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Dependent trait in chronic migraine may predict nonresponse to onabotulinumtoxin A
according to research published in the January issue of Headache. The research may be the first to show that personality traits predict response to onabotulinumtoxin A in this population.
“These findings point out that conducting an evaluation of personality traits in patients with chronic migraine might be helpful in the prediction of the course and election of the treatment, as well as identifying patients who might benefit from a multidisciplinary approach,” wrote Alicia Gonzalez-Martinez, MD, of the Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria de La Princesa in Madrid and colleagues. “Categorical questionnaires such as the Salamanca screening test seem to be useful for this purpose.”
Researchers used ICD-10 personality criteria
Personality patterns in patients with migraine and other primary headaches have been the subject of decades of research. Munoz et al. found that certain personality traits are associated with migraine and chronic migraine, and this association may influence clinical management and treatment. The effect of personality traits on response to treatment, however, had not been studied previously.
Dr. Gonzalez-Martinez and colleagues hypothesized that cluster C traits (e.g., obsessive-compulsive, dependent, and anxious), as defined by ICD-10, are associated with nonresponse to onabotulinumtoxin A. To test this hypothesis, they conducted a case-control observational study in a cohort of patients with chronic migraine. Eligible patients presented to one of two headache units of a tertiary hospital between January and May 2018. The investigators obtained a complete headache history and demographic information from each patient. Patients had at least two treatment cycles of onabotulinumtoxin A. Dr. Gonzalez-Martinez and colleagues defined treatment response as a reduction in the number of monthly migraine days of at least 50% after at least two treatment cycles.
The investigators assessed participants’ personality traits by administering the Salamanca test, a brief categorical inventory that examines 11 personality traits using 22 questions. Patients completed the test at the beginning of the study period and before they were classified as responders or nonresponders.
Medication overuse was a potential confounder
The study population included 112 patients with chronic migraine. One hundred patients (89%) were women. Participants’ mean age at initiation of onabotulinumtoxin A treatment was 43 years. The population’s mean duration of chronic migraine was 29 months. Eighty-three patients (74.1%) had medication overuse, and 96 (85.7%) responded to onabotulinumtoxin A.
Cluster A traits in the population included paranoid (prevalence, 10.7%), schizoid (38.4%), and schizotypal (7.1%). Cluster B traits included histrionic (50%), antisocial (1.8%), narcissistic (9.8%), emotional instability subtype impulsive (27.7%), and emotional instability subtype limit (EISL, 24.1%). Cluster C traits were anxious (58.9%) anancastic (i.e., obsessive-compulsive, 54.5%), and dependent (32.1%).
The investigators found no differences in demographics between responders and nonresponders. In a univariate analysis, dependent traits (e.g., passivity and emotional overdependence on others) and EISL traits (e.g., impulsivity and disturbed self-image) were significantly more common among nonresponders. In a multivariate analysis, dependent traits remained significantly associated with nonresponse to onabotulinumtoxin A.
Medication overuse was a potential confounder in the study, according to Dr. Gonzalez-Martinez and colleagues. One of the study’s limitations was its absence of a healthy control group. Another was the fact that the psychometrics of the Salamanca screening test have not been published in a peer-reviewed journal and may need further examination.
Dependent personality “may also be part of the proposed chronic pain sufferer personality,” wrote the investigators. “Early detection of personality traits could improve management and outcome of chronic migraine patients. Additionally, the possibility to predict the effectiveness of onabotulinumtoxin A therapy may reduce costs and latency time of effect in patients with improbable effectiveness.”
The study had no outside funding, and the authors reported no conflicts of interest.
SOURCE: Gonzalez-Martinez A et al. Headache. 2020;60(1):153-61.
according to research published in the January issue of Headache. The research may be the first to show that personality traits predict response to onabotulinumtoxin A in this population.
“These findings point out that conducting an evaluation of personality traits in patients with chronic migraine might be helpful in the prediction of the course and election of the treatment, as well as identifying patients who might benefit from a multidisciplinary approach,” wrote Alicia Gonzalez-Martinez, MD, of the Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria de La Princesa in Madrid and colleagues. “Categorical questionnaires such as the Salamanca screening test seem to be useful for this purpose.”
Researchers used ICD-10 personality criteria
Personality patterns in patients with migraine and other primary headaches have been the subject of decades of research. Munoz et al. found that certain personality traits are associated with migraine and chronic migraine, and this association may influence clinical management and treatment. The effect of personality traits on response to treatment, however, had not been studied previously.
Dr. Gonzalez-Martinez and colleagues hypothesized that cluster C traits (e.g., obsessive-compulsive, dependent, and anxious), as defined by ICD-10, are associated with nonresponse to onabotulinumtoxin A. To test this hypothesis, they conducted a case-control observational study in a cohort of patients with chronic migraine. Eligible patients presented to one of two headache units of a tertiary hospital between January and May 2018. The investigators obtained a complete headache history and demographic information from each patient. Patients had at least two treatment cycles of onabotulinumtoxin A. Dr. Gonzalez-Martinez and colleagues defined treatment response as a reduction in the number of monthly migraine days of at least 50% after at least two treatment cycles.
The investigators assessed participants’ personality traits by administering the Salamanca test, a brief categorical inventory that examines 11 personality traits using 22 questions. Patients completed the test at the beginning of the study period and before they were classified as responders or nonresponders.
Medication overuse was a potential confounder
The study population included 112 patients with chronic migraine. One hundred patients (89%) were women. Participants’ mean age at initiation of onabotulinumtoxin A treatment was 43 years. The population’s mean duration of chronic migraine was 29 months. Eighty-three patients (74.1%) had medication overuse, and 96 (85.7%) responded to onabotulinumtoxin A.
Cluster A traits in the population included paranoid (prevalence, 10.7%), schizoid (38.4%), and schizotypal (7.1%). Cluster B traits included histrionic (50%), antisocial (1.8%), narcissistic (9.8%), emotional instability subtype impulsive (27.7%), and emotional instability subtype limit (EISL, 24.1%). Cluster C traits were anxious (58.9%) anancastic (i.e., obsessive-compulsive, 54.5%), and dependent (32.1%).
The investigators found no differences in demographics between responders and nonresponders. In a univariate analysis, dependent traits (e.g., passivity and emotional overdependence on others) and EISL traits (e.g., impulsivity and disturbed self-image) were significantly more common among nonresponders. In a multivariate analysis, dependent traits remained significantly associated with nonresponse to onabotulinumtoxin A.
Medication overuse was a potential confounder in the study, according to Dr. Gonzalez-Martinez and colleagues. One of the study’s limitations was its absence of a healthy control group. Another was the fact that the psychometrics of the Salamanca screening test have not been published in a peer-reviewed journal and may need further examination.
Dependent personality “may also be part of the proposed chronic pain sufferer personality,” wrote the investigators. “Early detection of personality traits could improve management and outcome of chronic migraine patients. Additionally, the possibility to predict the effectiveness of onabotulinumtoxin A therapy may reduce costs and latency time of effect in patients with improbable effectiveness.”
The study had no outside funding, and the authors reported no conflicts of interest.
SOURCE: Gonzalez-Martinez A et al. Headache. 2020;60(1):153-61.
according to research published in the January issue of Headache. The research may be the first to show that personality traits predict response to onabotulinumtoxin A in this population.
“These findings point out that conducting an evaluation of personality traits in patients with chronic migraine might be helpful in the prediction of the course and election of the treatment, as well as identifying patients who might benefit from a multidisciplinary approach,” wrote Alicia Gonzalez-Martinez, MD, of the Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria de La Princesa in Madrid and colleagues. “Categorical questionnaires such as the Salamanca screening test seem to be useful for this purpose.”
Researchers used ICD-10 personality criteria
Personality patterns in patients with migraine and other primary headaches have been the subject of decades of research. Munoz et al. found that certain personality traits are associated with migraine and chronic migraine, and this association may influence clinical management and treatment. The effect of personality traits on response to treatment, however, had not been studied previously.
Dr. Gonzalez-Martinez and colleagues hypothesized that cluster C traits (e.g., obsessive-compulsive, dependent, and anxious), as defined by ICD-10, are associated with nonresponse to onabotulinumtoxin A. To test this hypothesis, they conducted a case-control observational study in a cohort of patients with chronic migraine. Eligible patients presented to one of two headache units of a tertiary hospital between January and May 2018. The investigators obtained a complete headache history and demographic information from each patient. Patients had at least two treatment cycles of onabotulinumtoxin A. Dr. Gonzalez-Martinez and colleagues defined treatment response as a reduction in the number of monthly migraine days of at least 50% after at least two treatment cycles.
The investigators assessed participants’ personality traits by administering the Salamanca test, a brief categorical inventory that examines 11 personality traits using 22 questions. Patients completed the test at the beginning of the study period and before they were classified as responders or nonresponders.
Medication overuse was a potential confounder
The study population included 112 patients with chronic migraine. One hundred patients (89%) were women. Participants’ mean age at initiation of onabotulinumtoxin A treatment was 43 years. The population’s mean duration of chronic migraine was 29 months. Eighty-three patients (74.1%) had medication overuse, and 96 (85.7%) responded to onabotulinumtoxin A.
Cluster A traits in the population included paranoid (prevalence, 10.7%), schizoid (38.4%), and schizotypal (7.1%). Cluster B traits included histrionic (50%), antisocial (1.8%), narcissistic (9.8%), emotional instability subtype impulsive (27.7%), and emotional instability subtype limit (EISL, 24.1%). Cluster C traits were anxious (58.9%) anancastic (i.e., obsessive-compulsive, 54.5%), and dependent (32.1%).
The investigators found no differences in demographics between responders and nonresponders. In a univariate analysis, dependent traits (e.g., passivity and emotional overdependence on others) and EISL traits (e.g., impulsivity and disturbed self-image) were significantly more common among nonresponders. In a multivariate analysis, dependent traits remained significantly associated with nonresponse to onabotulinumtoxin A.
Medication overuse was a potential confounder in the study, according to Dr. Gonzalez-Martinez and colleagues. One of the study’s limitations was its absence of a healthy control group. Another was the fact that the psychometrics of the Salamanca screening test have not been published in a peer-reviewed journal and may need further examination.
Dependent personality “may also be part of the proposed chronic pain sufferer personality,” wrote the investigators. “Early detection of personality traits could improve management and outcome of chronic migraine patients. Additionally, the possibility to predict the effectiveness of onabotulinumtoxin A therapy may reduce costs and latency time of effect in patients with improbable effectiveness.”
The study had no outside funding, and the authors reported no conflicts of interest.
SOURCE: Gonzalez-Martinez A et al. Headache. 2020;60(1):153-61.
FROM HEADACHE
Dietary flavonol intake linked to reduced risk of Alzheimer’s
Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.
The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.
The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.
“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.
Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.
“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.
Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.
However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.
“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.
The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.
Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.
To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.
The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.
The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.
Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.
Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.
Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.
“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.
The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.
SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.
Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.
The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.
The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.
“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.
Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.
“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.
Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.
However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.
“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.
The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.
Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.
To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.
The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.
The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.
Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.
Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.
Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.
“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.
The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.
SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.
Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.
The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.
The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.
“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.
Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.
“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.
Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.
However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.
“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.
The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.
Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.
To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.
The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.
The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.
Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.
Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.
Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.
“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.
The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.
SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.
FROM NEUROLOGY
Celecoxib oral solution treats migraine effectively in randomized trial
, according to trial results published in the January issue of Headache.
Two hours after treatment, a significantly greater proportion of patients who received the liquid solution, known as DFN-15, had freedom from pain and freedom from their most bothersome accompanying symptom – nausea, photophobia, or phonophobia – compared with patients who received placebo. The pain freedom rates were 35.6% with celecoxib oral solution and 21.7% with placebo. The rates of freedom from the most bothersome symptom were 57.8% with celecoxib oral solution and 44.8% with placebo.
About 9% of patients who received celecoxib oral solution had treatment-emergent adverse events related to the study drug, the most common of which were dysgeusia (4.2%) and nausea (3.2%). In comparison, about 6% of patients who received placebo had treatment-emergent adverse events. There were no serious treatment-emergent adverse events.
“DFN‐15 has the potential to become a reliable and convenient acute therapeutic option for patients with migraine,” said lead author Richard B. Lipton, MD, and colleagues. Dr. Lipton is affiliated with the Albert Einstein College of Medicine in New York.
Assessing celecoxib in migraineurs
Evidence-based guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, diclofenac, ibuprofen, and naproxen, as effective acute migraine treatments, but these medications may increase the risk of adverse gastrointestinal events, the authors said. Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is indicated for the treatment of acute pain in patients with ankylosing spondylitis, osteoarthritis, primary dysmenorrhea, and rheumatoid arthritis. Although it produces analgesia similar to other NSAIDs, among patients with osteoarthritis and rheumatoid arthritis, celecoxib is associated with significantly lower risk of gastrointestinal events, compared with naproxen and ibuprofen, and significantly lower risk of renal events, compared with ibuprofen.
Researchers have studied an oral capsule form of celecoxib (Celebrex, Pfizer) as an acute treatment for migraine in an open-label study that compared celecoxib with naproxen sodium. “While preliminary results suggest comparable efficacy but better tolerability than widely used and guideline-recommended NSAIDs, celecoxib is not currently approved for migraine,” the authors said.
Compared with the oral capsule formulation, the oral liquid solution DFN-15 has a faster median time to peak concentration under fasting conditions (within 1 hour vs. 2.5 hours), which “could translate into more rapid onset of pain relief,” the authors said. In addition, DFN-15 may have greater bioavailability, which could lower dose requirements and improve safety and tolerability. To compare the efficacy, tolerability, and safety of 120-mg DFN-15 with placebo for the acute treatment of migraine, researchers conducted a randomized, double-blind, placebo-controlled study.
Participants used single-dose bottles
Researchers randomized 622 patients 1:1 to DFN-15 or placebo, and 567 treated a migraine during the trial. Patients had a mean age of 40 years, and 87% were female. Patients had episodic migraine with or without aura, no signs of medication overuse, and two-eight migraine attacks per month. For the trial, patients treated a single migraine attack of moderate to severe intensity within 1 hour of onset. “Each subject was given a single‐dose bottle of DFN‐15 120 mg or matching placebo containing 4.8 mL liquid,” Dr. Lipton and colleagues said. “They were instructed to drink the entire contents of the bottle to ensure complete consumption of study medication.”
Freedom from pain and freedom from the most bothersome symptom at 2 hours were the coprimary endpoints. “DFN‐15 was also significantly superior to placebo on multiple secondary 2‐hour endpoints, including freedom from photophobia, pain relief, change in functional disability from baseline, overall and 24‐hour satisfaction with treatment, and use of rescue medication,” they reported.
“A new COX‐2 inhibitor that is effective and rapidly absorbed could provide an important new option for a wide range of patients,” the authors said. “Though cross‐study comparisons are problematic, the current results for DFN‐15 indicate that its efficacy is similar to that of NSAIDs and small‐molecule calcitonin gene‐related peptide receptor antagonists (gepants), based on placebo‐subtracted rates pain freedom in acute treatment trials (14%‐21%). DFN‐15 may also be useful among triptan users, who are at elevated risk of medication‐overuse headache and for whom TEAEs within 24 hours postdose are common. ... The form and delivery system of DFN‐15 – a ready‐to‐use solution in a 4.8‐mL single‐use bottle – may support patient adherence.”
The trial had robust placebo response rates, which may have been influenced by “the novelty of a ready‐made oral solution, which has not been previously tested for the acute treatment of migraine,” the authors noted. In addition, the trial does not address the treatment of mild pain or treatment across multiple attacks.
The trial was supported by Dr. Reddy’s Laboratories, manufacturer of DFN-15. Two authors are employed by and own stock in Dr. Reddy’s. Dr. Lipton and a coauthor disclosed research support from and consulting for Dr. Reddy’s.
SOURCE: Lipton RB et al. Headache. 2020;60(1):58-70. doi: 10.1111/head.13663.
, according to trial results published in the January issue of Headache.
Two hours after treatment, a significantly greater proportion of patients who received the liquid solution, known as DFN-15, had freedom from pain and freedom from their most bothersome accompanying symptom – nausea, photophobia, or phonophobia – compared with patients who received placebo. The pain freedom rates were 35.6% with celecoxib oral solution and 21.7% with placebo. The rates of freedom from the most bothersome symptom were 57.8% with celecoxib oral solution and 44.8% with placebo.
About 9% of patients who received celecoxib oral solution had treatment-emergent adverse events related to the study drug, the most common of which were dysgeusia (4.2%) and nausea (3.2%). In comparison, about 6% of patients who received placebo had treatment-emergent adverse events. There were no serious treatment-emergent adverse events.
“DFN‐15 has the potential to become a reliable and convenient acute therapeutic option for patients with migraine,” said lead author Richard B. Lipton, MD, and colleagues. Dr. Lipton is affiliated with the Albert Einstein College of Medicine in New York.
Assessing celecoxib in migraineurs
Evidence-based guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, diclofenac, ibuprofen, and naproxen, as effective acute migraine treatments, but these medications may increase the risk of adverse gastrointestinal events, the authors said. Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is indicated for the treatment of acute pain in patients with ankylosing spondylitis, osteoarthritis, primary dysmenorrhea, and rheumatoid arthritis. Although it produces analgesia similar to other NSAIDs, among patients with osteoarthritis and rheumatoid arthritis, celecoxib is associated with significantly lower risk of gastrointestinal events, compared with naproxen and ibuprofen, and significantly lower risk of renal events, compared with ibuprofen.
Researchers have studied an oral capsule form of celecoxib (Celebrex, Pfizer) as an acute treatment for migraine in an open-label study that compared celecoxib with naproxen sodium. “While preliminary results suggest comparable efficacy but better tolerability than widely used and guideline-recommended NSAIDs, celecoxib is not currently approved for migraine,” the authors said.
Compared with the oral capsule formulation, the oral liquid solution DFN-15 has a faster median time to peak concentration under fasting conditions (within 1 hour vs. 2.5 hours), which “could translate into more rapid onset of pain relief,” the authors said. In addition, DFN-15 may have greater bioavailability, which could lower dose requirements and improve safety and tolerability. To compare the efficacy, tolerability, and safety of 120-mg DFN-15 with placebo for the acute treatment of migraine, researchers conducted a randomized, double-blind, placebo-controlled study.
Participants used single-dose bottles
Researchers randomized 622 patients 1:1 to DFN-15 or placebo, and 567 treated a migraine during the trial. Patients had a mean age of 40 years, and 87% were female. Patients had episodic migraine with or without aura, no signs of medication overuse, and two-eight migraine attacks per month. For the trial, patients treated a single migraine attack of moderate to severe intensity within 1 hour of onset. “Each subject was given a single‐dose bottle of DFN‐15 120 mg or matching placebo containing 4.8 mL liquid,” Dr. Lipton and colleagues said. “They were instructed to drink the entire contents of the bottle to ensure complete consumption of study medication.”
Freedom from pain and freedom from the most bothersome symptom at 2 hours were the coprimary endpoints. “DFN‐15 was also significantly superior to placebo on multiple secondary 2‐hour endpoints, including freedom from photophobia, pain relief, change in functional disability from baseline, overall and 24‐hour satisfaction with treatment, and use of rescue medication,” they reported.
“A new COX‐2 inhibitor that is effective and rapidly absorbed could provide an important new option for a wide range of patients,” the authors said. “Though cross‐study comparisons are problematic, the current results for DFN‐15 indicate that its efficacy is similar to that of NSAIDs and small‐molecule calcitonin gene‐related peptide receptor antagonists (gepants), based on placebo‐subtracted rates pain freedom in acute treatment trials (14%‐21%). DFN‐15 may also be useful among triptan users, who are at elevated risk of medication‐overuse headache and for whom TEAEs within 24 hours postdose are common. ... The form and delivery system of DFN‐15 – a ready‐to‐use solution in a 4.8‐mL single‐use bottle – may support patient adherence.”
The trial had robust placebo response rates, which may have been influenced by “the novelty of a ready‐made oral solution, which has not been previously tested for the acute treatment of migraine,” the authors noted. In addition, the trial does not address the treatment of mild pain or treatment across multiple attacks.
The trial was supported by Dr. Reddy’s Laboratories, manufacturer of DFN-15. Two authors are employed by and own stock in Dr. Reddy’s. Dr. Lipton and a coauthor disclosed research support from and consulting for Dr. Reddy’s.
SOURCE: Lipton RB et al. Headache. 2020;60(1):58-70. doi: 10.1111/head.13663.
, according to trial results published in the January issue of Headache.
Two hours after treatment, a significantly greater proportion of patients who received the liquid solution, known as DFN-15, had freedom from pain and freedom from their most bothersome accompanying symptom – nausea, photophobia, or phonophobia – compared with patients who received placebo. The pain freedom rates were 35.6% with celecoxib oral solution and 21.7% with placebo. The rates of freedom from the most bothersome symptom were 57.8% with celecoxib oral solution and 44.8% with placebo.
About 9% of patients who received celecoxib oral solution had treatment-emergent adverse events related to the study drug, the most common of which were dysgeusia (4.2%) and nausea (3.2%). In comparison, about 6% of patients who received placebo had treatment-emergent adverse events. There were no serious treatment-emergent adverse events.
“DFN‐15 has the potential to become a reliable and convenient acute therapeutic option for patients with migraine,” said lead author Richard B. Lipton, MD, and colleagues. Dr. Lipton is affiliated with the Albert Einstein College of Medicine in New York.
Assessing celecoxib in migraineurs
Evidence-based guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, diclofenac, ibuprofen, and naproxen, as effective acute migraine treatments, but these medications may increase the risk of adverse gastrointestinal events, the authors said. Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is indicated for the treatment of acute pain in patients with ankylosing spondylitis, osteoarthritis, primary dysmenorrhea, and rheumatoid arthritis. Although it produces analgesia similar to other NSAIDs, among patients with osteoarthritis and rheumatoid arthritis, celecoxib is associated with significantly lower risk of gastrointestinal events, compared with naproxen and ibuprofen, and significantly lower risk of renal events, compared with ibuprofen.
Researchers have studied an oral capsule form of celecoxib (Celebrex, Pfizer) as an acute treatment for migraine in an open-label study that compared celecoxib with naproxen sodium. “While preliminary results suggest comparable efficacy but better tolerability than widely used and guideline-recommended NSAIDs, celecoxib is not currently approved for migraine,” the authors said.
Compared with the oral capsule formulation, the oral liquid solution DFN-15 has a faster median time to peak concentration under fasting conditions (within 1 hour vs. 2.5 hours), which “could translate into more rapid onset of pain relief,” the authors said. In addition, DFN-15 may have greater bioavailability, which could lower dose requirements and improve safety and tolerability. To compare the efficacy, tolerability, and safety of 120-mg DFN-15 with placebo for the acute treatment of migraine, researchers conducted a randomized, double-blind, placebo-controlled study.
Participants used single-dose bottles
Researchers randomized 622 patients 1:1 to DFN-15 or placebo, and 567 treated a migraine during the trial. Patients had a mean age of 40 years, and 87% were female. Patients had episodic migraine with or without aura, no signs of medication overuse, and two-eight migraine attacks per month. For the trial, patients treated a single migraine attack of moderate to severe intensity within 1 hour of onset. “Each subject was given a single‐dose bottle of DFN‐15 120 mg or matching placebo containing 4.8 mL liquid,” Dr. Lipton and colleagues said. “They were instructed to drink the entire contents of the bottle to ensure complete consumption of study medication.”
Freedom from pain and freedom from the most bothersome symptom at 2 hours were the coprimary endpoints. “DFN‐15 was also significantly superior to placebo on multiple secondary 2‐hour endpoints, including freedom from photophobia, pain relief, change in functional disability from baseline, overall and 24‐hour satisfaction with treatment, and use of rescue medication,” they reported.
“A new COX‐2 inhibitor that is effective and rapidly absorbed could provide an important new option for a wide range of patients,” the authors said. “Though cross‐study comparisons are problematic, the current results for DFN‐15 indicate that its efficacy is similar to that of NSAIDs and small‐molecule calcitonin gene‐related peptide receptor antagonists (gepants), based on placebo‐subtracted rates pain freedom in acute treatment trials (14%‐21%). DFN‐15 may also be useful among triptan users, who are at elevated risk of medication‐overuse headache and for whom TEAEs within 24 hours postdose are common. ... The form and delivery system of DFN‐15 – a ready‐to‐use solution in a 4.8‐mL single‐use bottle – may support patient adherence.”
The trial had robust placebo response rates, which may have been influenced by “the novelty of a ready‐made oral solution, which has not been previously tested for the acute treatment of migraine,” the authors noted. In addition, the trial does not address the treatment of mild pain or treatment across multiple attacks.
The trial was supported by Dr. Reddy’s Laboratories, manufacturer of DFN-15. Two authors are employed by and own stock in Dr. Reddy’s. Dr. Lipton and a coauthor disclosed research support from and consulting for Dr. Reddy’s.
SOURCE: Lipton RB et al. Headache. 2020;60(1):58-70. doi: 10.1111/head.13663.
FROM HEADACHE
Genetic factor linked to impaired memory after heading many soccer balls
according to authors of a recent longitudinal study. Worse verbal memory was linked to high levels of ball heading among those players who were APOE e4–positive, compared with those who were APOE e4–negative, according to the authors, led by Liane E. Hunter, PhD, of the Gruss Magnetic Resonance Imaging Center at Albert Einstein College of Medicine, New York.
These findings, while preliminary, do raise the possibility that “safe levels for soccer heading” could be proposed to protect players from harm or that APOE e4-positive players might be advised to limit their exposure to head impacts, Dr. Hunter and coauthors wrote in a report in JAMA Neurology.
However, the findings should “in no way” be used to justify APOE testing to make clinical decisions regarding the safety of playing soccer, said Sarah J. Banks, PhD, of the University of California, San Diego, and Jesse Mez, MD, of Boston University in a related editorial (doi: 10.1001/jamaneurol.2019.4451). “Like most good science, the study provides an important, but incremental, step to understanding gene-environment interactions in sports,” Dr. Banks and Dr. Mez wrote in their editorial.
While there are some studies tying APOE e4 to poorer neuropsychiatric performance in boxers and U.S. football players, there are no such studies looking at the role of APOE e4 in soccer players exposed to repetitive “subconcussive” ball heading, according to Dr. Hunter and coresearchers. Accordingly, they sought to analyze APOE e4 and neuropsychological performance in relation to ball heading in 352 adult amateur soccer players enrolled in the Einstein Soccer Study between November 2013 and January 2018. About three-quarters of the players were male, and the median age at enrollment was 23 years.
The players completed a computer-based questionnaire designed to estimate their exposure to soccer heading at enrollment and at follow-up visits every 3-6 months. To test verbal memory at each visit, players were asked to memorize a 12-item grocery list, and then asked to recall the items 20 minutes later.
High levels of heading were linked to poorer performance on the verbal memory task, similar to one previously reported study, investigators said.
There was no association overall of APOE e4 and heading with performance on the shopping list task, according to investigators. By contrast, there was a 4.1-fold increased deficit in verbal memory for APOE e4–positive players with high heading exposure, compared with those with low exposure, investigators reported. Likewise, there was an 8.5-fold increased deficit in verbal memory for APOE e4–positive players with high versus moderate heading exposure.
That said, the absolute difference in performance was “subtle” and difficult to interpret in the context of a cross-sectional study, Dr. Banks and Dr. Mez said in their editorial.
In absolute terms, the mean decrease in scores on the 13-point shopping list task between the high and low heading exposure was 1.13 points greater for the APOE e4–positive group, compared with the APOE e4–negative group, and the decrease between the high and moderate heading exposure groups was 0.98 points greater, according to the report.
“The effect size of our interaction is relatively small,” Dr. Hunter and colleagues acknowledged in their report. “However, similar to the widely cited model of disease evolution in Alzheimer disease, our findings may be evidence of early subclinical effects, which could accumulate in APOE e4–positive players over a protracted time frame and ultimately be associated with overt clinical dysfunction.”
Several study authors said they had received grants from the National Institutes of Health and affiliated institutes, the Migraine Research Foundation, and the National Headache Foundation. They reported disclosures related to Amgen, Avanir, Biohaven Holdings, Biovision, Boston Scientific, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, and Pfizer, among others.
SOURCE: Hunter LE et al. JAMA Neurol. 2020 Jan 27. doi: 10.1001/jamaneurol.2019.4828.
according to authors of a recent longitudinal study. Worse verbal memory was linked to high levels of ball heading among those players who were APOE e4–positive, compared with those who were APOE e4–negative, according to the authors, led by Liane E. Hunter, PhD, of the Gruss Magnetic Resonance Imaging Center at Albert Einstein College of Medicine, New York.
These findings, while preliminary, do raise the possibility that “safe levels for soccer heading” could be proposed to protect players from harm or that APOE e4-positive players might be advised to limit their exposure to head impacts, Dr. Hunter and coauthors wrote in a report in JAMA Neurology.
However, the findings should “in no way” be used to justify APOE testing to make clinical decisions regarding the safety of playing soccer, said Sarah J. Banks, PhD, of the University of California, San Diego, and Jesse Mez, MD, of Boston University in a related editorial (doi: 10.1001/jamaneurol.2019.4451). “Like most good science, the study provides an important, but incremental, step to understanding gene-environment interactions in sports,” Dr. Banks and Dr. Mez wrote in their editorial.
While there are some studies tying APOE e4 to poorer neuropsychiatric performance in boxers and U.S. football players, there are no such studies looking at the role of APOE e4 in soccer players exposed to repetitive “subconcussive” ball heading, according to Dr. Hunter and coresearchers. Accordingly, they sought to analyze APOE e4 and neuropsychological performance in relation to ball heading in 352 adult amateur soccer players enrolled in the Einstein Soccer Study between November 2013 and January 2018. About three-quarters of the players were male, and the median age at enrollment was 23 years.
The players completed a computer-based questionnaire designed to estimate their exposure to soccer heading at enrollment and at follow-up visits every 3-6 months. To test verbal memory at each visit, players were asked to memorize a 12-item grocery list, and then asked to recall the items 20 minutes later.
High levels of heading were linked to poorer performance on the verbal memory task, similar to one previously reported study, investigators said.
There was no association overall of APOE e4 and heading with performance on the shopping list task, according to investigators. By contrast, there was a 4.1-fold increased deficit in verbal memory for APOE e4–positive players with high heading exposure, compared with those with low exposure, investigators reported. Likewise, there was an 8.5-fold increased deficit in verbal memory for APOE e4–positive players with high versus moderate heading exposure.
That said, the absolute difference in performance was “subtle” and difficult to interpret in the context of a cross-sectional study, Dr. Banks and Dr. Mez said in their editorial.
In absolute terms, the mean decrease in scores on the 13-point shopping list task between the high and low heading exposure was 1.13 points greater for the APOE e4–positive group, compared with the APOE e4–negative group, and the decrease between the high and moderate heading exposure groups was 0.98 points greater, according to the report.
“The effect size of our interaction is relatively small,” Dr. Hunter and colleagues acknowledged in their report. “However, similar to the widely cited model of disease evolution in Alzheimer disease, our findings may be evidence of early subclinical effects, which could accumulate in APOE e4–positive players over a protracted time frame and ultimately be associated with overt clinical dysfunction.”
Several study authors said they had received grants from the National Institutes of Health and affiliated institutes, the Migraine Research Foundation, and the National Headache Foundation. They reported disclosures related to Amgen, Avanir, Biohaven Holdings, Biovision, Boston Scientific, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, and Pfizer, among others.
SOURCE: Hunter LE et al. JAMA Neurol. 2020 Jan 27. doi: 10.1001/jamaneurol.2019.4828.
according to authors of a recent longitudinal study. Worse verbal memory was linked to high levels of ball heading among those players who were APOE e4–positive, compared with those who were APOE e4–negative, according to the authors, led by Liane E. Hunter, PhD, of the Gruss Magnetic Resonance Imaging Center at Albert Einstein College of Medicine, New York.
These findings, while preliminary, do raise the possibility that “safe levels for soccer heading” could be proposed to protect players from harm or that APOE e4-positive players might be advised to limit their exposure to head impacts, Dr. Hunter and coauthors wrote in a report in JAMA Neurology.
However, the findings should “in no way” be used to justify APOE testing to make clinical decisions regarding the safety of playing soccer, said Sarah J. Banks, PhD, of the University of California, San Diego, and Jesse Mez, MD, of Boston University in a related editorial (doi: 10.1001/jamaneurol.2019.4451). “Like most good science, the study provides an important, but incremental, step to understanding gene-environment interactions in sports,” Dr. Banks and Dr. Mez wrote in their editorial.
While there are some studies tying APOE e4 to poorer neuropsychiatric performance in boxers and U.S. football players, there are no such studies looking at the role of APOE e4 in soccer players exposed to repetitive “subconcussive” ball heading, according to Dr. Hunter and coresearchers. Accordingly, they sought to analyze APOE e4 and neuropsychological performance in relation to ball heading in 352 adult amateur soccer players enrolled in the Einstein Soccer Study between November 2013 and January 2018. About three-quarters of the players were male, and the median age at enrollment was 23 years.
The players completed a computer-based questionnaire designed to estimate their exposure to soccer heading at enrollment and at follow-up visits every 3-6 months. To test verbal memory at each visit, players were asked to memorize a 12-item grocery list, and then asked to recall the items 20 minutes later.
High levels of heading were linked to poorer performance on the verbal memory task, similar to one previously reported study, investigators said.
There was no association overall of APOE e4 and heading with performance on the shopping list task, according to investigators. By contrast, there was a 4.1-fold increased deficit in verbal memory for APOE e4–positive players with high heading exposure, compared with those with low exposure, investigators reported. Likewise, there was an 8.5-fold increased deficit in verbal memory for APOE e4–positive players with high versus moderate heading exposure.
That said, the absolute difference in performance was “subtle” and difficult to interpret in the context of a cross-sectional study, Dr. Banks and Dr. Mez said in their editorial.
In absolute terms, the mean decrease in scores on the 13-point shopping list task between the high and low heading exposure was 1.13 points greater for the APOE e4–positive group, compared with the APOE e4–negative group, and the decrease between the high and moderate heading exposure groups was 0.98 points greater, according to the report.
“The effect size of our interaction is relatively small,” Dr. Hunter and colleagues acknowledged in their report. “However, similar to the widely cited model of disease evolution in Alzheimer disease, our findings may be evidence of early subclinical effects, which could accumulate in APOE e4–positive players over a protracted time frame and ultimately be associated with overt clinical dysfunction.”
Several study authors said they had received grants from the National Institutes of Health and affiliated institutes, the Migraine Research Foundation, and the National Headache Foundation. They reported disclosures related to Amgen, Avanir, Biohaven Holdings, Biovision, Boston Scientific, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, and Pfizer, among others.
SOURCE: Hunter LE et al. JAMA Neurol. 2020 Jan 27. doi: 10.1001/jamaneurol.2019.4828.
FROM JAMA Neurology
Race, ethnicity may influence outcomes after supratentorial intracerebral hemorrhage
researchers reported Jan. 22 in Neurology.
“There has been considerable research on stroke in older people, but there is still much to be learned about stroke in younger people and how it affects people of different races and ethnicities,” study author Daniel Woo, MD, professor of neurology at the University of Cincinnati, said in a news release. “Our study found that, even when you account for factors that affect outcomes, such as how big the stroke is, race and ethnicity were still independent predictors of how well people would recover.”
A subset of ERICH participants
To examine predictors of functional outcome in young patients with ICH, researchers analyzed data from a subset of patients in the Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study. ERICH enrolled patients with nontraumatic ICHs at 42 sites in the United States. It included 1,000 non-Hispanic black patients, 1,000 non-Hispanic white patients, and 1,000 Hispanic patients. Participants self-reported race and ethnicity.
Lead author Laura C. Miyares from Yale School of Medicine in New Haven, Conn., and colleagues analyzed data from 418 patients in ERICH who were aged 18-49 years and had supratentorial ICH. The cohort had an average age of 43 years, and 69% were male. In this subset, 41% were black, 12% were white, and 47% were Hispanic.
The primary outcome was modified Rankin Scale (mRS) score 3 months after the ICH, and the investigators defined a poor outcome as a score of 4 or greater. At 3 months, 35% had a poor functional outcome. Approximately 18% were unable to walk without assistance and attend to their bodily needs (mRS 4); 8% were bedridden, incontinent, and required nursing care (mRS 5); and 10% had died (mRS 6).
The percentage of patients with a poor functional outcome was 52% among white patients, 35% among black patients, and 31% among Hispanic patients. In a univariable analysis, black patients had a 51% reduction in odds of a poor outcome, compared with white patients, and Hispanic patients had a 59% reduction.
“The association between race/ethnicity and 3-month post-ICH functional outcome remained significant after adjusting for age, sex, premorbid disability, ICH location, ICH volume, [intraventricular hemorrhage] extension, systolic blood pressure, and [Glasgow Coma Scale] score on admission,” the researchers said. “In multivariable analysis, using white patients as the reference category, black patients had a 58% reduction in the odds of poor functional outcome at 3 months and Hispanic patients had a 66% reduction in the same odds.”
Their analysis identified the importance of other risk factors as well. “The volume of the hematoma, the most powerful predictor of outcome in older patients with ICH, was also found to be the most significant predictor of poor outcome in young patients,” they said.
Vascular risks and oral anticoagulants
About 80% of the young adults with ICH had a history of diagnosed hypertension. In nearly half, the condition was untreated. “After hypertension, the most common stroke risk factors in the young were diabetes, high cholesterol, smoking, and alcohol abuse,” the authors said. “In combination, these results indicate that vascular risk factors, especially untreated, could explain a large proportion of cases of ICH in the young.”
“Our results also point to treatment with oral anticoagulants before hospitalization as a potential mediator of the effect of race/ethnicity on short-term functional outcomes,” they said. About 8% of the white patients used oral anticoagulants, compared with 4% of the black patients and 1% of the Hispanic patients. Oral anticoagulant treatment “is a known risk factor for ICH and an established predictor of poor outcome in this condition. However, because only a small proportion of enrolled young patients with ICH were on [oral anticoagulants] prior to presentation, these results should be further validated by future studies.”
The study’s limitations include the broad categorization of racial and ethnic groups, the fact that younger patients with supratentorial ICH were more likely to be black or Hispanic and less likely to be white, and the exclusion of a significant proportion of cases of young white patients with smaller ICH volumes because of missing data, the researchers noted. Although the cohort was large, researchers may need to study more patients to capture differences among racial and ethnic groups, the investigators said.
The association between race/ethnicity and functional outcome could relate to “distinct pathophysiologies of the initial bleed or unique mechanisms of secondary injury,” the researchers suggested. “Future studies are necessary to probe the potential biological and social mediators of these findings to elucidate the role of race/ethnicity in ICH severity and functional recovery, and to develop improved prognostication for a racially varied population.”
ERICH is supported by the National Institute of Neurological Disorders and Stroke. Authors disclosed grants from the government, professional societies, and a university.
SOURCE: Miyares LC et al. Neurology. 2020 Jan 22. doi: 10.1212/WNL.0000000000008930.
researchers reported Jan. 22 in Neurology.
“There has been considerable research on stroke in older people, but there is still much to be learned about stroke in younger people and how it affects people of different races and ethnicities,” study author Daniel Woo, MD, professor of neurology at the University of Cincinnati, said in a news release. “Our study found that, even when you account for factors that affect outcomes, such as how big the stroke is, race and ethnicity were still independent predictors of how well people would recover.”
A subset of ERICH participants
To examine predictors of functional outcome in young patients with ICH, researchers analyzed data from a subset of patients in the Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study. ERICH enrolled patients with nontraumatic ICHs at 42 sites in the United States. It included 1,000 non-Hispanic black patients, 1,000 non-Hispanic white patients, and 1,000 Hispanic patients. Participants self-reported race and ethnicity.
Lead author Laura C. Miyares from Yale School of Medicine in New Haven, Conn., and colleagues analyzed data from 418 patients in ERICH who were aged 18-49 years and had supratentorial ICH. The cohort had an average age of 43 years, and 69% were male. In this subset, 41% were black, 12% were white, and 47% were Hispanic.
The primary outcome was modified Rankin Scale (mRS) score 3 months after the ICH, and the investigators defined a poor outcome as a score of 4 or greater. At 3 months, 35% had a poor functional outcome. Approximately 18% were unable to walk without assistance and attend to their bodily needs (mRS 4); 8% were bedridden, incontinent, and required nursing care (mRS 5); and 10% had died (mRS 6).
The percentage of patients with a poor functional outcome was 52% among white patients, 35% among black patients, and 31% among Hispanic patients. In a univariable analysis, black patients had a 51% reduction in odds of a poor outcome, compared with white patients, and Hispanic patients had a 59% reduction.
“The association between race/ethnicity and 3-month post-ICH functional outcome remained significant after adjusting for age, sex, premorbid disability, ICH location, ICH volume, [intraventricular hemorrhage] extension, systolic blood pressure, and [Glasgow Coma Scale] score on admission,” the researchers said. “In multivariable analysis, using white patients as the reference category, black patients had a 58% reduction in the odds of poor functional outcome at 3 months and Hispanic patients had a 66% reduction in the same odds.”
Their analysis identified the importance of other risk factors as well. “The volume of the hematoma, the most powerful predictor of outcome in older patients with ICH, was also found to be the most significant predictor of poor outcome in young patients,” they said.
Vascular risks and oral anticoagulants
About 80% of the young adults with ICH had a history of diagnosed hypertension. In nearly half, the condition was untreated. “After hypertension, the most common stroke risk factors in the young were diabetes, high cholesterol, smoking, and alcohol abuse,” the authors said. “In combination, these results indicate that vascular risk factors, especially untreated, could explain a large proportion of cases of ICH in the young.”
“Our results also point to treatment with oral anticoagulants before hospitalization as a potential mediator of the effect of race/ethnicity on short-term functional outcomes,” they said. About 8% of the white patients used oral anticoagulants, compared with 4% of the black patients and 1% of the Hispanic patients. Oral anticoagulant treatment “is a known risk factor for ICH and an established predictor of poor outcome in this condition. However, because only a small proportion of enrolled young patients with ICH were on [oral anticoagulants] prior to presentation, these results should be further validated by future studies.”
The study’s limitations include the broad categorization of racial and ethnic groups, the fact that younger patients with supratentorial ICH were more likely to be black or Hispanic and less likely to be white, and the exclusion of a significant proportion of cases of young white patients with smaller ICH volumes because of missing data, the researchers noted. Although the cohort was large, researchers may need to study more patients to capture differences among racial and ethnic groups, the investigators said.
The association between race/ethnicity and functional outcome could relate to “distinct pathophysiologies of the initial bleed or unique mechanisms of secondary injury,” the researchers suggested. “Future studies are necessary to probe the potential biological and social mediators of these findings to elucidate the role of race/ethnicity in ICH severity and functional recovery, and to develop improved prognostication for a racially varied population.”
ERICH is supported by the National Institute of Neurological Disorders and Stroke. Authors disclosed grants from the government, professional societies, and a university.
SOURCE: Miyares LC et al. Neurology. 2020 Jan 22. doi: 10.1212/WNL.0000000000008930.
researchers reported Jan. 22 in Neurology.
“There has been considerable research on stroke in older people, but there is still much to be learned about stroke in younger people and how it affects people of different races and ethnicities,” study author Daniel Woo, MD, professor of neurology at the University of Cincinnati, said in a news release. “Our study found that, even when you account for factors that affect outcomes, such as how big the stroke is, race and ethnicity were still independent predictors of how well people would recover.”
A subset of ERICH participants
To examine predictors of functional outcome in young patients with ICH, researchers analyzed data from a subset of patients in the Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study. ERICH enrolled patients with nontraumatic ICHs at 42 sites in the United States. It included 1,000 non-Hispanic black patients, 1,000 non-Hispanic white patients, and 1,000 Hispanic patients. Participants self-reported race and ethnicity.
Lead author Laura C. Miyares from Yale School of Medicine in New Haven, Conn., and colleagues analyzed data from 418 patients in ERICH who were aged 18-49 years and had supratentorial ICH. The cohort had an average age of 43 years, and 69% were male. In this subset, 41% were black, 12% were white, and 47% were Hispanic.
The primary outcome was modified Rankin Scale (mRS) score 3 months after the ICH, and the investigators defined a poor outcome as a score of 4 or greater. At 3 months, 35% had a poor functional outcome. Approximately 18% were unable to walk without assistance and attend to their bodily needs (mRS 4); 8% were bedridden, incontinent, and required nursing care (mRS 5); and 10% had died (mRS 6).
The percentage of patients with a poor functional outcome was 52% among white patients, 35% among black patients, and 31% among Hispanic patients. In a univariable analysis, black patients had a 51% reduction in odds of a poor outcome, compared with white patients, and Hispanic patients had a 59% reduction.
“The association between race/ethnicity and 3-month post-ICH functional outcome remained significant after adjusting for age, sex, premorbid disability, ICH location, ICH volume, [intraventricular hemorrhage] extension, systolic blood pressure, and [Glasgow Coma Scale] score on admission,” the researchers said. “In multivariable analysis, using white patients as the reference category, black patients had a 58% reduction in the odds of poor functional outcome at 3 months and Hispanic patients had a 66% reduction in the same odds.”
Their analysis identified the importance of other risk factors as well. “The volume of the hematoma, the most powerful predictor of outcome in older patients with ICH, was also found to be the most significant predictor of poor outcome in young patients,” they said.
Vascular risks and oral anticoagulants
About 80% of the young adults with ICH had a history of diagnosed hypertension. In nearly half, the condition was untreated. “After hypertension, the most common stroke risk factors in the young were diabetes, high cholesterol, smoking, and alcohol abuse,” the authors said. “In combination, these results indicate that vascular risk factors, especially untreated, could explain a large proportion of cases of ICH in the young.”
“Our results also point to treatment with oral anticoagulants before hospitalization as a potential mediator of the effect of race/ethnicity on short-term functional outcomes,” they said. About 8% of the white patients used oral anticoagulants, compared with 4% of the black patients and 1% of the Hispanic patients. Oral anticoagulant treatment “is a known risk factor for ICH and an established predictor of poor outcome in this condition. However, because only a small proportion of enrolled young patients with ICH were on [oral anticoagulants] prior to presentation, these results should be further validated by future studies.”
The study’s limitations include the broad categorization of racial and ethnic groups, the fact that younger patients with supratentorial ICH were more likely to be black or Hispanic and less likely to be white, and the exclusion of a significant proportion of cases of young white patients with smaller ICH volumes because of missing data, the researchers noted. Although the cohort was large, researchers may need to study more patients to capture differences among racial and ethnic groups, the investigators said.
The association between race/ethnicity and functional outcome could relate to “distinct pathophysiologies of the initial bleed or unique mechanisms of secondary injury,” the researchers suggested. “Future studies are necessary to probe the potential biological and social mediators of these findings to elucidate the role of race/ethnicity in ICH severity and functional recovery, and to develop improved prognostication for a racially varied population.”
ERICH is supported by the National Institute of Neurological Disorders and Stroke. Authors disclosed grants from the government, professional societies, and a university.
SOURCE: Miyares LC et al. Neurology. 2020 Jan 22. doi: 10.1212/WNL.0000000000008930.
FROM NEUROLOGY
Key clinical point: Among young adults with supratentorial intracerebral hemorrhage (ICH), black race and Hispanic ethnicity are associated with better functional outcomes, compared with white race.
Major finding: In multivariable analysis, black patients had a 58% reduction in the odds of poor functional outcome at 3 months, compared with white patients, and Hispanic patients had a 66% reduction.
Study details: An analysis of data from a subset of 418 patients in the Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study.
Disclosures: ERICH is supported by the National Institute of Neurological Disorders and Stroke. Authors disclosed grants from the government, professional societies, and a university.
Source: Miyares LC et al. Neurology. 2020 Jan 22. doi: 10.1212/WNL.0000000000008930.
AED exposure from breastfeeding appears to be low
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
FROM JAMA NEUROLOGY
Delayed clinical care after concussion may prolong recovery
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
FROM JAMA NEUROLOGY
More phase 3 ubrogepant data published as FDA decision nears
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.
Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.
Assessing a gepant for acute migraine treatment
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.
To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.
In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.
The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.
The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”
“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”
The CGRP therapeutic landscape
“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.
Ubrogepant stands to join other treatments targeting CGRP.
“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”
Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Compared with placebo, ubrogepant tablets result in higher rates of pain freedom and freedom from the most bothersome migraine-associated symptom at 2 hours following treatment.
Major finding: About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo.
Study details: A randomized trial that enrolled 1,672 adults with migraine with or without aura. Participants treated a single migraine attack.
Disclosures: Allergan funded the trial, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.
Source: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.
Antibiotic use may increase the risk of Parkinson’s disease
according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.
In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.
Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.
“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.
Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.
“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.
With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.
The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.
The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.
The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”
The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.
SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.
according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.
In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.
Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.
“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.
Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.
“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.
With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.
The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.
The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.
The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”
The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.
SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.
according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.
In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.
Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.
“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.
Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.
“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.
With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.
The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.
The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.
The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”
The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.
SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.
FROM MOVEMENT DISORDERS
Trial finds three drugs equally effective for established status epilepticus
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
FROM NEJM
Key clinical point: Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients.
Major finding: Absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
Study details: The Established Status Epilepticus Treatment Trial (ESETT) was a blinded, comparative-effectiveness trial that enrolled 384 patients at 57 hospital EDs in the United States.
Disclosures: The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Source: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.