default mode network (DMN), a system of brain regions that is active during wakeful rest. Changes in the DMN are observed in patients with mental disorders. Decreased connectivity within the network is also associated with traumatic brain injury.

“The DMN exists in the deep gray matter areas of the brain,” said Elizabeth M. Davenport, PhD, a postdoctoral researcher in the Advanced NeuroScience Imaging Research (ANSIR) lab at UT Southwestern’s O’Donnell Brain Institute. “It includes structures that activate when we are awake and engaging in introspection or processing emotions, which are activities that are important for brain health.”

In the first study, researchers studied youth football players without a history of concussion to identify the effect of repeated subconcussive impacts on the DMN.

“Over a season of football, players are exposed to numerous head impacts. The vast majority of these do not result in concussion,” said Gowtham Krishnan Murugesan, a PhD student in biomedical engineering and member of the ANSIR laboratory. “This work adds to a growing body of literature indicating that subconcussive head impacts can have an effect on the brain. This is a highly understudied area at the youth and high school level.”

For the study, 26 youth football players (ages 9–13) were outfitted with the Head Impact Telemetry System (HITS) for an entire football season. HITS helmets are lined with accelerometers that measure the magnitude, location, and direction of impacts to the head. Impact data from the helmets were used to calculate a risk of concussion exposure for each player.

Players were separated into high and low concussion exposure groups. Players with a history of concussion were excluded. A third group of 13 noncontact sport controls was established. Pre- and post-season resting functional MRI (fMRI) scans were performed on all players and controls, and connectivity within the DMN subcomponents was analyzed. The researchers used machine learning to analyze the fMRI data.

“Machine learning has a lot to add to our research because it gives us a fresh perspective and an ability to analyze the complex relationships within the data,” said Mr. Murugesan. “Our results suggest an increasing functional change in the brain with increasing head impact exposure.”

Five machine learning classification algorithms were used to predict whether players were in the high-exposure, low-exposure or noncontact groups, based on the fMRI results. The algorithm discriminated between high-impact exposure and noncontact controls with 82% accuracy, and between low-impact exposure and noncontact controls with 70% accuracy. The results suggest an increasing functional change with increasing head-impact exposure.

“The brains of these youth and adolescent athletes are undergoing rapid maturation in this age range. This study demonstrates that playing a season of contact sports at the youth level can produce neuroimaging brain changes, particularly for the DMN,” Mr. Murugesan said.

In the second study, 20 high school football players (median age, 16.9) wore helmets outfitted with HITS for a season. Of the 20 players, five had experienced at least one concussion, and 15 had no history of concussion.

Before and following the season, the players underwent an eight-minute magnetoencephalography (MEG) scan, which records and analyzes the magnetic fields produced by brain activity. Researchers then analyzed the MEG power associated with the eight brain regions of the DMN.

Post-season, the five players with a history of concussion had significantly lower connectivity between DMN regions. Players with no history of concussion had, on average, an increase in DMN connectivity.

The results demonstrate that concussions from previous years can influence the changes occurring in the brain during the current season, suggesting that longitudinal effects of concussion affect brain function.

“The brain’s DMN changes differently as a result of previous concussion,” said Dr. Davenport. “Previous concussion seems to prime the brain for additional changes. Concussion history may be affecting the brain’s ability to compensate for subconcussive impacts.”

Both researchers said that larger data sets, longitudinal studies that follow young football players, and research that combines MEG and fMRI are needed to better understand the complex factors involved in concussions.

Neurofeedback May Help Treat Tinnitus

Functional MRI (fMRI) suggests that neurofeedback training has the potential to reduce the severity of tinnitus or eliminate it.

Tinnitus affects approximately one in five people. As patients focus more on the noise, they become more frustrated and anxious, which in turn makes the noise seem worse. The primary auditory cortex has been implicated in tinnitus-related distress.

Researchers examined a potential way to treat tinnitus by having people use neurofeedback training to divert their focus from the sounds in their ears. Neurofeedback is a way of training the brain by allowing an individual to view an external indicator of brain activity and attempt to exert control over it.

“The idea is that in people with tinnitus, there is an overattention drawn to the auditory cortex, making it more active than in a healthy person,” said Matthew S. Sherwood, PhD, a research engineer in the Department of Biomedical, Industrial, and Human Factors Engineering at Wright State University in Fairborn, Ohio. “Our hope is that tinnitus sufferers could use neurofeedback to divert attention away from their tinnitus and possibly make it go away.”

To determine the potential efficacy of this approach, the researchers asked 18 healthy volunteers with normal hearing to undergo five fMRI-neurofeedback training sessions. Study participants were given earplugs through which white noise could be introduced. The earplugs also blocked out the scanner noise.

To obtain fMRI results, the researchers used single-shot echoplanar imaging, an MRI technique that is sensitive to blood oxygen levels, providing an indirect measure of brain activity.

“We started with alternating periods of sound and no sound in order to create a map of the brain and find areas that produced the highest activity during the sound phase,” said Dr. Sherwood. “Then we selected the voxels that were heavily activated when sound was being played.”

The subjects then participated in the fMRI-neurofeedback training phase while inside the MRI scanner. They received white noise through their earplugs and were able to view the activity in their primary auditory cortex as a bar on a screen. Each fMRI-neurofeedback training session contained eight blocks separated into a 30-second “relax” period, followed by a 30-second “lower” period. Participants were instructed to watch the bar during the relax period and attempt to lower it by decreasing primary auditory cortex activity during the lower phase. The researchers gave the participants techniques to help them do this, such as trying to divert attention from sound to other sensations like touch and sight.

“Many focused on breathing because it gave them a feeling of control,” said Dr. Sherwood. “By diverting their attention away from sound, the participants’ auditory cortex activity went down, and the signal we were measuring also went down.”

A control group of nine individuals was provided sham neurofeedback. They performed the same tasks as the other group, but the feedback came not from them, but from a random participant. By performing the exact same procedures with both groups using either real or sham neurofeedback, the researchers were able to distinguish the effect of real neurofeedback on control of the primary auditory cortex.

The study represents the first time that fMRI-neurofeedback training has been applied to demonstrate that there is a significant relationship between control of the primary auditory cortex and attentional processes. This result is important to therapeutic development, said Dr. Sherwood, because the neural mechanisms of tinnitus are unknown, but likely related to attention.

The results represent a promising avenue of research that could lead to improvements in other areas of health, like pain management, according to Dr. Sherwood. “Ultimately, we would like to take what we learned from MRI and develop a neurofeedback program that does not require MRI to use, such as an app or home-based therapy that could apply to tinnitus and other conditions,” he said.

Migraine Is Associated With High Sodium Levels in CSF

Migraineurs have significantly higher sodium concentrations in their CSF than people without migraine, according to the first study to use a technique called sodium MRI to examine patients with migraine.

Diagnosis of migraine is challenging, as the characteristics of migraines and the types of attacks vary widely among patients. Consequently, many patients with migraine are undiagnosed and untreated. Other patients, in contrast, are treated with medications for migraines even though they have a different type of headache, such as tension-type headache.

“It would be helpful to have a diagnostic tool supporting or even diagnosing migraine and differentiating migraine from all other types of headache,” said Melissa Meyer, MD, a radiology resident at the Institute of Clinical Radiology and Nuclear Medicine at University Hospital Mannheim and Heidelberg University in Heidelberg, Germany.

Dr. Meyer and colleagues explored a technique called cerebral sodium MRI as a possible means to help in the diagnosis and understanding of migraine. While MRI most often relies on protons to generate an image, sodium can be visualized as well. Research has shown that sodium plays an important role in brain chemistry.

The researchers recruited 12 women (mean age, 34) who had been clinically evaluated for migraine. The women filled out a questionnaire regarding the length, intensity, and frequency of their migraine attacks and accompanying auras. The researchers also enrolled 12 healthy women of similar age as a control group. Both groups underwent cerebral sodium MRI. Sodium concentrations of patients with migraine and healthy controls were compared and statistically analyzed.

The researchers found no significant differences between the two groups in sodium concentrations in the gray and white matter, brainstem, and cerebellum. Significant differences emerged, however, when the researchers looked at sodium concentrations in the CSF. Overall, sodium concentrations were significantly higher in the CSF of migraineurs than in healthy controls.

“These findings might facilitate the challenging diagnosis of a migraine,” said Dr. Meyer. The researchers hope to learn more about the connection between migraine and sodium in future studies. “As this was an exploratory study, we plan to examine more patients, preferably during or shortly after a migraine attack, for further validation.”

Gadolinium May Not Cause Neurologic Harm

There is no evidence that accumulation of gadolinium in the brain speeds cognitive decline, according to researchers.

“Approximately 400 million doses of gadolinium have been administered since 1988,” said Robert J. McDonald, MD, PhD, a neuroradiologist at the Mayo Clinic in Rochester, Minnesota. “Gadolinium contrast material is used in 40% to 50% of MRI scans performed today.”

Scientists previously believed that gadolinium contrast material could not cross the blood–brain barrier. Recent studies, however, including one by Dr. McDonald and colleagues, found that traces of gadolinium could be retained in the brain for years after MRI.

On September 8, 2017, the FDA recommended adding a warning about gadolinium retention in various organs, including the brain, to labels for gadolinium-based contrast agents used during MRI. The FDA highlighted several specific patient populations at greater risk, including children and pregnant women. Yet little is known about the health effects, if any, of gadolinium that is retained in the brain.

For this study, Dr. McDonald and colleagues set out to identify the neurotoxic potential of intracranial gadolinium deposition following IV administration of gadolinium-based contrast agents during MRI. The researchers used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychologic testing at baseline and 15-month follow-up intervals. Neurologic and neurocognitive scores were compared using standard methods between MCSA patients with no history of prior gadolinium exposure and those who had undergone prior MRI with gadolinium-based contrast agents. Progression from normal cognitive status to mild cognitive impairment and dementia was assessed using multistate Markov model analysis.

The study included 4,261 cognitively normal men and women between ages 50 and 90 (mean age, 72). Mean length of study participation was 3.7 years. Of the 4,261 participants, 1,092 (25.6%) had received one or more doses of gadolinium-based contrast agents, with at least one participant receiving as many as 28 prior doses. Median time since first gadolinium exposure was 5.6 years.

After adjusting for age, sex, education level, baseline neurocognitive performance, and other factors, gadolinium exposure was not a significant predictor of cognitive decline, dementia, diminished neuropsychologic performance, or diminished motor performance. No dose-related effects were observed among these metrics. Gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia in this study group.

“There is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” said Dr. McDonald. “This study provides useful data that at the reasonable doses [that] 95% of the population is likely to receive in their lifetime, there is no evidence at this point that gadolinium retention in the brain is associated with adverse clinical outcomes.”

Imaging Shows Youth Football’s Effects on the Brain

School-age football players with a history of concussion and high impact exposure undergo brain changes after one season of play, according to two studies conducted at the University of Texas Southwestern Medical Center in Dallas and Wake Forest University in Winston-Salem, North Carolina.

Both studies analyzed the default mode network (DMN), a system of brain regions that is active during wakeful rest. Changes in the DMN are observed in patients with mental disorders. Decreased connectivity within the network is also associated with traumatic brain injury.

“The DMN exists in the deep gray matter areas of the brain,” said Elizabeth M. Davenport, PhD, a postdoctoral researcher in the Advanced NeuroScience Imaging Research (ANSIR) lab at UT Southwestern’s O’Donnell Brain Institute. “It includes structures that activate when we are awake and engaging in introspection or processing emotions, which are activities that are important for brain health.”

In the first study, researchers studied youth football players without a history of concussion to identify the effect of repeated subconcussive impacts on the DMN.

“Over a season of football, players are exposed to numerous head impacts. The vast majority of these do not result in concussion,” said Gowtham Krishnan Murugesan, a PhD student in biomedical engineering and member of the ANSIR laboratory. “This work adds to a growing body of literature indicating that subconcussive head impacts can have an effect on the brain. This is a highly understudied area at the youth and high school level.”

For the study, 26 youth football players (ages 9–13) were outfitted with the Head Impact Telemetry System (HITS) for an entire football season. HITS helmets are lined with accelerometers that measure the magnitude, location, and direction of impacts to the head. Impact data from the helmets were used to calculate a risk of concussion exposure for each player.

Players were separated into high and low concussion exposure groups. Players with a history of concussion were excluded. A third group of 13 noncontact sport controls was established. Pre- and post-season resting functional MRI (fMRI) scans were performed on all players and controls, and connectivity within the DMN subcomponents was analyzed. The researchers used machine learning to analyze the fMRI data.

“Machine learning has a lot to add to our research because it gives us a fresh perspective and an ability to analyze the complex relationships within the data,” said Mr. Murugesan. “Our results suggest an increasing functional change in the brain with increasing head impact exposure.”

Five machine learning classification algorithms were used to predict whether players were in the high-exposure, low-exposure or noncontact groups, based on the fMRI results. The algorithm discriminated between high-impact exposure and noncontact controls with 82% accuracy, and between low-impact exposure and noncontact controls with 70% accuracy. The results suggest an increasing functional change with increasing head-impact exposure.

“The brains of these youth and adolescent athletes are undergoing rapid maturation in this age range. This study demonstrates that playing a season of contact sports at the youth level can produce neuroimaging brain changes, particularly for the DMN,” Mr. Murugesan said.

In the second study, 20 high school football players (median age, 16.9) wore helmets outfitted with HITS for a season. Of the 20 players, five had experienced at least one concussion, and 15 had no history of concussion.

Before and following the season, the players underwent an eight-minute magnetoencephalography (MEG) scan, which records and analyzes the magnetic fields produced by brain activity. Researchers then analyzed the MEG power associated with the eight brain regions of the DMN.

Post-season, the five players with a history of concussion had significantly lower connectivity between DMN regions. Players with no history of concussion had, on average, an increase in DMN connectivity.

The results demonstrate that concussions from previous years can influence the changes occurring in the brain during the current season, suggesting that longitudinal effects of concussion affect brain function.

“The brain’s DMN changes differently as a result of previous concussion,” said Dr. Davenport. “Previous concussion seems to prime the brain for additional changes. Concussion history may be affecting the brain’s ability to compensate for subconcussive impacts.”

Both researchers said that larger data sets, longitudinal studies that follow young football players, and research that combines MEG and fMRI are needed to better understand the complex factors involved in concussions.

Neurofeedback May Help Treat Tinnitus

Functional MRI (fMRI) suggests that neurofeedback training has the potential to reduce the severity of tinnitus or eliminate it.

Tinnitus affects approximately one in five people. As patients focus more on the noise, they become more frustrated and anxious, which in turn makes the noise seem worse. The primary auditory cortex has been implicated in tinnitus-related distress.

Researchers examined a potential way to treat tinnitus by having people use neurofeedback training to divert their focus from the sounds in their ears. Neurofeedback is a way of training the brain by allowing an individual to view an external indicator of brain activity and attempt to exert control over it.

“The idea is that in people with tinnitus, there is an overattention drawn to the auditory cortex, making it more active than in a healthy person,” said Matthew S. Sherwood, PhD, a research engineer in the Department of Biomedical, Industrial, and Human Factors Engineering at Wright State University in Fairborn, Ohio. “Our hope is that tinnitus sufferers could use neurofeedback to divert attention away from their tinnitus and possibly make it go away.”

To determine the potential efficacy of this approach, the researchers asked 18 healthy volunteers with normal hearing to undergo five fMRI-neurofeedback training sessions. Study participants were given earplugs through which white noise could be introduced. The earplugs also blocked out the scanner noise.

To obtain fMRI results, the researchers used single-shot echoplanar imaging, an MRI technique that is sensitive to blood oxygen levels, providing an indirect measure of brain activity.

“We started with alternating periods of sound and no sound in order to create a map of the brain and find areas that produced the highest activity during the sound phase,” said Dr. Sherwood. “Then we selected the voxels that were heavily activated when sound was being played.”

The subjects then participated in the fMRI-neurofeedback training phase while inside the MRI scanner. They received white noise through their earplugs and were able to view the activity in their primary auditory cortex as a bar on a screen. Each fMRI-neurofeedback training session contained eight blocks separated into a 30-second “relax” period, followed by a 30-second “lower” period. Participants were instructed to watch the bar during the relax period and attempt to lower it by decreasing primary auditory cortex activity during the lower phase. The researchers gave the participants techniques to help them do this, such as trying to divert attention from sound to other sensations like touch and sight.

“Many focused on breathing because it gave them a feeling of control,” said Dr. Sherwood. “By diverting their attention away from sound, the participants’ auditory cortex activity went down, and the signal we were measuring also went down.”

A control group of nine individuals was provided sham neurofeedback. They performed the same tasks as the other group, but the feedback came not from them, but from a random participant. By performing the exact same procedures with both groups using either real or sham neurofeedback, the researchers were able to distinguish the effect of real neurofeedback on control of the primary auditory cortex.

The study represents the first time that fMRI-neurofeedback training has been applied to demonstrate that there is a significant relationship between control of the primary auditory cortex and attentional processes. This result is important to therapeutic development, said Dr. Sherwood, because the neural mechanisms of tinnitus are unknown, but likely related to attention.

The results represent a promising avenue of research that could lead to improvements in other areas of health, like pain management, according to Dr. Sherwood. “Ultimately, we would like to take what we learned from MRI and develop a neurofeedback program that does not require MRI to use, such as an app or home-based therapy that could apply to tinnitus and other conditions,” he said.

Migraine Is Associated With High Sodium Levels in CSF

Migraineurs have significantly higher sodium concentrations in their CSF than people without migraine, according to the first study to use a technique called sodium MRI to examine patients with migraine.

Diagnosis of migraine is challenging, as the characteristics of migraines and the types of attacks vary widely among patients. Consequently, many patients with migraine are undiagnosed and untreated. Other patients, in contrast, are treated with medications for migraines even though they have a different type of headache, such as tension-type headache.

“It would be helpful to have a diagnostic tool supporting or even diagnosing migraine and differentiating migraine from all other types of headache,” said Melissa Meyer, MD, a radiology resident at the Institute of Clinical Radiology and Nuclear Medicine at University Hospital Mannheim and Heidelberg University in Heidelberg, Germany.

Dr. Meyer and colleagues explored a technique called cerebral sodium MRI as a possible means to help in the diagnosis and understanding of migraine. While MRI most often relies on protons to generate an image, sodium can be visualized as well. Research has shown that sodium plays an important role in brain chemistry.

The researchers recruited 12 women (mean age, 34) who had been clinically evaluated for migraine. The women filled out a questionnaire regarding the length, intensity, and frequency of their migraine attacks and accompanying auras. The researchers also enrolled 12 healthy women of similar age as a control group. Both groups underwent cerebral sodium MRI. Sodium concentrations of patients with migraine and healthy controls were compared and statistically analyzed.

The researchers found no significant differences between the two groups in sodium concentrations in the gray and white matter, brainstem, and cerebellum. Significant differences emerged, however, when the researchers looked at sodium concentrations in the CSF. Overall, sodium concentrations were significantly higher in the CSF of migraineurs than in healthy controls.

“These findings might facilitate the challenging diagnosis of a migraine,” said Dr. Meyer. The researchers hope to learn more about the connection between migraine and sodium in future studies. “As this was an exploratory study, we plan to examine more patients, preferably during or shortly after a migraine attack, for further validation.”

Gadolinium May Not Cause Neurologic Harm

There is no evidence that accumulation of gadolinium in the brain speeds cognitive decline, according to researchers.

“Approximately 400 million doses of gadolinium have been administered since 1988,” said Robert J. McDonald, MD, PhD, a neuroradiologist at the Mayo Clinic in Rochester, Minnesota. “Gadolinium contrast material is used in 40% to 50% of MRI scans performed today.”

Scientists previously believed that gadolinium contrast material could not cross the blood–brain barrier. Recent studies, however, including one by Dr. McDonald and colleagues, found that traces of gadolinium could be retained in the brain for years after MRI.

On September 8, 2017, the FDA recommended adding a warning about gadolinium retention in various organs, including the brain, to labels for gadolinium-based contrast agents used during MRI. The FDA highlighted several specific patient populations at greater risk, including children and pregnant women. Yet little is known about the health effects, if any, of gadolinium that is retained in the brain.

For this study, Dr. McDonald and colleagues set out to identify the neurotoxic potential of intracranial gadolinium deposition following IV administration of gadolinium-based contrast agents during MRI. The researchers used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychologic testing at baseline and 15-month follow-up intervals. Neurologic and neurocognitive scores were compared using standard methods between MCSA patients with no history of prior gadolinium exposure and those who had undergone prior MRI with gadolinium-based contrast agents. Progression from normal cognitive status to mild cognitive impairment and dementia was assessed using multistate Markov model analysis.

The study included 4,261 cognitively normal men and women between ages 50 and 90 (mean age, 72). Mean length of study participation was 3.7 years. Of the 4,261 participants, 1,092 (25.6%) had received one or more doses of gadolinium-based contrast agents, with at least one participant receiving as many as 28 prior doses. Median time since first gadolinium exposure was 5.6 years.

After adjusting for age, sex, education level, baseline neurocognitive performance, and other factors, gadolinium exposure was not a significant predictor of cognitive decline, dementia, diminished neuropsychologic performance, or diminished motor performance. No dose-related effects were observed among these metrics. Gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia in this study group.

“There is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” said Dr. McDonald. “This study provides useful data that at the reasonable doses [that] 95% of the population is likely to receive in their lifetime, there is no evidence at this point that gadolinium retention in the brain is associated with adverse clinical outcomes.”

Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology, and recent studies have identified interactions between ovarian steroid hormones, CGRP, and the trigeminovascular system, according to a review published online ahead of print October 30, 2017, in Cephalalgia.

“Numerous animal and human studies have shown that cyclic fluctuations of ovarian hormones (mainly estrogen) modulate CGRP in the peripheral and central trigeminovascular system; this [effect] is especially relevant now that novel antibodies directed against CGRP or its receptor are currently in clinical trials,” said Alejandro Labastida-Ramírez of the Division of Vascular Medicine and Pharmacology at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues.

The relationship between estrogen and CGRP seems to be “a key factor involved in the higher prevalence of migraine in women,” the authors said. “Future studies should focus on how fluctuations of gonadal hormones influence migraine pathophysiology in both genders…. Hopefully, these sex-related differences may contribute to the development of gender-specific therapies.”

Interplay of Hormones and CGRP

A clinical study by Stevenson et al in 1986 was one of the first to discover a relationship between female sex hormones and CGRP. In this study, concentrations of immunoreactive plasma CGRP in healthy women were significantly increased throughout pregnancy and decreased after delivery. A 1990 study by Valdemarsson et al found that in healthy subjects, immunoreactive plasma CGRP levels were significantly higher in females than in males. “The use of combined contraceptive pills was associated with even higher levels of immunoreactive CGRP in plasma,” said the review authors. “Accordingly, in postmenopausal women, decreased estradiol serum levels were positively correlated with decreased plasma immunoreactive CGRP concentrations, [suggesting] that the CGRP system could be influenced directly by endogenous or exogenous ovarian steroid hormones.”

Ibrahimi et al in 2017 used an experimental model to explore gender differences in CGRP-dependent dermal blood flow in healthy subjects and migraineurs. Dermal blood flow in males did not vary over time and was comparable between healthy subjects and migraineurs. In healthy women, fluctuations of ovarian steroid hormones influenced CGRP-dependent dermal blood flow. “Interestingly, in female migraine patients, dermal blood flow responses were elevated, compared to healthy subjects, but these responses were independent of the menstrual cycle,” the review authors noted.

Therapeutic Trials

Three humanized monoclonal antibodies targeting CGRP and one fully human monoclonal antibody targeting the CGRP receptor are in development.

While trials indicate that CGRP blockade is effective for treating migraine, further studies are needed to “elucidate whether these novel drugs are safe in individuals with cardiovascular risk factors, if there are any consequences of chronic CGRP inhibition in young reproductive women with a normal menstrual cycle, and whether efficacy depends on the phase of the menstrual cycle,” the authors said.

—Jake Remaly

Suggested Reading

Ibrahimi K, Vermeersch S, Frederiks P, et al. The influence of migraine and female hormones on capsaicin-induced dermal blood flow. Cephalalgia. 2017;37(12):1164-1172.

Labastida-Ramírez A, Rubio-Beltrán E, Villalón CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia. 2017 Oct 30 [Epub ahead of print].

Stevenson JC, Macdonald DW, Warren RC, et al. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329-1330.

Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest. 1990;50(4):385-388.

Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology, and recent studies have identified interactions between ovarian steroid hormones, CGRP, and the trigeminovascular system, according to a review published online ahead of print October 30, 2017, in Cephalalgia.

“Numerous animal and human studies have shown that cyclic fluctuations of ovarian hormones (mainly estrogen) modulate CGRP in the peripheral and central trigeminovascular system; this [effect] is especially relevant now that novel antibodies directed against CGRP or its receptor are currently in clinical trials,” said Alejandro Labastida-Ramírez of the Division of Vascular Medicine and Pharmacology at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues.

The relationship between estrogen and CGRP seems to be “a key factor involved in the higher prevalence of migraine in women,” the authors said. “Future studies should focus on how fluctuations of gonadal hormones influence migraine pathophysiology in both genders…. Hopefully, these sex-related differences may contribute to the development of gender-specific therapies.”

Interplay of Hormones and CGRP

A clinical study by Stevenson et al in 1986 was one of the first to discover a relationship between female sex hormones and CGRP. In this study, concentrations of immunoreactive plasma CGRP in healthy women were significantly increased throughout pregnancy and decreased after delivery. A 1990 study by Valdemarsson et al found that in healthy subjects, immunoreactive plasma CGRP levels were significantly higher in females than in males. “The use of combined contraceptive pills was associated with even higher levels of immunoreactive CGRP in plasma,” said the review authors. “Accordingly, in postmenopausal women, decreased estradiol serum levels were positively correlated with decreased plasma immunoreactive CGRP concentrations, [suggesting] that the CGRP system could be influenced directly by endogenous or exogenous ovarian steroid hormones.”

Ibrahimi et al in 2017 used an experimental model to explore gender differences in CGRP-dependent dermal blood flow in healthy subjects and migraineurs. Dermal blood flow in males did not vary over time and was comparable between healthy subjects and migraineurs. In healthy women, fluctuations of ovarian steroid hormones influenced CGRP-dependent dermal blood flow. “Interestingly, in female migraine patients, dermal blood flow responses were elevated, compared to healthy subjects, but these responses were independent of the menstrual cycle,” the review authors noted.

Therapeutic Trials

Three humanized monoclonal antibodies targeting CGRP and one fully human monoclonal antibody targeting the CGRP receptor are in development.

While trials indicate that CGRP blockade is effective for treating migraine, further studies are needed to “elucidate whether these novel drugs are safe in individuals with cardiovascular risk factors, if there are any consequences of chronic CGRP inhibition in young reproductive women with a normal menstrual cycle, and whether efficacy depends on the phase of the menstrual cycle,” the authors said.

—Jake Remaly

Suggested Reading

Ibrahimi K, Vermeersch S, Frederiks P, et al. The influence of migraine and female hormones on capsaicin-induced dermal blood flow. Cephalalgia. 2017;37(12):1164-1172.

Labastida-Ramírez A, Rubio-Beltrán E, Villalón CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia. 2017 Oct 30 [Epub ahead of print].

Stevenson JC, Macdonald DW, Warren RC, et al. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329-1330.

Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest. 1990;50(4):385-388.

Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology, and recent studies have identified interactions between ovarian steroid hormones, CGRP, and the trigeminovascular system, according to a review published online ahead of print October 30, 2017, in Cephalalgia.

“Numerous animal and human studies have shown that cyclic fluctuations of ovarian hormones (mainly estrogen) modulate CGRP in the peripheral and central trigeminovascular system; this [effect] is especially relevant now that novel antibodies directed against CGRP or its receptor are currently in clinical trials,” said Alejandro Labastida-Ramírez of the Division of Vascular Medicine and Pharmacology at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues.

The relationship between estrogen and CGRP seems to be “a key factor involved in the higher prevalence of migraine in women,” the authors said. “Future studies should focus on how fluctuations of gonadal hormones influence migraine pathophysiology in both genders…. Hopefully, these sex-related differences may contribute to the development of gender-specific therapies.”

Interplay of Hormones and CGRP

A clinical study by Stevenson et al in 1986 was one of the first to discover a relationship between female sex hormones and CGRP. In this study, concentrations of immunoreactive plasma CGRP in healthy women were significantly increased throughout pregnancy and decreased after delivery. A 1990 study by Valdemarsson et al found that in healthy subjects, immunoreactive plasma CGRP levels were significantly higher in females than in males. “The use of combined contraceptive pills was associated with even higher levels of immunoreactive CGRP in plasma,” said the review authors. “Accordingly, in postmenopausal women, decreased estradiol serum levels were positively correlated with decreased plasma immunoreactive CGRP concentrations, [suggesting] that the CGRP system could be influenced directly by endogenous or exogenous ovarian steroid hormones.”

Ibrahimi et al in 2017 used an experimental model to explore gender differences in CGRP-dependent dermal blood flow in healthy subjects and migraineurs. Dermal blood flow in males did not vary over time and was comparable between healthy subjects and migraineurs. In healthy women, fluctuations of ovarian steroid hormones influenced CGRP-dependent dermal blood flow. “Interestingly, in female migraine patients, dermal blood flow responses were elevated, compared to healthy subjects, but these responses were independent of the menstrual cycle,” the review authors noted.

Therapeutic Trials

Three humanized monoclonal antibodies targeting CGRP and one fully human monoclonal antibody targeting the CGRP receptor are in development.

While trials indicate that CGRP blockade is effective for treating migraine, further studies are needed to “elucidate whether these novel drugs are safe in individuals with cardiovascular risk factors, if there are any consequences of chronic CGRP inhibition in young reproductive women with a normal menstrual cycle, and whether efficacy depends on the phase of the menstrual cycle,” the authors said.

—Jake Remaly

Suggested Reading

Ibrahimi K, Vermeersch S, Frederiks P, et al. The influence of migraine and female hormones on capsaicin-induced dermal blood flow. Cephalalgia. 2017;37(12):1164-1172.

Labastida-Ramírez A, Rubio-Beltrán E, Villalón CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia. 2017 Oct 30 [Epub ahead of print].

Stevenson JC, Macdonald DW, Warren RC, et al. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329-1330.

Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest. 1990;50(4):385-388.

Ketamine May Help Treat Medically Refractory Migraine Pain

Ketamine, a medication commonly used for pain relief and increasingly used for depression, may help alleviate migraine pain in patients who have not been helped by other treatments, a study suggests.

The trial of 61 patients found that almost 75% had an improvement in their migraine intensity after a three- to seven-day course of inpatient treatment with ketamine. The drug is used to induce general anesthesia, but also provides powerful pain control for patients with many painful conditions in lower doses than its anesthetic use.

“Ketamine may hold promise as a treatment for migraine headaches in patients who have failed other treatments,” said study coauthor Eric Schwenk, MD, Director of Orthopedic Anesthesia at Thomas Jefferson University Hospital in Philadelphia. “Our study focused only on short-term relief, but it is encouraging that this treatment might have the potential to help patients [in the] long-term. Our work provides the basis for future prospective studies that involve larger numbers of patients.”

An estimated 12% of the US population has migraines. A subset of these patients, along with those who have other types of headaches, does not respond to treatment. During a migraine, people are often sensitive to light and sound and may become nauseated or vomit. Migraines are three times more common in women than in men.

The researchers reviewed data for patients who received ketamine infusions for intractable migraine headaches—migraines that had failed all other therapies. On a scale of 0 to 10, the average migraine headache pain rating at admission was 7.5, compared with 3.4 at discharge. The average length of infusion was 5.1 days, and the day of lowest pain ratings was day 4. Adverse effects were generally mild.

Dr. Schwenk said that while his hospital uses ketamine to treat intractable migraines, the treatment is not yet widely available. Thomas Jefferson University Hospital will open a new infusion center that will treat more patients with headaches using ketamine. “We hope to expand its use to both more patients and more conditions in the future,” he said.

“Due to the retrospective nature of the study, we cannot definitively say that ketamine is entirely responsible for the pain relief, but we have provided a basis for additional larger studies to be undertaken,” Dr. Schwenk added.

Opioid Abuse Plateaus at a High Level

Although the rapid increase in opioid abuse has leveled off, the prevalence of abuse remains high and does not appear to be declining, according to an analysis of national data.

More than 13% of Americans age 12 and older—nearly one in seven—have abused prescription opioids at some point in their lives, researchers determined after analyzing the latest data from the National Survey on Drug Use and Health (NSDUH), an annual survey sponsored by the Substance Abuse and Mental Health Services Administration. Additionally, while 8.6% of Americans abused opioids in 2000, by 2003 that number increased to 13.2%, and it has remained at that level since.

“The amount of opioid prescriptions being written in the United States is breathtaking—essentially enough for every American adult to have a bottle of the pain killers in their medicine cabinet,” said Asokumar Buvanendran, MD, lead author of the study, Director of Orthopedic Anesthesia and Vice Chair for Research at Rush Medical College in Chicago, and chair of the American Society of Anesthesiologists (ASA) Committee on Pain Medicine. “This in turn leads to opioid abuse because people may take more than needed, or the pills fall into the wrong hands. That has got to change.”

Because opioids can produce euphoria, they are highly likely to be abused. Opioid prescriptions are often written for an excessive number of pills, so patients may take more medication than they need and become addicted. Additionally, unused medication can be diverted to another person for illicit use. More than half of the people who misuse prescribed opioids get them from a friend or relative, not a physician, according to NSDUH data.

The NSDUH survey asked Americans whether they had taken prescription opioids without a prescription written for them (which constitutes abuse) anytime in their lives. The researchers determined that in 2014 (the last year for which data was available), 13.6% of Americans had abused prescription opioids. Use of hydrocodone (including Vicodin, a combination of hydrocodone and acetaminophen) increased from 3.2% in 2000 to 9.1% in 2014. Use of oxycontin increased from less than 1% in 2000 to 3% in 2014.

Hydrocodone is the most frequently prescribed and therefore the most frequently abused opioid, researchers noted.

“While the illicit opioid use trend seems to have plateaued, there is no evidence of a decline yet,” said Mario Moric, coauthor of the study and a biostatistician at Rush Medical College. “Hopefully, with increased national attention to the problem we will see a significant drop in abuse.”

“Opioids are still an important tool for dealing with pain, but doctors need to prescribe smaller quantities,” said Dr. Buvanendran. “Also, patients need to be educated about the dangers of overuse and abuse and understand that pain usually cannot be solved solely with a pill, but needs to include exercise, physical therapy, eating right, having a social support system, and developing good coping skills.”

The ASA is committed to ending opioid abuse and has launched several initiatives to combat the epidemic.

Botox May Benefit Children With Hard-to-Treat Migraines

Injections of botulinum toxin (Botox) may provide significant relief for children with migraine headaches that do not respond to traditional treatment, suggests a small preliminary study.

Botox is approved by the FDA to treat migraines in adults. One in 10 school-aged children and teens have migraines, but there are few FDA-approved medications for this age group. Some children and teens do not respond well to available options, such as certain migraine rescue pain medications, and the pain and disability of migraines can have a severe impact on their lives. Preventative medications may help sometimes. Only one preventative migraine medication, topiramate, is approved for adolescents, however.

“When children and teens have migraine pain, it can severely affect their lives and ability to function. They miss school, their grades suffer, and they are left behind, often unable to reach their full potential. Clearly, there is a need for an alternative treatment for those who have not found relief,” said Shalini Shah, MD, lead author of the study and Chief of the Division of Pain Medicine at the University of California, Irvine. “After treatment, we saw improvement in functional aspects in all of the children and teens. In fact, one patient was hospitalized monthly for her migraine pain prior to Botox treatment and was expected to be held back in school. After treatment, she only has one or two migraines a year, and is excelling in college.”

The study included nine children and teens (ages 8 to 17) who had migraines on eight to 29.5 days per month. Most participants had tried numerous medications and other therapies without much relief. All received Botox injections in the front and back of the head and neck every 12 weeks and were evaluated during a five-year period. After treatment, the patients had migraines on two to 10 days per month.

In addition, when treated participants did have migraines, their headaches did not last as long. Patients’ migraines lasted from 30 minutes to 24 hours before treatment, and 15 minutes to seven hours after treatment. Their headaches also were not as painful. Patient-reported pain on a scale of 1–10 (from no pain to worst pain imaginable) ranged from 4 to 8 before treatment and 1.75 to 5 after treatment.

Eight adverse events were reported during the study. Most resulted from pain at the injection site. No severe adverse events were reported.

If the results of the current study are confirmed, Botox could provide an alternative for patients without treatment options, said Dr. Shah. Her team is enrolling patients to study this treatment in a prospective, randomized, double-blinded trial to compare Botox with placebo.

“Many current migraine medications have side effects, including sedation, dry mouth, and confusion, which are not well-tolerated in children and teens,” said Dr. Shah. “Our research of Botox is part of an effort to find better treatments for children and teens with migraines so they can realize their full potential.”

The study authors received no funding from the manufacturer of Botox.

Diabetes Increases Risk of Cognitive Problems After Surgery

Older patients with diabetes may be at an 84% higher risk of developing postoperative cognitive dysfunction (POCD) than those who are not diabetic, new research suggests.

“With POCD, a patient’s mental ability declines after surgery, compared to their cognitive performance before surgery, resulting not only in increased complications and potential death, but also impairing the patient’s quality of life,” said Gunnar Lachmann, MD, Department of Anesthesiology and Operative Intensive Care Medicine, Charité—Universitätsmedizin Berlin. “POCD is increasingly recognized as a common complication after major surgery, affecting 10% to 13% of patients, with seniors being especially vulnerable.”

POCD is a major form of cognitive disturbance that can occur after anesthesia and surgery, but little is known about its potential risk factors. An association between diabetes and age-related cognitive impairment is well established, but the role diabetes has in the development of POCD is unknown.

In the study, researchers performed a secondary analysis of three studies, comprising 1,034 patients (481 who had cardiac surgery and 553 who had noncardiac surgery), to examine whether diabetes was a risk factor for POCD. Patients’ mean age was 66.4. Of the 1,034 participants, 18.6% had diabetes. The association of diabetes with risk of POCD was determined using logistic regression models at the longest patient follow-up period for each study, which was three or 12 months. Risk estimates were pooled across all three studies.

After adjusting for age, sex, surgery type, randomization, obesity, and hypertension, the researchers determined that diabetes was associated with an 84% higher risk of POCD. Patients age 65 or older were at particularly high risk.

“Our findings suggest that consideration of diabetes status may be helpful for the assessment of POCD risk among patients undergoing surgery,” said Dr. Lachmann. “Further studies are warranted to examine the potential mechanisms of this association, to ultimately help in the development of potential strategies for prevention.”

In 2015, the American Society of Anesthesiologists launched a patient safety initiative—the Brain Health Initiative—to provide physician anesthesiologists and other clinicians involved in perioperative care, as well as patients and their families caring for older surgical patients, with the tools and resources necessary to optimize the cognitive recovery and perioperative experience for adults age 65 and older undergoing surgery.

Ketamine May Help Treat Medically Refractory Migraine Pain

Ketamine, a medication commonly used for pain relief and increasingly used for depression, may help alleviate migraine pain in patients who have not been helped by other treatments, a study suggests.

The trial of 61 patients found that almost 75% had an improvement in their migraine intensity after a three- to seven-day course of inpatient treatment with ketamine. The drug is used to induce general anesthesia, but also provides powerful pain control for patients with many painful conditions in lower doses than its anesthetic use.

“Ketamine may hold promise as a treatment for migraine headaches in patients who have failed other treatments,” said study coauthor Eric Schwenk, MD, Director of Orthopedic Anesthesia at Thomas Jefferson University Hospital in Philadelphia. “Our study focused only on short-term relief, but it is encouraging that this treatment might have the potential to help patients [in the] long-term. Our work provides the basis for future prospective studies that involve larger numbers of patients.”

An estimated 12% of the US population has migraines. A subset of these patients, along with those who have other types of headaches, does not respond to treatment. During a migraine, people are often sensitive to light and sound and may become nauseated or vomit. Migraines are three times more common in women than in men.

The researchers reviewed data for patients who received ketamine infusions for intractable migraine headaches—migraines that had failed all other therapies. On a scale of 0 to 10, the average migraine headache pain rating at admission was 7.5, compared with 3.4 at discharge. The average length of infusion was 5.1 days, and the day of lowest pain ratings was day 4. Adverse effects were generally mild.

Dr. Schwenk said that while his hospital uses ketamine to treat intractable migraines, the treatment is not yet widely available. Thomas Jefferson University Hospital will open a new infusion center that will treat more patients with headaches using ketamine. “We hope to expand its use to both more patients and more conditions in the future,” he said.

“Due to the retrospective nature of the study, we cannot definitively say that ketamine is entirely responsible for the pain relief, but we have provided a basis for additional larger studies to be undertaken,” Dr. Schwenk added.

Opioid Abuse Plateaus at a High Level

Although the rapid increase in opioid abuse has leveled off, the prevalence of abuse remains high and does not appear to be declining, according to an analysis of national data.

More than 13% of Americans age 12 and older—nearly one in seven—have abused prescription opioids at some point in their lives, researchers determined after analyzing the latest data from the National Survey on Drug Use and Health (NSDUH), an annual survey sponsored by the Substance Abuse and Mental Health Services Administration. Additionally, while 8.6% of Americans abused opioids in 2000, by 2003 that number increased to 13.2%, and it has remained at that level since.

“The amount of opioid prescriptions being written in the United States is breathtaking—essentially enough for every American adult to have a bottle of the pain killers in their medicine cabinet,” said Asokumar Buvanendran, MD, lead author of the study, Director of Orthopedic Anesthesia and Vice Chair for Research at Rush Medical College in Chicago, and chair of the American Society of Anesthesiologists (ASA) Committee on Pain Medicine. “This in turn leads to opioid abuse because people may take more than needed, or the pills fall into the wrong hands. That has got to change.”

Because opioids can produce euphoria, they are highly likely to be abused. Opioid prescriptions are often written for an excessive number of pills, so patients may take more medication than they need and become addicted. Additionally, unused medication can be diverted to another person for illicit use. More than half of the people who misuse prescribed opioids get them from a friend or relative, not a physician, according to NSDUH data.

The NSDUH survey asked Americans whether they had taken prescription opioids without a prescription written for them (which constitutes abuse) anytime in their lives. The researchers determined that in 2014 (the last year for which data was available), 13.6% of Americans had abused prescription opioids. Use of hydrocodone (including Vicodin, a combination of hydrocodone and acetaminophen) increased from 3.2% in 2000 to 9.1% in 2014. Use of oxycontin increased from less than 1% in 2000 to 3% in 2014.

Hydrocodone is the most frequently prescribed and therefore the most frequently abused opioid, researchers noted.

“While the illicit opioid use trend seems to have plateaued, there is no evidence of a decline yet,” said Mario Moric, coauthor of the study and a biostatistician at Rush Medical College. “Hopefully, with increased national attention to the problem we will see a significant drop in abuse.”

“Opioids are still an important tool for dealing with pain, but doctors need to prescribe smaller quantities,” said Dr. Buvanendran. “Also, patients need to be educated about the dangers of overuse and abuse and understand that pain usually cannot be solved solely with a pill, but needs to include exercise, physical therapy, eating right, having a social support system, and developing good coping skills.”

The ASA is committed to ending opioid abuse and has launched several initiatives to combat the epidemic.

Botox May Benefit Children With Hard-to-Treat Migraines

Injections of botulinum toxin (Botox) may provide significant relief for children with migraine headaches that do not respond to traditional treatment, suggests a small preliminary study.

Botox is approved by the FDA to treat migraines in adults. One in 10 school-aged children and teens have migraines, but there are few FDA-approved medications for this age group. Some children and teens do not respond well to available options, such as certain migraine rescue pain medications, and the pain and disability of migraines can have a severe impact on their lives. Preventative medications may help sometimes. Only one preventative migraine medication, topiramate, is approved for adolescents, however.

“When children and teens have migraine pain, it can severely affect their lives and ability to function. They miss school, their grades suffer, and they are left behind, often unable to reach their full potential. Clearly, there is a need for an alternative treatment for those who have not found relief,” said Shalini Shah, MD, lead author of the study and Chief of the Division of Pain Medicine at the University of California, Irvine. “After treatment, we saw improvement in functional aspects in all of the children and teens. In fact, one patient was hospitalized monthly for her migraine pain prior to Botox treatment and was expected to be held back in school. After treatment, she only has one or two migraines a year, and is excelling in college.”

The study included nine children and teens (ages 8 to 17) who had migraines on eight to 29.5 days per month. Most participants had tried numerous medications and other therapies without much relief. All received Botox injections in the front and back of the head and neck every 12 weeks and were evaluated during a five-year period. After treatment, the patients had migraines on two to 10 days per month.

In addition, when treated participants did have migraines, their headaches did not last as long. Patients’ migraines lasted from 30 minutes to 24 hours before treatment, and 15 minutes to seven hours after treatment. Their headaches also were not as painful. Patient-reported pain on a scale of 1–10 (from no pain to worst pain imaginable) ranged from 4 to 8 before treatment and 1.75 to 5 after treatment.

Eight adverse events were reported during the study. Most resulted from pain at the injection site. No severe adverse events were reported.

If the results of the current study are confirmed, Botox could provide an alternative for patients without treatment options, said Dr. Shah. Her team is enrolling patients to study this treatment in a prospective, randomized, double-blinded trial to compare Botox with placebo.

“Many current migraine medications have side effects, including sedation, dry mouth, and confusion, which are not well-tolerated in children and teens,” said Dr. Shah. “Our research of Botox is part of an effort to find better treatments for children and teens with migraines so they can realize their full potential.”

The study authors received no funding from the manufacturer of Botox.

Diabetes Increases Risk of Cognitive Problems After Surgery

Older patients with diabetes may be at an 84% higher risk of developing postoperative cognitive dysfunction (POCD) than those who are not diabetic, new research suggests.

“With POCD, a patient’s mental ability declines after surgery, compared to their cognitive performance before surgery, resulting not only in increased complications and potential death, but also impairing the patient’s quality of life,” said Gunnar Lachmann, MD, Department of Anesthesiology and Operative Intensive Care Medicine, Charité—Universitätsmedizin Berlin. “POCD is increasingly recognized as a common complication after major surgery, affecting 10% to 13% of patients, with seniors being especially vulnerable.”

POCD is a major form of cognitive disturbance that can occur after anesthesia and surgery, but little is known about its potential risk factors. An association between diabetes and age-related cognitive impairment is well established, but the role diabetes has in the development of POCD is unknown.

In the study, researchers performed a secondary analysis of three studies, comprising 1,034 patients (481 who had cardiac surgery and 553 who had noncardiac surgery), to examine whether diabetes was a risk factor for POCD. Patients’ mean age was 66.4. Of the 1,034 participants, 18.6% had diabetes. The association of diabetes with risk of POCD was determined using logistic regression models at the longest patient follow-up period for each study, which was three or 12 months. Risk estimates were pooled across all three studies.

After adjusting for age, sex, surgery type, randomization, obesity, and hypertension, the researchers determined that diabetes was associated with an 84% higher risk of POCD. Patients age 65 or older were at particularly high risk.

“Our findings suggest that consideration of diabetes status may be helpful for the assessment of POCD risk among patients undergoing surgery,” said Dr. Lachmann. “Further studies are warranted to examine the potential mechanisms of this association, to ultimately help in the development of potential strategies for prevention.”

In 2015, the American Society of Anesthesiologists launched a patient safety initiative—the Brain Health Initiative—to provide physician anesthesiologists and other clinicians involved in perioperative care, as well as patients and their families caring for older surgical patients, with the tools and resources necessary to optimize the cognitive recovery and perioperative experience for adults age 65 and older undergoing surgery.

Ketamine May Help Treat Medically Refractory Migraine Pain

Ketamine, a medication commonly used for pain relief and increasingly used for depression, may help alleviate migraine pain in patients who have not been helped by other treatments, a study suggests.

The trial of 61 patients found that almost 75% had an improvement in their migraine intensity after a three- to seven-day course of inpatient treatment with ketamine. The drug is used to induce general anesthesia, but also provides powerful pain control for patients with many painful conditions in lower doses than its anesthetic use.

“Ketamine may hold promise as a treatment for migraine headaches in patients who have failed other treatments,” said study coauthor Eric Schwenk, MD, Director of Orthopedic Anesthesia at Thomas Jefferson University Hospital in Philadelphia. “Our study focused only on short-term relief, but it is encouraging that this treatment might have the potential to help patients [in the] long-term. Our work provides the basis for future prospective studies that involve larger numbers of patients.”

An estimated 12% of the US population has migraines. A subset of these patients, along with those who have other types of headaches, does not respond to treatment. During a migraine, people are often sensitive to light and sound and may become nauseated or vomit. Migraines are three times more common in women than in men.

The researchers reviewed data for patients who received ketamine infusions for intractable migraine headaches—migraines that had failed all other therapies. On a scale of 0 to 10, the average migraine headache pain rating at admission was 7.5, compared with 3.4 at discharge. The average length of infusion was 5.1 days, and the day of lowest pain ratings was day 4. Adverse effects were generally mild.

Dr. Schwenk said that while his hospital uses ketamine to treat intractable migraines, the treatment is not yet widely available. Thomas Jefferson University Hospital will open a new infusion center that will treat more patients with headaches using ketamine. “We hope to expand its use to both more patients and more conditions in the future,” he said.

“Due to the retrospective nature of the study, we cannot definitively say that ketamine is entirely responsible for the pain relief, but we have provided a basis for additional larger studies to be undertaken,” Dr. Schwenk added.

Opioid Abuse Plateaus at a High Level

Although the rapid increase in opioid abuse has leveled off, the prevalence of abuse remains high and does not appear to be declining, according to an analysis of national data.

More than 13% of Americans age 12 and older—nearly one in seven—have abused prescription opioids at some point in their lives, researchers determined after analyzing the latest data from the National Survey on Drug Use and Health (NSDUH), an annual survey sponsored by the Substance Abuse and Mental Health Services Administration. Additionally, while 8.6% of Americans abused opioids in 2000, by 2003 that number increased to 13.2%, and it has remained at that level since.

“The amount of opioid prescriptions being written in the United States is breathtaking—essentially enough for every American adult to have a bottle of the pain killers in their medicine cabinet,” said Asokumar Buvanendran, MD, lead author of the study, Director of Orthopedic Anesthesia and Vice Chair for Research at Rush Medical College in Chicago, and chair of the American Society of Anesthesiologists (ASA) Committee on Pain Medicine. “This in turn leads to opioid abuse because people may take more than needed, or the pills fall into the wrong hands. That has got to change.”

Because opioids can produce euphoria, they are highly likely to be abused. Opioid prescriptions are often written for an excessive number of pills, so patients may take more medication than they need and become addicted. Additionally, unused medication can be diverted to another person for illicit use. More than half of the people who misuse prescribed opioids get them from a friend or relative, not a physician, according to NSDUH data.

The NSDUH survey asked Americans whether they had taken prescription opioids without a prescription written for them (which constitutes abuse) anytime in their lives. The researchers determined that in 2014 (the last year for which data was available), 13.6% of Americans had abused prescription opioids. Use of hydrocodone (including Vicodin, a combination of hydrocodone and acetaminophen) increased from 3.2% in 2000 to 9.1% in 2014. Use of oxycontin increased from less than 1% in 2000 to 3% in 2014.

Hydrocodone is the most frequently prescribed and therefore the most frequently abused opioid, researchers noted.

“While the illicit opioid use trend seems to have plateaued, there is no evidence of a decline yet,” said Mario Moric, coauthor of the study and a biostatistician at Rush Medical College. “Hopefully, with increased national attention to the problem we will see a significant drop in abuse.”

“Opioids are still an important tool for dealing with pain, but doctors need to prescribe smaller quantities,” said Dr. Buvanendran. “Also, patients need to be educated about the dangers of overuse and abuse and understand that pain usually cannot be solved solely with a pill, but needs to include exercise, physical therapy, eating right, having a social support system, and developing good coping skills.”

The ASA is committed to ending opioid abuse and has launched several initiatives to combat the epidemic.

Botox May Benefit Children With Hard-to-Treat Migraines

Injections of botulinum toxin (Botox) may provide significant relief for children with migraine headaches that do not respond to traditional treatment, suggests a small preliminary study.

Botox is approved by the FDA to treat migraines in adults. One in 10 school-aged children and teens have migraines, but there are few FDA-approved medications for this age group. Some children and teens do not respond well to available options, such as certain migraine rescue pain medications, and the pain and disability of migraines can have a severe impact on their lives. Preventative medications may help sometimes. Only one preventative migraine medication, topiramate, is approved for adolescents, however.

“When children and teens have migraine pain, it can severely affect their lives and ability to function. They miss school, their grades suffer, and they are left behind, often unable to reach their full potential. Clearly, there is a need for an alternative treatment for those who have not found relief,” said Shalini Shah, MD, lead author of the study and Chief of the Division of Pain Medicine at the University of California, Irvine. “After treatment, we saw improvement in functional aspects in all of the children and teens. In fact, one patient was hospitalized monthly for her migraine pain prior to Botox treatment and was expected to be held back in school. After treatment, she only has one or two migraines a year, and is excelling in college.”

The study included nine children and teens (ages 8 to 17) who had migraines on eight to 29.5 days per month. Most participants had tried numerous medications and other therapies without much relief. All received Botox injections in the front and back of the head and neck every 12 weeks and were evaluated during a five-year period. After treatment, the patients had migraines on two to 10 days per month.

In addition, when treated participants did have migraines, their headaches did not last as long. Patients’ migraines lasted from 30 minutes to 24 hours before treatment, and 15 minutes to seven hours after treatment. Their headaches also were not as painful. Patient-reported pain on a scale of 1–10 (from no pain to worst pain imaginable) ranged from 4 to 8 before treatment and 1.75 to 5 after treatment.

Eight adverse events were reported during the study. Most resulted from pain at the injection site. No severe adverse events were reported.

If the results of the current study are confirmed, Botox could provide an alternative for patients without treatment options, said Dr. Shah. Her team is enrolling patients to study this treatment in a prospective, randomized, double-blinded trial to compare Botox with placebo.

“Many current migraine medications have side effects, including sedation, dry mouth, and confusion, which are not well-tolerated in children and teens,” said Dr. Shah. “Our research of Botox is part of an effort to find better treatments for children and teens with migraines so they can realize their full potential.”

The study authors received no funding from the manufacturer of Botox.

Diabetes Increases Risk of Cognitive Problems After Surgery

Older patients with diabetes may be at an 84% higher risk of developing postoperative cognitive dysfunction (POCD) than those who are not diabetic, new research suggests.

“With POCD, a patient’s mental ability declines after surgery, compared to their cognitive performance before surgery, resulting not only in increased complications and potential death, but also impairing the patient’s quality of life,” said Gunnar Lachmann, MD, Department of Anesthesiology and Operative Intensive Care Medicine, Charité—Universitätsmedizin Berlin. “POCD is increasingly recognized as a common complication after major surgery, affecting 10% to 13% of patients, with seniors being especially vulnerable.”

POCD is a major form of cognitive disturbance that can occur after anesthesia and surgery, but little is known about its potential risk factors. An association between diabetes and age-related cognitive impairment is well established, but the role diabetes has in the development of POCD is unknown.

In the study, researchers performed a secondary analysis of three studies, comprising 1,034 patients (481 who had cardiac surgery and 553 who had noncardiac surgery), to examine whether diabetes was a risk factor for POCD. Patients’ mean age was 66.4. Of the 1,034 participants, 18.6% had diabetes. The association of diabetes with risk of POCD was determined using logistic regression models at the longest patient follow-up period for each study, which was three or 12 months. Risk estimates were pooled across all three studies.

After adjusting for age, sex, surgery type, randomization, obesity, and hypertension, the researchers determined that diabetes was associated with an 84% higher risk of POCD. Patients age 65 or older were at particularly high risk.

“Our findings suggest that consideration of diabetes status may be helpful for the assessment of POCD risk among patients undergoing surgery,” said Dr. Lachmann. “Further studies are warranted to examine the potential mechanisms of this association, to ultimately help in the development of potential strategies for prevention.”

In 2015, the American Society of Anesthesiologists launched a patient safety initiative—the Brain Health Initiative—to provide physician anesthesiologists and other clinicians involved in perioperative care, as well as patients and their families caring for older surgical patients, with the tools and resources necessary to optimize the cognitive recovery and perioperative experience for adults age 65 and older undergoing surgery.

Opiates are overused, and acute analgesics with high-quality evidence may be underused, for the treatment of migraine, according to research published online ahead of print June 26 in Cephalalgia. In addition, migraine may be undertreated with preventive medications. These prescribing patterns do not significantly differ by patients’ race, however.

Analyzing Nationally Representative Data

In the US, racial disparities in migraine burden have been reported. Migraine in African Americans is more frequent, more severe, more likely to become chronic, and associated with more depression and lower quality of life, compared with migraine in non-Hispanic whites. Lower-quality medication treatment for migraine may explain this difference, but little is known about the quality of migraine prescribing patterns in the US or whether racial differences exist.

Dr. Charleston and James F. Burke, MD, Associate Professor of Neurology at the University of Michigan Medical School, hypothesized that racial differences in the use of high-quality abortive, prophylactic medications would exist in ambulatory care settings, and that the quality of medical treatment for migraine disorders would be suboptimal in minority populations. To test these hypotheses, they analyzed all headache visits for patients over age 18 in the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2013.

The investigators defined quality of migraine care by using the American Academy of Neurology Headache Quality Measure Set. Researchers then assigned patients to one of three race or ethnicity categories—non-Hispanic white, African American, and Hispanic. Patients who reported other races or ethnicities were excluded.

The researchers assigned patients to one of four abortive agent categories—no abortive agent prescribed, all high-quality abortive agents (ie, triptans or dihydroergotamine), some low-quality abortive agents, or any opiate agent. In addition, the investigators assigned patients to one of four prophylactic agent categories—no prophylactic agent, all high-quality prophylaxis, some low-quality prophylaxis, or all low-quality prophylaxis. Finally, researchers made racial comparisons using descriptive statistics after applying NAMCS survey weights.

Prophylactic Agents Are Likely Underused

A total of 2,860 visits were included in the study, representing approximately 50 million migraine visits in the US from 2006 to 2013; 76% of patients were non-Hispanic white, 10% were African American, and 10% were Hispanic. Hispanic patients were more likely to be seen in a given practice for the first time, compared with non-Hispanic whites or African Americans. Researchers also observed a trend toward less private insurance and more Medicaid among African American and Hispanic patients, compared with non-Hispanic white patients.

Although overall migraine prescribing patterns were suboptimal, researchers did not find any major differences by race. “It is possible, though, that more modest racial differences in abortive prescribing exist, but that we lacked statistical power to identify those differences,” said Drs. Charleston and Burke.

In all, 41.3% of African Americans, 40.8% of non-Hispanic whites, and 41.2% of Hispanic patients received no prophylactic treatment. A total of 18.8% of African Americans, 11.9% of non-Hispanic whites, and 6.9% of Hispanic patients received exclusively Level A prophylaxis.

Forty-seven percent of African Americans, 38.2% of non-Hispanic whites, and 36.3% of Hispanic patients received no abortive treatments. In all, 15.3% of African Americans, 19.4% of non-Hispanic whites, and 17.7% of Hispanic patients received exclusively Level A abortive agents. About 15.2% of patients had a prescription for opiates, but no racial differences were observed.

In addition, African Americans were 4% less likely to receive all high-quality abortive agents, and Hispanic patients were 5% less likely to receive all high-quality prophylactic agents, compared with non-Hispanic whites. Neither of these differences was statistically significant, said the researchers.

“Understanding what drives these prescribing patterns and improving overall migraine prescribing should be a central concern for headache care practitioners and quality-improvement initiatives, and a target of future interventions,” said Drs. Charleston and Burke.

One limitation of this study was that researchers had no details on headache severity or duration. Another limitation was that the researchers did not control for socioeconomic status.

—Erica Tricarico

Suggested Reading

Charleston IV L, Burke JF. Do racial/ethnic disparities exist in recommended migraine treatments in US ambulatory care? Cephalalgia. 2017 Jun 26 [Epub ahead of print].

Opiates are overused, and acute analgesics with high-quality evidence may be underused, for the treatment of migraine, according to research published online ahead of print June 26 in Cephalalgia. In addition, migraine may be undertreated with preventive medications. These prescribing patterns do not significantly differ by patients’ race, however.

Analyzing Nationally Representative Data

In the US, racial disparities in migraine burden have been reported. Migraine in African Americans is more frequent, more severe, more likely to become chronic, and associated with more depression and lower quality of life, compared with migraine in non-Hispanic whites. Lower-quality medication treatment for migraine may explain this difference, but little is known about the quality of migraine prescribing patterns in the US or whether racial differences exist.

Dr. Charleston and James F. Burke, MD, Associate Professor of Neurology at the University of Michigan Medical School, hypothesized that racial differences in the use of high-quality abortive, prophylactic medications would exist in ambulatory care settings, and that the quality of medical treatment for migraine disorders would be suboptimal in minority populations. To test these hypotheses, they analyzed all headache visits for patients over age 18 in the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2013.

The investigators defined quality of migraine care by using the American Academy of Neurology Headache Quality Measure Set. Researchers then assigned patients to one of three race or ethnicity categories—non-Hispanic white, African American, and Hispanic. Patients who reported other races or ethnicities were excluded.

The researchers assigned patients to one of four abortive agent categories—no abortive agent prescribed, all high-quality abortive agents (ie, triptans or dihydroergotamine), some low-quality abortive agents, or any opiate agent. In addition, the investigators assigned patients to one of four prophylactic agent categories—no prophylactic agent, all high-quality prophylaxis, some low-quality prophylaxis, or all low-quality prophylaxis. Finally, researchers made racial comparisons using descriptive statistics after applying NAMCS survey weights.

Prophylactic Agents Are Likely Underused

A total of 2,860 visits were included in the study, representing approximately 50 million migraine visits in the US from 2006 to 2013; 76% of patients were non-Hispanic white, 10% were African American, and 10% were Hispanic. Hispanic patients were more likely to be seen in a given practice for the first time, compared with non-Hispanic whites or African Americans. Researchers also observed a trend toward less private insurance and more Medicaid among African American and Hispanic patients, compared with non-Hispanic white patients.

Although overall migraine prescribing patterns were suboptimal, researchers did not find any major differences by race. “It is possible, though, that more modest racial differences in abortive prescribing exist, but that we lacked statistical power to identify those differences,” said Drs. Charleston and Burke.

In all, 41.3% of African Americans, 40.8% of non-Hispanic whites, and 41.2% of Hispanic patients received no prophylactic treatment. A total of 18.8% of African Americans, 11.9% of non-Hispanic whites, and 6.9% of Hispanic patients received exclusively Level A prophylaxis.

Forty-seven percent of African Americans, 38.2% of non-Hispanic whites, and 36.3% of Hispanic patients received no abortive treatments. In all, 15.3% of African Americans, 19.4% of non-Hispanic whites, and 17.7% of Hispanic patients received exclusively Level A abortive agents. About 15.2% of patients had a prescription for opiates, but no racial differences were observed.

In addition, African Americans were 4% less likely to receive all high-quality abortive agents, and Hispanic patients were 5% less likely to receive all high-quality prophylactic agents, compared with non-Hispanic whites. Neither of these differences was statistically significant, said the researchers.

“Understanding what drives these prescribing patterns and improving overall migraine prescribing should be a central concern for headache care practitioners and quality-improvement initiatives, and a target of future interventions,” said Drs. Charleston and Burke.

One limitation of this study was that researchers had no details on headache severity or duration. Another limitation was that the researchers did not control for socioeconomic status.

—Erica Tricarico

Suggested Reading

Charleston IV L, Burke JF. Do racial/ethnic disparities exist in recommended migraine treatments in US ambulatory care? Cephalalgia. 2017 Jun 26 [Epub ahead of print].

Opiates are overused, and acute analgesics with high-quality evidence may be underused, for the treatment of migraine, according to research published online ahead of print June 26 in Cephalalgia. In addition, migraine may be undertreated with preventive medications. These prescribing patterns do not significantly differ by patients’ race, however.

Analyzing Nationally Representative Data

In the US, racial disparities in migraine burden have been reported. Migraine in African Americans is more frequent, more severe, more likely to become chronic, and associated with more depression and lower quality of life, compared with migraine in non-Hispanic whites. Lower-quality medication treatment for migraine may explain this difference, but little is known about the quality of migraine prescribing patterns in the US or whether racial differences exist.

Dr. Charleston and James F. Burke, MD, Associate Professor of Neurology at the University of Michigan Medical School, hypothesized that racial differences in the use of high-quality abortive, prophylactic medications would exist in ambulatory care settings, and that the quality of medical treatment for migraine disorders would be suboptimal in minority populations. To test these hypotheses, they analyzed all headache visits for patients over age 18 in the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2013.

The investigators defined quality of migraine care by using the American Academy of Neurology Headache Quality Measure Set. Researchers then assigned patients to one of three race or ethnicity categories—non-Hispanic white, African American, and Hispanic. Patients who reported other races or ethnicities were excluded.

The researchers assigned patients to one of four abortive agent categories—no abortive agent prescribed, all high-quality abortive agents (ie, triptans or dihydroergotamine), some low-quality abortive agents, or any opiate agent. In addition, the investigators assigned patients to one of four prophylactic agent categories—no prophylactic agent, all high-quality prophylaxis, some low-quality prophylaxis, or all low-quality prophylaxis. Finally, researchers made racial comparisons using descriptive statistics after applying NAMCS survey weights.

Prophylactic Agents Are Likely Underused

A total of 2,860 visits were included in the study, representing approximately 50 million migraine visits in the US from 2006 to 2013; 76% of patients were non-Hispanic white, 10% were African American, and 10% were Hispanic. Hispanic patients were more likely to be seen in a given practice for the first time, compared with non-Hispanic whites or African Americans. Researchers also observed a trend toward less private insurance and more Medicaid among African American and Hispanic patients, compared with non-Hispanic white patients.

Although overall migraine prescribing patterns were suboptimal, researchers did not find any major differences by race. “It is possible, though, that more modest racial differences in abortive prescribing exist, but that we lacked statistical power to identify those differences,” said Drs. Charleston and Burke.

In all, 41.3% of African Americans, 40.8% of non-Hispanic whites, and 41.2% of Hispanic patients received no prophylactic treatment. A total of 18.8% of African Americans, 11.9% of non-Hispanic whites, and 6.9% of Hispanic patients received exclusively Level A prophylaxis.

Forty-seven percent of African Americans, 38.2% of non-Hispanic whites, and 36.3% of Hispanic patients received no abortive treatments. In all, 15.3% of African Americans, 19.4% of non-Hispanic whites, and 17.7% of Hispanic patients received exclusively Level A abortive agents. About 15.2% of patients had a prescription for opiates, but no racial differences were observed.

In addition, African Americans were 4% less likely to receive all high-quality abortive agents, and Hispanic patients were 5% less likely to receive all high-quality prophylactic agents, compared with non-Hispanic whites. Neither of these differences was statistically significant, said the researchers.

“Understanding what drives these prescribing patterns and improving overall migraine prescribing should be a central concern for headache care practitioners and quality-improvement initiatives, and a target of future interventions,” said Drs. Charleston and Burke.

One limitation of this study was that researchers had no details on headache severity or duration. Another limitation was that the researchers did not control for socioeconomic status.

—Erica Tricarico

Suggested Reading

Charleston IV L, Burke JF. Do racial/ethnic disparities exist in recommended migraine treatments in US ambulatory care? Cephalalgia. 2017 Jun 26 [Epub ahead of print].

STANFORD, CA—Headache specialists have created a new app intended to support patients with headache pain. Developed by board-certified headache specialists in collaboration with a machine learning and artificial intelligence professional, the BonTriage Headache Compass may help patients with headache better manage and improve their condition. When used consistently over time, this app is intended to help patients reduce the frequency, severity, and duration of headaches, as well as the disability they cause.

“The BonTriage Headache Compass provides a diagnostic clinical impression and monitoring, which patients can take to their doctor or just use to gain insight into their condition,” said Robert Cowan, MD, Professor of Neurology and Chief of the Division of Headache Medicine at Stanford University and a co-creator of the new app.

Personalized Data

The BonTriage Headache Compass app is the second product developed by BonTriage. The first is a detailed web-based questionnaire, available at www.bontriage.com, that creates a detailed report about a patient’s headache. The questionnaire has been validated and its accuracy is greater than 90%. Once completed, the questionnaire can be printed and shared with the patient’s physician.

The app works together with the questionnaire, but can be used independently. “When you first download the app, it asks the questions that are necessary to make the diagnostic clinical impression,” Dr. Cowan said. After asking basic demographic questions, the app poses specific questions about the characteristics of typical and current headaches and other related conditions. This information, which takes about 10 minutes to enter, will populate the app and generate a clinical impression similar to one formed at an initial clinical presentation.

The BonTriage Headache Compass then prompts users daily for data on headaches, medications, triggers, and lifestyle factors. Based on these data, the app can predict headache frequency; report the effect of treatment strategies on headache frequency, severity, and duration in real time; and answer questions based on personalized data. Users can thus see potential connections between their headaches, triggers, and behaviors. Data entry requires a minute or two each day.

 Individualized Advice

The app’s internal analytics analyze data to interpret the personalized information that it collects. This analysis is intended to help patients with headache avoid factors (behaviors, triggers, etc) that worsen their headaches and enhance behaviors that reduce their headaches. The app also provides feedback to indicate which management strategies are working. “One critical piece of information we want to feed back to patients is whether they are getting better or not, based on how they are treating their headaches,” said Dr. Cowan. The data that the BonTriage Headache Compass app collects can inform patients about their specific headache triggers, lifestyle choices, medication, or environmental factors, and about how they influence their headache. After a month of consistent data entry … the app can begin to predict headaches. With continued use, the app could, for example, send a text message advising the user that a storm is coming to their area and he orshe did not sleep well the night before, so he or she should skip wine with dinner because of an increased risk of headache on that particular night.

Users of the BonTriage Headache Compass can query the app for data on areas of personal concern. For example, it can compare headache severity or frequency between months or examine the relationship between exercise or sleep and headache duration or frequency. The Headache Compass tool can provide visual representations and headache indices (ie, scores) to compare a current headache with previous headaches.

The BonTriage Headache Compass is available for free in the iPhone App Store.

—Glenn S. Williams

STANFORD, CA—Headache specialists have created a new app intended to support patients with headache pain. Developed by board-certified headache specialists in collaboration with a machine learning and artificial intelligence professional, the BonTriage Headache Compass may help patients with headache better manage and improve their condition. When used consistently over time, this app is intended to help patients reduce the frequency, severity, and duration of headaches, as well as the disability they cause.

“The BonTriage Headache Compass provides a diagnostic clinical impression and monitoring, which patients can take to their doctor or just use to gain insight into their condition,” said Robert Cowan, MD, Professor of Neurology and Chief of the Division of Headache Medicine at Stanford University and a co-creator of the new app.

Personalized Data

The BonTriage Headache Compass app is the second product developed by BonTriage. The first is a detailed web-based questionnaire, available at www.bontriage.com, that creates a detailed report about a patient’s headache. The questionnaire has been validated and its accuracy is greater than 90%. Once completed, the questionnaire can be printed and shared with the patient’s physician.

The app works together with the questionnaire, but can be used independently. “When you first download the app, it asks the questions that are necessary to make the diagnostic clinical impression,” Dr. Cowan said. After asking basic demographic questions, the app poses specific questions about the characteristics of typical and current headaches and other related conditions. This information, which takes about 10 minutes to enter, will populate the app and generate a clinical impression similar to one formed at an initial clinical presentation.

The BonTriage Headache Compass then prompts users daily for data on headaches, medications, triggers, and lifestyle factors. Based on these data, the app can predict headache frequency; report the effect of treatment strategies on headache frequency, severity, and duration in real time; and answer questions based on personalized data. Users can thus see potential connections between their headaches, triggers, and behaviors. Data entry requires a minute or two each day.

 Individualized Advice

The app’s internal analytics analyze data to interpret the personalized information that it collects. This analysis is intended to help patients with headache avoid factors (behaviors, triggers, etc) that worsen their headaches and enhance behaviors that reduce their headaches. The app also provides feedback to indicate which management strategies are working. “One critical piece of information we want to feed back to patients is whether they are getting better or not, based on how they are treating their headaches,” said Dr. Cowan. The data that the BonTriage Headache Compass app collects can inform patients about their specific headache triggers, lifestyle choices, medication, or environmental factors, and about how they influence their headache. After a month of consistent data entry … the app can begin to predict headaches. With continued use, the app could, for example, send a text message advising the user that a storm is coming to their area and he orshe did not sleep well the night before, so he or she should skip wine with dinner because of an increased risk of headache on that particular night.

Users of the BonTriage Headache Compass can query the app for data on areas of personal concern. For example, it can compare headache severity or frequency between months or examine the relationship between exercise or sleep and headache duration or frequency. The Headache Compass tool can provide visual representations and headache indices (ie, scores) to compare a current headache with previous headaches.

The BonTriage Headache Compass is available for free in the iPhone App Store.

—Glenn S. Williams

STANFORD, CA—Headache specialists have created a new app intended to support patients with headache pain. Developed by board-certified headache specialists in collaboration with a machine learning and artificial intelligence professional, the BonTriage Headache Compass may help patients with headache better manage and improve their condition. When used consistently over time, this app is intended to help patients reduce the frequency, severity, and duration of headaches, as well as the disability they cause.

“The BonTriage Headache Compass provides a diagnostic clinical impression and monitoring, which patients can take to their doctor or just use to gain insight into their condition,” said Robert Cowan, MD, Professor of Neurology and Chief of the Division of Headache Medicine at Stanford University and a co-creator of the new app.

Personalized Data

The BonTriage Headache Compass app is the second product developed by BonTriage. The first is a detailed web-based questionnaire, available at www.bontriage.com, that creates a detailed report about a patient’s headache. The questionnaire has been validated and its accuracy is greater than 90%. Once completed, the questionnaire can be printed and shared with the patient’s physician.

The app works together with the questionnaire, but can be used independently. “When you first download the app, it asks the questions that are necessary to make the diagnostic clinical impression,” Dr. Cowan said. After asking basic demographic questions, the app poses specific questions about the characteristics of typical and current headaches and other related conditions. This information, which takes about 10 minutes to enter, will populate the app and generate a clinical impression similar to one formed at an initial clinical presentation.

The BonTriage Headache Compass then prompts users daily for data on headaches, medications, triggers, and lifestyle factors. Based on these data, the app can predict headache frequency; report the effect of treatment strategies on headache frequency, severity, and duration in real time; and answer questions based on personalized data. Users can thus see potential connections between their headaches, triggers, and behaviors. Data entry requires a minute or two each day.

 Individualized Advice

The app’s internal analytics analyze data to interpret the personalized information that it collects. This analysis is intended to help patients with headache avoid factors (behaviors, triggers, etc) that worsen their headaches and enhance behaviors that reduce their headaches. The app also provides feedback to indicate which management strategies are working. “One critical piece of information we want to feed back to patients is whether they are getting better or not, based on how they are treating their headaches,” said Dr. Cowan. The data that the BonTriage Headache Compass app collects can inform patients about their specific headache triggers, lifestyle choices, medication, or environmental factors, and about how they influence their headache. After a month of consistent data entry … the app can begin to predict headaches. With continued use, the app could, for example, send a text message advising the user that a storm is coming to their area and he orshe did not sleep well the night before, so he or she should skip wine with dinner because of an increased risk of headache on that particular night.

Users of the BonTriage Headache Compass can query the app for data on areas of personal concern. For example, it can compare headache severity or frequency between months or examine the relationship between exercise or sleep and headache duration or frequency. The Headache Compass tool can provide visual representations and headache indices (ie, scores) to compare a current headache with previous headaches.

The BonTriage Headache Compass is available for free in the iPhone App Store.

—Glenn S. Williams

BOSTON—The interpretation of clinical trial results can stray from the data in many ways. Creating spin (ie, stressing an experimental treatment’s advantages) may or may not be the intention of the researchers or of people who write press releases, but clinicians evaluating the results should not be distracted from the key characteristics of a meaningful trial. They can use several strategies to keep the facts in focus, according to a researcher.

“Here are some words that should put you on alert: ‘revolutionary,’ ‘groundbreaking,’ and ‘first-line.’ It is time to be cautious when you are hearing the spin and the results at the same time,” said Elizabeth W. Loder, MD, MPH, Professor of Neurology at Harvard Medical School in Boston. At the 59th Annual Scientific Meeting of the American Headache Society, Dr. Loder spoke about migraine prevention trials, but she allowed that her remarks are relevant to any clinical trial.

Guidelines Aim to Increase Objectivity

The potential for overinterpretation, misinterpretation, or misleading interpretation of trial results was reduced greatly in 2005. At that time, the International Committee of Medical Journal Editors agreed that trials accepted for publication should first be registered and have their methodology defined before study initiation. Establishing the trial design and primary end points in advance makes selective reporting and data manipulation more difficult. The approach, however, does not eliminate the potential for spin, said Dr. Loder. “The trial registrations on sites like ClinicalTrials.gov are easy to find, and it is worth looking back to compare what was registered to what was reported. There can be some surprises,” Dr. Loder explained.

One potential surprise may be a discrepancy between the prespecified outcomes and the outcomes that the researchers stress at the conclusion of the study. The peer-review process of a high-quality journal limits claims based on secondary outcomes, but press releases do not have similar constraints. In addition, favorable reporting on outcomes that did not appear in the trial registration should arouse suspicion. “It is fair to include data on outcomes that were not prespecified, but they should be flagged. These are hypothesis-generating and should not be given the same weight as those prespecified,” Dr. Loder explained.

Guidelines to improve the objectivity of data gathered and reported for trials are growing increasingly rigorous, according to Dr. Loder. For headache prevention trials, the International Headache Society has issued specific recommendations about trial conduct and the measurement of end points. Although Dr. Loder conceded that strict constraints may make reports of trial results formulaic or tedious, the consistency of the formula, which progresses from an introduction through methods, results, discussion, and conclusions, makes the findings easier to interpret and to place into context.

Data Should Guide Interpretation of Results

A paper’s discussion section may cloud the reader’s understanding of the trial’s findings, Dr. Loder cautioned. In a properly reported study, the results section confines itself to the facts. In the discussion section, interpretation of the facts varies with perspective, according to Dr. Loder. The authors’ perception of relative benefit following a favorable outcome or of the burden of an adverse event is subjective. The potential for intentional or unintentional spin is substantial.

“Examples of spin include focusing on an outcome [that] the trial was not designed to study, focusing on subgroups rather than [on] the overall population, and downplaying adverse safety data,” explained Dr. Loder. Dr. Loder cited several studies that compared reader reaction to abstracts with and without spin. The studies showed that spin was persuasive. Moreover, Dr. Loder noted that spin in abstracts is typically passed on in press releases, news stories, and other accounts of the studies.

One strategy for remaining circumspect about new data is to consult one of many watchdog organizations that monitor clinical data and evaluate data collection and analysis. One such organization is HealthNewsReview.org, which has an editorial team that routinely critiques claims made about drugs, devices, vitamins, and surgical procedures. According to Dr. Loder, the website has examined migraine therapies and provided a perspective that was fully independent of the trials’ sponsors, their authors, and sometimes of the prevailing view.

Pure objectivity may not be appealing for those who want to draw attention to their research, and spin is hard to resist in the desire to develop an engaging narrative. Whether or not those who focus on the most favorable findings of a trial are conscious of their disservice to scientific inquiry, spin has been found repeatedly in systematic reviews of study data. Dr. Loder cited one study that found spin in 47% of 498 press releases on scientific articles.

“There were various types of spin, but 19% of the press releases failed to acknowledge that the primary end point was not statistically significant,” Dr. Loder noted. When abstracts that provided the basis for the press releases were analyzed, 40% were found to contain spin.

The Value of Common Sense

Randomized controlled trials are considered the gold standard for objectively evaluating most treatment strategies, but Dr. Loder cautioned that this design by itself is not enough to ensure reproducible results. The results of the study should include not only how many patients were randomized, but also how many patients received treatment and how many were followed to the trial’s end. Low enrollment or high dropout rates are red flags. These problems can be detected by critical thinking.

“There really is no substitute for common sense,” Dr. Loder said. She suggested that studies that include all of the standard points of discussion, such as the generalizability of results, the limitations of the design, the statistical significance of the findings, and a fair interpretation of benefits and hazards, establish credibility and are generally recognizable with a discerning eye.

“For clinicians considering how to interpret results, one question to ask is whether the patients enrolled are representative of the ones that are in front of you,” Dr. Loder suggested.

A critical view of new data helps to avoid the fads that some critics have observed in the treatment of headaches and in clinical medicine overall. Typically, excessive enthusiasm about positive trial results is followed by a period of disillusionment until clinicians finally arrive at a realistic perspective of the strengths and weaknesses of a new therapeutic option. Warning of a coming brace of headache trial results, which will include studies of devices, apps, and new drugs, Dr. Loder urged clinicians to read the studies rather than the press releases, applying the criteria that define a well designed and fairly reported trial.

—Theodore Bosworth

Suggested Reading

Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 2012;32(1):6-38.

Yavchitz A, Boutron I, Bafeta A, et al. Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study. PLoS Med. 2012;9(9):e1001308.

BOSTON—The interpretation of clinical trial results can stray from the data in many ways. Creating spin (ie, stressing an experimental treatment’s advantages) may or may not be the intention of the researchers or of people who write press releases, but clinicians evaluating the results should not be distracted from the key characteristics of a meaningful trial. They can use several strategies to keep the facts in focus, according to a researcher.

“Here are some words that should put you on alert: ‘revolutionary,’ ‘groundbreaking,’ and ‘first-line.’ It is time to be cautious when you are hearing the spin and the results at the same time,” said Elizabeth W. Loder, MD, MPH, Professor of Neurology at Harvard Medical School in Boston. At the 59th Annual Scientific Meeting of the American Headache Society, Dr. Loder spoke about migraine prevention trials, but she allowed that her remarks are relevant to any clinical trial.

Guidelines Aim to Increase Objectivity

The potential for overinterpretation, misinterpretation, or misleading interpretation of trial results was reduced greatly in 2005. At that time, the International Committee of Medical Journal Editors agreed that trials accepted for publication should first be registered and have their methodology defined before study initiation. Establishing the trial design and primary end points in advance makes selective reporting and data manipulation more difficult. The approach, however, does not eliminate the potential for spin, said Dr. Loder. “The trial registrations on sites like ClinicalTrials.gov are easy to find, and it is worth looking back to compare what was registered to what was reported. There can be some surprises,” Dr. Loder explained.

One potential surprise may be a discrepancy between the prespecified outcomes and the outcomes that the researchers stress at the conclusion of the study. The peer-review process of a high-quality journal limits claims based on secondary outcomes, but press releases do not have similar constraints. In addition, favorable reporting on outcomes that did not appear in the trial registration should arouse suspicion. “It is fair to include data on outcomes that were not prespecified, but they should be flagged. These are hypothesis-generating and should not be given the same weight as those prespecified,” Dr. Loder explained.

Guidelines to improve the objectivity of data gathered and reported for trials are growing increasingly rigorous, according to Dr. Loder. For headache prevention trials, the International Headache Society has issued specific recommendations about trial conduct and the measurement of end points. Although Dr. Loder conceded that strict constraints may make reports of trial results formulaic or tedious, the consistency of the formula, which progresses from an introduction through methods, results, discussion, and conclusions, makes the findings easier to interpret and to place into context.

Data Should Guide Interpretation of Results

A paper’s discussion section may cloud the reader’s understanding of the trial’s findings, Dr. Loder cautioned. In a properly reported study, the results section confines itself to the facts. In the discussion section, interpretation of the facts varies with perspective, according to Dr. Loder. The authors’ perception of relative benefit following a favorable outcome or of the burden of an adverse event is subjective. The potential for intentional or unintentional spin is substantial.

“Examples of spin include focusing on an outcome [that] the trial was not designed to study, focusing on subgroups rather than [on] the overall population, and downplaying adverse safety data,” explained Dr. Loder. Dr. Loder cited several studies that compared reader reaction to abstracts with and without spin. The studies showed that spin was persuasive. Moreover, Dr. Loder noted that spin in abstracts is typically passed on in press releases, news stories, and other accounts of the studies.

One strategy for remaining circumspect about new data is to consult one of many watchdog organizations that monitor clinical data and evaluate data collection and analysis. One such organization is HealthNewsReview.org, which has an editorial team that routinely critiques claims made about drugs, devices, vitamins, and surgical procedures. According to Dr. Loder, the website has examined migraine therapies and provided a perspective that was fully independent of the trials’ sponsors, their authors, and sometimes of the prevailing view.

Pure objectivity may not be appealing for those who want to draw attention to their research, and spin is hard to resist in the desire to develop an engaging narrative. Whether or not those who focus on the most favorable findings of a trial are conscious of their disservice to scientific inquiry, spin has been found repeatedly in systematic reviews of study data. Dr. Loder cited one study that found spin in 47% of 498 press releases on scientific articles.

“There were various types of spin, but 19% of the press releases failed to acknowledge that the primary end point was not statistically significant,” Dr. Loder noted. When abstracts that provided the basis for the press releases were analyzed, 40% were found to contain spin.

The Value of Common Sense

Randomized controlled trials are considered the gold standard for objectively evaluating most treatment strategies, but Dr. Loder cautioned that this design by itself is not enough to ensure reproducible results. The results of the study should include not only how many patients were randomized, but also how many patients received treatment and how many were followed to the trial’s end. Low enrollment or high dropout rates are red flags. These problems can be detected by critical thinking.

“There really is no substitute for common sense,” Dr. Loder said. She suggested that studies that include all of the standard points of discussion, such as the generalizability of results, the limitations of the design, the statistical significance of the findings, and a fair interpretation of benefits and hazards, establish credibility and are generally recognizable with a discerning eye.

“For clinicians considering how to interpret results, one question to ask is whether the patients enrolled are representative of the ones that are in front of you,” Dr. Loder suggested.

A critical view of new data helps to avoid the fads that some critics have observed in the treatment of headaches and in clinical medicine overall. Typically, excessive enthusiasm about positive trial results is followed by a period of disillusionment until clinicians finally arrive at a realistic perspective of the strengths and weaknesses of a new therapeutic option. Warning of a coming brace of headache trial results, which will include studies of devices, apps, and new drugs, Dr. Loder urged clinicians to read the studies rather than the press releases, applying the criteria that define a well designed and fairly reported trial.

—Theodore Bosworth

Suggested Reading

Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 2012;32(1):6-38.

Yavchitz A, Boutron I, Bafeta A, et al. Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study. PLoS Med. 2012;9(9):e1001308.

BOSTON—The interpretation of clinical trial results can stray from the data in many ways. Creating spin (ie, stressing an experimental treatment’s advantages) may or may not be the intention of the researchers or of people who write press releases, but clinicians evaluating the results should not be distracted from the key characteristics of a meaningful trial. They can use several strategies to keep the facts in focus, according to a researcher.

“Here are some words that should put you on alert: ‘revolutionary,’ ‘groundbreaking,’ and ‘first-line.’ It is time to be cautious when you are hearing the spin and the results at the same time,” said Elizabeth W. Loder, MD, MPH, Professor of Neurology at Harvard Medical School in Boston. At the 59th Annual Scientific Meeting of the American Headache Society, Dr. Loder spoke about migraine prevention trials, but she allowed that her remarks are relevant to any clinical trial.

Guidelines Aim to Increase Objectivity

The potential for overinterpretation, misinterpretation, or misleading interpretation of trial results was reduced greatly in 2005. At that time, the International Committee of Medical Journal Editors agreed that trials accepted for publication should first be registered and have their methodology defined before study initiation. Establishing the trial design and primary end points in advance makes selective reporting and data manipulation more difficult. The approach, however, does not eliminate the potential for spin, said Dr. Loder. “The trial registrations on sites like ClinicalTrials.gov are easy to find, and it is worth looking back to compare what was registered to what was reported. There can be some surprises,” Dr. Loder explained.

One potential surprise may be a discrepancy between the prespecified outcomes and the outcomes that the researchers stress at the conclusion of the study. The peer-review process of a high-quality journal limits claims based on secondary outcomes, but press releases do not have similar constraints. In addition, favorable reporting on outcomes that did not appear in the trial registration should arouse suspicion. “It is fair to include data on outcomes that were not prespecified, but they should be flagged. These are hypothesis-generating and should not be given the same weight as those prespecified,” Dr. Loder explained.

Guidelines to improve the objectivity of data gathered and reported for trials are growing increasingly rigorous, according to Dr. Loder. For headache prevention trials, the International Headache Society has issued specific recommendations about trial conduct and the measurement of end points. Although Dr. Loder conceded that strict constraints may make reports of trial results formulaic or tedious, the consistency of the formula, which progresses from an introduction through methods, results, discussion, and conclusions, makes the findings easier to interpret and to place into context.

Data Should Guide Interpretation of Results

A paper’s discussion section may cloud the reader’s understanding of the trial’s findings, Dr. Loder cautioned. In a properly reported study, the results section confines itself to the facts. In the discussion section, interpretation of the facts varies with perspective, according to Dr. Loder. The authors’ perception of relative benefit following a favorable outcome or of the burden of an adverse event is subjective. The potential for intentional or unintentional spin is substantial.

“Examples of spin include focusing on an outcome [that] the trial was not designed to study, focusing on subgroups rather than [on] the overall population, and downplaying adverse safety data,” explained Dr. Loder. Dr. Loder cited several studies that compared reader reaction to abstracts with and without spin. The studies showed that spin was persuasive. Moreover, Dr. Loder noted that spin in abstracts is typically passed on in press releases, news stories, and other accounts of the studies.

One strategy for remaining circumspect about new data is to consult one of many watchdog organizations that monitor clinical data and evaluate data collection and analysis. One such organization is HealthNewsReview.org, which has an editorial team that routinely critiques claims made about drugs, devices, vitamins, and surgical procedures. According to Dr. Loder, the website has examined migraine therapies and provided a perspective that was fully independent of the trials’ sponsors, their authors, and sometimes of the prevailing view.

Pure objectivity may not be appealing for those who want to draw attention to their research, and spin is hard to resist in the desire to develop an engaging narrative. Whether or not those who focus on the most favorable findings of a trial are conscious of their disservice to scientific inquiry, spin has been found repeatedly in systematic reviews of study data. Dr. Loder cited one study that found spin in 47% of 498 press releases on scientific articles.

“There were various types of spin, but 19% of the press releases failed to acknowledge that the primary end point was not statistically significant,” Dr. Loder noted. When abstracts that provided the basis for the press releases were analyzed, 40% were found to contain spin.

The Value of Common Sense

Randomized controlled trials are considered the gold standard for objectively evaluating most treatment strategies, but Dr. Loder cautioned that this design by itself is not enough to ensure reproducible results. The results of the study should include not only how many patients were randomized, but also how many patients received treatment and how many were followed to the trial’s end. Low enrollment or high dropout rates are red flags. These problems can be detected by critical thinking.

“There really is no substitute for common sense,” Dr. Loder said. She suggested that studies that include all of the standard points of discussion, such as the generalizability of results, the limitations of the design, the statistical significance of the findings, and a fair interpretation of benefits and hazards, establish credibility and are generally recognizable with a discerning eye.

“For clinicians considering how to interpret results, one question to ask is whether the patients enrolled are representative of the ones that are in front of you,” Dr. Loder suggested.

A critical view of new data helps to avoid the fads that some critics have observed in the treatment of headaches and in clinical medicine overall. Typically, excessive enthusiasm about positive trial results is followed by a period of disillusionment until clinicians finally arrive at a realistic perspective of the strengths and weaknesses of a new therapeutic option. Warning of a coming brace of headache trial results, which will include studies of devices, apps, and new drugs, Dr. Loder urged clinicians to read the studies rather than the press releases, applying the criteria that define a well designed and fairly reported trial.

—Theodore Bosworth

Suggested Reading

Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 2012;32(1):6-38.

Yavchitz A, Boutron I, Bafeta A, et al. Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study. PLoS Med. 2012;9(9):e1001308.

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.

Neurologists and patients may be able to predict migraine attacks using a model based on the level of stress from daily hassles, according to research published in the July issue of Headache. The model was well calibrated, but its forecasts were based on participants’ base rates of headache, said the authors. With additional adjustments, the model could enable patients to treat migraine attacks pre-emptively.

Although headache disorders are common, it remains unclear what triggers a migraine attack. Patients have identified many possible triggers, including perceived stress. In people with episodic migraine and chronic migraine, perceived stress is associated with the onset of headache. Researchers previously had not provided evidence that any of the potential triggers could predict a migraine attack, however.

Electronic Diaries Captured Headache Frequency

Timothy T. Houle, PhD, Associate Professor of Anesthesia at Massachusetts General Hospital in Boston, and colleagues conducted the prospective Headache Prediction Study to examine precipitating factors of migraine headache. They recruited participants with episodic migraine who had more than two headache attacks per month and had between four and 14 headache days per month. Secondary headache disorder and change in the nature of headache symptoms in the previous six weeks were among the exclusion criteria.

Participants completed morning and evening diary entries daily using electronic systems. In the entries, the participants recorded headaches, headache characteristics, and abortive medications used since the last entry. Participants used the Daily Stress Inventory to assess stress in their evening diary entries. Using these assessments, the investigators examined the frequency of stressors, the sum of the stress impact ratings, and the average stress impact ratings. The primary analysis was the prediction of a future headache attack based on current levels of stress and headache.

Potential for New Treatment Strategies

Dr. Houle and colleagues enrolled 100 participants between September 2009 and May 2014. Five participants dropped out. Approximately 91% of participants were female, and 87% were Caucasian. Mean age was 40. The 95 participants contributed 4,626 days of diary data. In all, 431 diary entries were missing or unavailable for analysis. Participants had a headache attack on approximately 39% of days. Days that preceded a headache were associated with greater stress than days that did not precede a headache.

After estimating a series of models, the researchers found that a generalized linear mixed-effects model using either the frequency of stressful events or the perceived intensity of stressful events fit the data well. The forecasting model had “promising predictive utility” in the training sample and in a validation sample, said the authors. The model had good calibration between forecast probabilities and observed headache frequencies, but had low levels of resolution, meaning that “the forecast probabilities are close to the individual’s long-run average,” said Dr. Houle.

“This appears to be the first evidence that individual headache attacks can be forecast within an individual sufferer, and this finding creates substantial opportunities for additional treatment strategies if the forecasting model can be refined,” said Dr. Houle. “A forecasting model could be used to enhance pharmacologic treatment opportunities, reduce anxiety about the unpredictability of attacks, increase locus-of-control beliefs, and lead to increased self-efficacy assessments about the self-management of migraine attacks.” Neurologists should consider the investigators’ stress model a first step toward headache prediction, and not a final model for widespread clinical use, he added.

Complexities Need Consideration

These data are “fascinating,” but neurologists should consider several complexities as they develop methods for the short-term prevention of predictable migraine, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York and Director of the Montefiore Headache Center, and colleagues in an accompanying editorial. First, they must distinguish group-level and within-person analyses of attack predictors. Trigger factors vary from person to person, and within-person analysis may be crucial to prediction and prevention, said Dr. Lipton. Second, in addition to stress, other trigger factors such as premonitory features, self-prediction, and biomarkers also may aid in forecasting attacks. Finally, researchers can measure and model predictors of impending attacks in various ways (eg, lead–lag effects and cumulative effects).

“Houle et al have set the stage for short-term prediction of headaches in persons with migraine as a potential foundation for short-term preventive therapies,” said Dr. Lipton. “To realize the potential of these approaches, we must refine the art of headache forecasting and then test targeted interventions in carefully selected patients.”

—Erik Greb

Suggested Reading

Houle TT, Turner DP, Golding AN, et al. Forecasting individual headache attacks using perceived stress: Development of a multivariable prediction model for persons with episodic migraine. Headache. 2017;57(7):1041-1050.

Lipton RB, Pavlovic JM, Buse DC. Why migraine forecasting matters. Headache. 2017;57(7):1023-1025.