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Also today, treating obstructive sleep apnea with positive airway pressure decreased amyloid levels, spending on medical marketing increased by more than $12 billion over that past two decades, and one expert has advice on how you can get your work published.
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Also today, treating obstructive sleep apnea with positive airway pressure decreased amyloid levels, spending on medical marketing increased by more than $12 billion over that past two decades, and one expert has advice on how you can get your work published.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, treating obstructive sleep apnea with positive airway pressure decreased amyloid levels, spending on medical marketing increased by more than $12 billion over that past two decades, and one expert has advice on how you can get your work published.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
RE-SPECT ESUS: Dabigatran matched aspirin for second stroke prevention
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
MONTREAL – For the second time in the past year, an anticoagulant failed to show superiority when it was compared with aspirin for preventing a second stroke in patients who had had an index embolic stroke of undetermined source (ESUS). But the most recent results gave a tantalizing suggestion that the anticoagulant approach might be effective for older patients, those at least 75 years old, possibly because these patients have the highest incidence of atrial fibrillation.
“The fact that we saw a treatment benefit in patients 75 and older [in a post hoc, subgroup analysis] means that development of atrial fibrillation (AF) is probably the most important factor,” Hans-Christoph Diener, MD, said at the World Stroke Congress. Another clue that incident AF drove a treatment benefit hidden in the new trial’s overall neutral result was that a post hoc, landmark analysis showed that, while the rate of second strokes was identical during the first year of follow-up in patients on either aspirin or the anticoagulant dabigatran (Pradaxa) after an index ESUS, patients on dabigatran had significantly fewer second strokes during subsequent follow-up.
More follow-up time was needed to see a benefit from anticoagulation because “it takes time for AF to develop, and then once a patient has AF, it takes time for a stroke to occur,” explained Dr. Diener, professor of neurology at the University of Duisburg-Essen in Essen, Germany.
The RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) trial randomized 5,390 patients at more than 500 sites in 41 countries, including the United States, within 6 months of an index ESUS who had no history of AF and no severe renal impairment. All enrollees had to have less than 6 minutes of AF episodes during at least 20 hours of cardiac monitoring, and they had to be free of flow-limiting stenoses (50% or more) in arteries supplying their stroke region. Patients received either 150 mg or 110 mg of dabigatran twice daily depending on their age and renal function or 100 mg of aspirin daily. About a quarter of patients randomized to dabigatran received the lower dosage. The enrolled patients averaged 66 years old, almost two-thirds were men, and they started treatment a median of 44 days after their index stroke.
During a median 19 months’ follow-up, the incidence of a second stroke of any type was 4.1%/year among the patients on dabigatran and 4.8%/year among those on aspirin, a difference that was not statistically significant. However, the post hoc landmark analysis showed a significant reduction in second strokes with dabigatran treatment after the first year. In addition, a post hoc subgroup analysis showed that, among patients aged at least 75 years old, treatment with dabigatran linked with a statistically significant 37% reduction in second strokes, compared with treatment with aspirin, Dr. Diener reported.
The primary safety endpoint was major bleeds, as defined by the International Society on Thrombosis and Haemostasis, which occurred in 1.7%/year of patients on dabigatran and 1.4%/year of those on aspirin, a difference that was not statistically significant. Patients on dabigatran had a significant excess of major bleeds combined with clinically significant nonmajor bleeds: 3.3%/year versus 2.3%/year among those on aspirin.
A little over 4 months before Dr. Diener’s report, a separate research group published primary results from the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial, which compared the anticoagulant rivaroxaban (Xarelto) with aspirin for prevention of a second stroke in 7,213 ESUS patients. The results showed no significant efficacy difference between rivaroxaban and aspirin (N Engl J Med. 2018 June 7;378[23]:2191-2201).
RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
SOURCE: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
REPORTING FROM THE WORLD STROKE CONGRESS
Key clinical point:
Major finding: A second stroke occurred at 4.1%/year with dabigatran and 4.8%/year with aspirin, not a statistically significant difference.
Study details: RE-SPECT ESUS, an international randomized trial with 5,390 ESUS patients.
Disclosures: RE-SPECT ESUS was funded by Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Diener has been a consultant to and has received research funding from Boehringer Ingelheim, as well as several other companies.
Source: Diener H-C et al. Int J Stroke. 2018;13(2_suppl):27. Abstract 100.
Autologous Hematopoietic Stem Cells May Treat Aggressive MS Effectively
The therapy may halt disease activity and promote sustained functional improvement.
BERLIN—Autologous hematopoietic stem cell transplantation (HSCT) could prevent disease activity and promote functional recovery in patients with aggressive multiple sclerosis (MS), according to a retrospective case series presented at ECTRIMS 2018.
A review article suggested that the likelihood of achieving no evidence of disease activity (NEDA) after two years of treatment ranges between 10% and 60%
Like other highly effective therapies, HSCT has been considered to entail significant safety risks. When the European Society for Blood and Marrow Transplantation (EBMT) reviewed their data, however, they identified one death related to HSCT between 2012 and 2016. The estimated risk of death from HSCT is thus approximately 0.2%. “Mortality associated with transplantation has decreased so much that it is almost into the range of other standard disease-modifying therapies,” said Joyutpal Das, MBBS, a neuroscientist at Royal Hallamshire Hospital in Sheffield, United Kingdom.
EBMT recommended that neurologists consider HSCT for patients with highly active radiologic and clinical disease who have failed to respond to standard disease-modifying therapy. The treatment can be considered as first-line therapy for patients with exceptionally active disease who have become disabled, they added.
A Retrospective Case Series
To examine the efficacy of HSCT in this patient population, Dr. Das and colleagues conducted a retrospective case series of 20 patients with MS from five centers in various countries. The patients’ treating physicians decided that HSCT should be their first-line therapy. Dr. Das and colleagues used NEDA-3 (which includes relapses, disability progression, and MRI activity) as their primary outcome. Each patient underwent brain MRI during the first six months of treatment and at six- to 12-month intervals thereafter.
The case series included equal numbers of men and women. All patients had frequent relapses, incomplete recovery, and multiple gadolinium enhancing lesions on serial MRI scans. The lesions often affected the brainstem, cerebellum, and spine. Patients’ median age of diagnosis and median age of treatment were 28. The time between the first onset of symptoms and treatment was nine months, and that between diagnosis and treatment was five months. Patients’ median pretreatment Expanded Disability Status Scale (EDSS) score was 6.5. Median follow-up duration was 2.5 years.
EDSS Score Improved
Three patients had new lesions during the first six months of treatment, but no patients had new lesions on subsequent MRI scans. “It has been suggested … that if you want to use NEDA to measure efficacy, the patient should have rebaseline imaging after the initiation of treatment,” said Dr. Das. “If we use our six-month scan as rebaseline imaging, then we have no further disease activity on MRI scan.”
After treatment initiation, the median EDSS score decreased from 6.5 to 2. Patients’ median improvement on EDSS score was 2.5 points, which was statistically significant. Seven patients had an EDSS score improvement of 3 points or greater. EDSS score improved for all but one patient. The results suggest that HSCT induced rapid and sustained remission, said Dr. Das.
The investigators observed typical transplant-related toxicity in the population, and no patient died. One woman conceived and gave birth to a healthy baby, and one man fathered a healthy baby.
—Erik Greb
Suggested Reading
Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017;23(2):201-204.
The therapy may halt disease activity and promote sustained functional improvement.
The therapy may halt disease activity and promote sustained functional improvement.
BERLIN—Autologous hematopoietic stem cell transplantation (HSCT) could prevent disease activity and promote functional recovery in patients with aggressive multiple sclerosis (MS), according to a retrospective case series presented at ECTRIMS 2018.
A review article suggested that the likelihood of achieving no evidence of disease activity (NEDA) after two years of treatment ranges between 10% and 60%
Like other highly effective therapies, HSCT has been considered to entail significant safety risks. When the European Society for Blood and Marrow Transplantation (EBMT) reviewed their data, however, they identified one death related to HSCT between 2012 and 2016. The estimated risk of death from HSCT is thus approximately 0.2%. “Mortality associated with transplantation has decreased so much that it is almost into the range of other standard disease-modifying therapies,” said Joyutpal Das, MBBS, a neuroscientist at Royal Hallamshire Hospital in Sheffield, United Kingdom.
EBMT recommended that neurologists consider HSCT for patients with highly active radiologic and clinical disease who have failed to respond to standard disease-modifying therapy. The treatment can be considered as first-line therapy for patients with exceptionally active disease who have become disabled, they added.
A Retrospective Case Series
To examine the efficacy of HSCT in this patient population, Dr. Das and colleagues conducted a retrospective case series of 20 patients with MS from five centers in various countries. The patients’ treating physicians decided that HSCT should be their first-line therapy. Dr. Das and colleagues used NEDA-3 (which includes relapses, disability progression, and MRI activity) as their primary outcome. Each patient underwent brain MRI during the first six months of treatment and at six- to 12-month intervals thereafter.
The case series included equal numbers of men and women. All patients had frequent relapses, incomplete recovery, and multiple gadolinium enhancing lesions on serial MRI scans. The lesions often affected the brainstem, cerebellum, and spine. Patients’ median age of diagnosis and median age of treatment were 28. The time between the first onset of symptoms and treatment was nine months, and that between diagnosis and treatment was five months. Patients’ median pretreatment Expanded Disability Status Scale (EDSS) score was 6.5. Median follow-up duration was 2.5 years.
EDSS Score Improved
Three patients had new lesions during the first six months of treatment, but no patients had new lesions on subsequent MRI scans. “It has been suggested … that if you want to use NEDA to measure efficacy, the patient should have rebaseline imaging after the initiation of treatment,” said Dr. Das. “If we use our six-month scan as rebaseline imaging, then we have no further disease activity on MRI scan.”
After treatment initiation, the median EDSS score decreased from 6.5 to 2. Patients’ median improvement on EDSS score was 2.5 points, which was statistically significant. Seven patients had an EDSS score improvement of 3 points or greater. EDSS score improved for all but one patient. The results suggest that HSCT induced rapid and sustained remission, said Dr. Das.
The investigators observed typical transplant-related toxicity in the population, and no patient died. One woman conceived and gave birth to a healthy baby, and one man fathered a healthy baby.
—Erik Greb
Suggested Reading
Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017;23(2):201-204.
BERLIN—Autologous hematopoietic stem cell transplantation (HSCT) could prevent disease activity and promote functional recovery in patients with aggressive multiple sclerosis (MS), according to a retrospective case series presented at ECTRIMS 2018.
A review article suggested that the likelihood of achieving no evidence of disease activity (NEDA) after two years of treatment ranges between 10% and 60%
Like other highly effective therapies, HSCT has been considered to entail significant safety risks. When the European Society for Blood and Marrow Transplantation (EBMT) reviewed their data, however, they identified one death related to HSCT between 2012 and 2016. The estimated risk of death from HSCT is thus approximately 0.2%. “Mortality associated with transplantation has decreased so much that it is almost into the range of other standard disease-modifying therapies,” said Joyutpal Das, MBBS, a neuroscientist at Royal Hallamshire Hospital in Sheffield, United Kingdom.
EBMT recommended that neurologists consider HSCT for patients with highly active radiologic and clinical disease who have failed to respond to standard disease-modifying therapy. The treatment can be considered as first-line therapy for patients with exceptionally active disease who have become disabled, they added.
A Retrospective Case Series
To examine the efficacy of HSCT in this patient population, Dr. Das and colleagues conducted a retrospective case series of 20 patients with MS from five centers in various countries. The patients’ treating physicians decided that HSCT should be their first-line therapy. Dr. Das and colleagues used NEDA-3 (which includes relapses, disability progression, and MRI activity) as their primary outcome. Each patient underwent brain MRI during the first six months of treatment and at six- to 12-month intervals thereafter.
The case series included equal numbers of men and women. All patients had frequent relapses, incomplete recovery, and multiple gadolinium enhancing lesions on serial MRI scans. The lesions often affected the brainstem, cerebellum, and spine. Patients’ median age of diagnosis and median age of treatment were 28. The time between the first onset of symptoms and treatment was nine months, and that between diagnosis and treatment was five months. Patients’ median pretreatment Expanded Disability Status Scale (EDSS) score was 6.5. Median follow-up duration was 2.5 years.
EDSS Score Improved
Three patients had new lesions during the first six months of treatment, but no patients had new lesions on subsequent MRI scans. “It has been suggested … that if you want to use NEDA to measure efficacy, the patient should have rebaseline imaging after the initiation of treatment,” said Dr. Das. “If we use our six-month scan as rebaseline imaging, then we have no further disease activity on MRI scan.”
After treatment initiation, the median EDSS score decreased from 6.5 to 2. Patients’ median improvement on EDSS score was 2.5 points, which was statistically significant. Seven patients had an EDSS score improvement of 3 points or greater. EDSS score improved for all but one patient. The results suggest that HSCT induced rapid and sustained remission, said Dr. Das.
The investigators observed typical transplant-related toxicity in the population, and no patient died. One woman conceived and gave birth to a healthy baby, and one man fathered a healthy baby.
—Erik Greb
Suggested Reading
Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017;23(2):201-204.
Alcohol use, psychological distress associated with possible RBD
(RBD), according to a population-based cohort study published in Neurology. In addition, the results also replicate previous findings of an association between possible RBD and smoking, low education, and male sex.
The risk factors for RBD have been studied comparatively little. “While much is still unknown about RBD, it can be caused by medications or it may be an early sign of another neurologic condition like Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy,” according to Ronald B. Postuma, MD, an associate professor at McGill University, Montreal. “Identifying lifestyle and personal risk factors linked to this sleep disorder may lead to finding ways to reduce the chances of developing it.”
To assess sociodemographic, socioeconomic, and clinical correlates of possible RBD, Dr. Postuma and his colleagues examined baseline data collected between 2012 and 2015 in the Canadian Longitudinal Study on Aging (CLSA), which included 30,097 participants. To screen for possible RBD, the CLSA researchers asked patients, “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep [e.g., punching, flailing your arms in the air, making running movements, etc.]?” Participants answered additional questions to rule out RBD mimics. Patients with symptom onset before age 20 years, positive apnea screen, or a diagnosis of dementia, Alzheimer’s disease, parkinsonism, or Parkinson’s disease were excluded from analysis.
In all, 3,271 participants screened positive for possible RBD. After the investigators excluded participants with potential mimics, 958 patients (about 3.2% of the total population) remained in the analysis. Approximately 59% of patients with possible RBD were male, compared with 42% of controls. Patients with possible RBD were more likely to be married, in a common-law relationship, or widowed.
Participants with possible RBD had slightly less education (estimated mean, 13.2 years vs. 13.6 years) and lower income, compared with controls. Participants with possible RBD retired at a slightly younger age (57.5 years vs. 58.6 years) and were more likely to have retired because of health concerns (28.9% vs. 22.0%), compared with controls.
In addition, patients with possible RBD were more likely to drink more and to be moderate to heavy drinkers than controls; they were also more likely to be current or past smokers. Antidepressant use was more frequent and psychological distress was greater among participants with possible RBD.
When the investigators performed a multivariable logistic regression analysis, the associations between possible RBD and male sex and relationship status remained. Lower educational level, but not income level, also remained associated with possible RBD. Furthermore, retirement age and having reported retirement because of health concerns remained significantly associated with possible RBD, as did the amount of alcohol consumed weekly and moderate to heavy drinking. Sensitivity analyses did not change the results significantly.
One of the study’s limitations is its reliance on self-report to identify participants with possible RBD, the authors wrote. The prevalence of possible RBD in the study was 3.2%, but research using polysomnography has found a prevalence of about 1%. Thus, the majority of cases in this study may have other disorders such as restless legs syndrome or periodic limb movements. Furthermore, many participants who enact their dreams (such as unmarried people) are likely unaware of it. Finally, the researchers did not measure several variables of interest, such as consumption of caffeinated products.
“The main advantages of our current study are the large sample size; the systematic population-based sampling; the capacity to adjust for diverse potential confounding variables, including mental illness; and the ability to screen out RBD mimics,” the authors concluded.
SOURCE: Postuma RB et al. Neurology. 2018 Dec 26. doi: 10.1212/WNL.0000000000006849.
(RBD), according to a population-based cohort study published in Neurology. In addition, the results also replicate previous findings of an association between possible RBD and smoking, low education, and male sex.
The risk factors for RBD have been studied comparatively little. “While much is still unknown about RBD, it can be caused by medications or it may be an early sign of another neurologic condition like Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy,” according to Ronald B. Postuma, MD, an associate professor at McGill University, Montreal. “Identifying lifestyle and personal risk factors linked to this sleep disorder may lead to finding ways to reduce the chances of developing it.”
To assess sociodemographic, socioeconomic, and clinical correlates of possible RBD, Dr. Postuma and his colleagues examined baseline data collected between 2012 and 2015 in the Canadian Longitudinal Study on Aging (CLSA), which included 30,097 participants. To screen for possible RBD, the CLSA researchers asked patients, “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep [e.g., punching, flailing your arms in the air, making running movements, etc.]?” Participants answered additional questions to rule out RBD mimics. Patients with symptom onset before age 20 years, positive apnea screen, or a diagnosis of dementia, Alzheimer’s disease, parkinsonism, or Parkinson’s disease were excluded from analysis.
In all, 3,271 participants screened positive for possible RBD. After the investigators excluded participants with potential mimics, 958 patients (about 3.2% of the total population) remained in the analysis. Approximately 59% of patients with possible RBD were male, compared with 42% of controls. Patients with possible RBD were more likely to be married, in a common-law relationship, or widowed.
Participants with possible RBD had slightly less education (estimated mean, 13.2 years vs. 13.6 years) and lower income, compared with controls. Participants with possible RBD retired at a slightly younger age (57.5 years vs. 58.6 years) and were more likely to have retired because of health concerns (28.9% vs. 22.0%), compared with controls.
In addition, patients with possible RBD were more likely to drink more and to be moderate to heavy drinkers than controls; they were also more likely to be current or past smokers. Antidepressant use was more frequent and psychological distress was greater among participants with possible RBD.
When the investigators performed a multivariable logistic regression analysis, the associations between possible RBD and male sex and relationship status remained. Lower educational level, but not income level, also remained associated with possible RBD. Furthermore, retirement age and having reported retirement because of health concerns remained significantly associated with possible RBD, as did the amount of alcohol consumed weekly and moderate to heavy drinking. Sensitivity analyses did not change the results significantly.
One of the study’s limitations is its reliance on self-report to identify participants with possible RBD, the authors wrote. The prevalence of possible RBD in the study was 3.2%, but research using polysomnography has found a prevalence of about 1%. Thus, the majority of cases in this study may have other disorders such as restless legs syndrome or periodic limb movements. Furthermore, many participants who enact their dreams (such as unmarried people) are likely unaware of it. Finally, the researchers did not measure several variables of interest, such as consumption of caffeinated products.
“The main advantages of our current study are the large sample size; the systematic population-based sampling; the capacity to adjust for diverse potential confounding variables, including mental illness; and the ability to screen out RBD mimics,” the authors concluded.
SOURCE: Postuma RB et al. Neurology. 2018 Dec 26. doi: 10.1212/WNL.0000000000006849.
(RBD), according to a population-based cohort study published in Neurology. In addition, the results also replicate previous findings of an association between possible RBD and smoking, low education, and male sex.
The risk factors for RBD have been studied comparatively little. “While much is still unknown about RBD, it can be caused by medications or it may be an early sign of another neurologic condition like Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy,” according to Ronald B. Postuma, MD, an associate professor at McGill University, Montreal. “Identifying lifestyle and personal risk factors linked to this sleep disorder may lead to finding ways to reduce the chances of developing it.”
To assess sociodemographic, socioeconomic, and clinical correlates of possible RBD, Dr. Postuma and his colleagues examined baseline data collected between 2012 and 2015 in the Canadian Longitudinal Study on Aging (CLSA), which included 30,097 participants. To screen for possible RBD, the CLSA researchers asked patients, “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep [e.g., punching, flailing your arms in the air, making running movements, etc.]?” Participants answered additional questions to rule out RBD mimics. Patients with symptom onset before age 20 years, positive apnea screen, or a diagnosis of dementia, Alzheimer’s disease, parkinsonism, or Parkinson’s disease were excluded from analysis.
In all, 3,271 participants screened positive for possible RBD. After the investigators excluded participants with potential mimics, 958 patients (about 3.2% of the total population) remained in the analysis. Approximately 59% of patients with possible RBD were male, compared with 42% of controls. Patients with possible RBD were more likely to be married, in a common-law relationship, or widowed.
Participants with possible RBD had slightly less education (estimated mean, 13.2 years vs. 13.6 years) and lower income, compared with controls. Participants with possible RBD retired at a slightly younger age (57.5 years vs. 58.6 years) and were more likely to have retired because of health concerns (28.9% vs. 22.0%), compared with controls.
In addition, patients with possible RBD were more likely to drink more and to be moderate to heavy drinkers than controls; they were also more likely to be current or past smokers. Antidepressant use was more frequent and psychological distress was greater among participants with possible RBD.
When the investigators performed a multivariable logistic regression analysis, the associations between possible RBD and male sex and relationship status remained. Lower educational level, but not income level, also remained associated with possible RBD. Furthermore, retirement age and having reported retirement because of health concerns remained significantly associated with possible RBD, as did the amount of alcohol consumed weekly and moderate to heavy drinking. Sensitivity analyses did not change the results significantly.
One of the study’s limitations is its reliance on self-report to identify participants with possible RBD, the authors wrote. The prevalence of possible RBD in the study was 3.2%, but research using polysomnography has found a prevalence of about 1%. Thus, the majority of cases in this study may have other disorders such as restless legs syndrome or periodic limb movements. Furthermore, many participants who enact their dreams (such as unmarried people) are likely unaware of it. Finally, the researchers did not measure several variables of interest, such as consumption of caffeinated products.
“The main advantages of our current study are the large sample size; the systematic population-based sampling; the capacity to adjust for diverse potential confounding variables, including mental illness; and the ability to screen out RBD mimics,” the authors concluded.
SOURCE: Postuma RB et al. Neurology. 2018 Dec 26. doi: 10.1212/WNL.0000000000006849.
FROM NEUROLOGY
Key clinical point: Alcohol use and psychological distress are associated with possible REM sleep behavior disorder.
Major finding: A self-report questionnaire yielded a 3.2% prevalence of possible REM sleep behavior disorder.
Study details: A prospective, population-based cohort study of 30,097 participants.
Disclosures: The Canadian government provided funding for the research.
Source: Postuma RB et al. Neurology. 2018 Dec 26. doi: 10.1212/WNL.0000000000006849.
Masterclass: First-episode psychosis with Dr. Henry A. Nasrallah
from the Psychopharmacology Update meeting in Cincinnati. Dr. Nasrallah is editor in chief of Current Psychiatry and is the Sydney W. Souers Endowed Chair and professor and chairman of the department of neurology and psychiatry and behavioral neuroscience at Saint Louis University.
If you would like to respond to any of Dr. Nasrallah’s comments in this Masterclass, email us at podcasts@mdedge.com.
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from the Psychopharmacology Update meeting in Cincinnati. Dr. Nasrallah is editor in chief of Current Psychiatry and is the Sydney W. Souers Endowed Chair and professor and chairman of the department of neurology and psychiatry and behavioral neuroscience at Saint Louis University.
If you would like to respond to any of Dr. Nasrallah’s comments in this Masterclass, email us at podcasts@mdedge.com.
Amazon
Apple Podcasts
Google Podcasts
Spotify
from the Psychopharmacology Update meeting in Cincinnati. Dr. Nasrallah is editor in chief of Current Psychiatry and is the Sydney W. Souers Endowed Chair and professor and chairman of the department of neurology and psychiatry and behavioral neuroscience at Saint Louis University.
If you would like to respond to any of Dr. Nasrallah’s comments in this Masterclass, email us at podcasts@mdedge.com.
Amazon
Apple Podcasts
Google Podcasts
Spotify
AAP guidance: How to ask about military service
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
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Apple Podcasts
Google Podcasts
Spotify
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Treating OSA with positive airway pressure decreased amyloid levels in CSF
Soluble amyloid-beta in cerebrospinal fluid (CSF) decreased when subjects with obstructive sleep apnea used a positive airway pressure device with good adherence, suggesting that improving sleep could reduce the risk of Alzheimer’s disease in this population.
The small decrease in cerebrospinal amyloid-beta 40 (Ab40) and Ab42 hints at decreased neuronal release of the neurotoxic protein, wrote Yo-El S. Ju, MD, and her colleagues. The report was published online in Annals of Neurology.
Alzheimer’s disease (AD) biomarker studies typically find decreased CSF levels associated with increased Ab brain plaques. But before plaques form, increased soluble Ab in CSF is a risk factor for aggregation. Thus, higher soluble Ab levels in mid-life may suggest a risk of later Ab pathology, wrote Dr. Ju of Washington University, St. Louis.
“We tested individuals without any AD pathology as assessed by Ab42 [in CSF], a highly sensitive biomarker of amyloid plaques,” Dr. Ju and her coauthors wrote. “This means our study findings can be extrapolated to the large population of people with OSA [obstructive sleep apnea], many of whom are middle-aged or younger, and have many years to accrue benefit from AD risk reduction ... The effect of OSA on SWA [slow wave activity], Ab, and possibly tau, is a probable proximal step in a cascade whereby OSA increases the risk of AD.”
The researchers recruited 35 subjects with mild to severe OSA and without abnormal Ab levels in CSF. Subjects used auto-titrating positive airway pressure (PAP) for 1-4 months; 18 were sufficiently compliant to be included in the analysis (more than 4 hours on more than 70% of 30 preceding nights as recorded by the machine). CSF was obtained after a baseline polysomnogram and after the treatment period lasting 1-4 months.
Of the 18 analyzed patients, 7 had mild OSA and 11 had moderate to severe OSA. They were an average of nearly 57 years old with a mean body mass index of 30.4 kg/m2; 7 patients had hypertension.
PAP treatment was effective, indicated by a normalized apnea-hypopnea index and decreased time in hypoxemia. Total sleep time and sleep efficiency were unchanged, but slow-wave activity did increase. As expected, hourly arousals and time in hypoxemia decreased, and hypoxic nadir shifted from an oxygen saturation of 82.5% to 91%.
“As a group, there was no significant change in Ab with treatment,” the researchers wrote. But a correlational analysis found that “greater improvement in OSA was associated with greater decrease in Ab40 and Ab42. Additionally, we found that change in tau negatively correlated with OSA improvement.”
The team suggested a two-factor model to explain the relationship between OSA and Ab levels. “Due to decreased SWA, there would be relatively increased release of Ab into the [interstitial fluid]. However, as OSA severity worsens, pressure effects of obstructive respiratory events impede the clearance of Ab and tau out of the interstitial space, resulting in lower levels in the CSF and an inverse U-shaped curve. In this model, a small improvement in OSA may result in an increase in Ab or tau, whereas a larger improvement in OSA – that ameliorates both SWA and clearance mechanisms – will result in a decrease in Ab and tau.”
The project was funded in part by Philips-Respironics, which provided the devices, and by the National Institutes of Health. Philips-Respironics had no input or role in any other part of the study. The authors had no financial disclosures.
SOURCE: Ju YS et al. Ann Neurol. 2018 Dec 31. doi: 10.1002/ana.25408.
Soluble amyloid-beta in cerebrospinal fluid (CSF) decreased when subjects with obstructive sleep apnea used a positive airway pressure device with good adherence, suggesting that improving sleep could reduce the risk of Alzheimer’s disease in this population.
The small decrease in cerebrospinal amyloid-beta 40 (Ab40) and Ab42 hints at decreased neuronal release of the neurotoxic protein, wrote Yo-El S. Ju, MD, and her colleagues. The report was published online in Annals of Neurology.
Alzheimer’s disease (AD) biomarker studies typically find decreased CSF levels associated with increased Ab brain plaques. But before plaques form, increased soluble Ab in CSF is a risk factor for aggregation. Thus, higher soluble Ab levels in mid-life may suggest a risk of later Ab pathology, wrote Dr. Ju of Washington University, St. Louis.
“We tested individuals without any AD pathology as assessed by Ab42 [in CSF], a highly sensitive biomarker of amyloid plaques,” Dr. Ju and her coauthors wrote. “This means our study findings can be extrapolated to the large population of people with OSA [obstructive sleep apnea], many of whom are middle-aged or younger, and have many years to accrue benefit from AD risk reduction ... The effect of OSA on SWA [slow wave activity], Ab, and possibly tau, is a probable proximal step in a cascade whereby OSA increases the risk of AD.”
The researchers recruited 35 subjects with mild to severe OSA and without abnormal Ab levels in CSF. Subjects used auto-titrating positive airway pressure (PAP) for 1-4 months; 18 were sufficiently compliant to be included in the analysis (more than 4 hours on more than 70% of 30 preceding nights as recorded by the machine). CSF was obtained after a baseline polysomnogram and after the treatment period lasting 1-4 months.
Of the 18 analyzed patients, 7 had mild OSA and 11 had moderate to severe OSA. They were an average of nearly 57 years old with a mean body mass index of 30.4 kg/m2; 7 patients had hypertension.
PAP treatment was effective, indicated by a normalized apnea-hypopnea index and decreased time in hypoxemia. Total sleep time and sleep efficiency were unchanged, but slow-wave activity did increase. As expected, hourly arousals and time in hypoxemia decreased, and hypoxic nadir shifted from an oxygen saturation of 82.5% to 91%.
“As a group, there was no significant change in Ab with treatment,” the researchers wrote. But a correlational analysis found that “greater improvement in OSA was associated with greater decrease in Ab40 and Ab42. Additionally, we found that change in tau negatively correlated with OSA improvement.”
The team suggested a two-factor model to explain the relationship between OSA and Ab levels. “Due to decreased SWA, there would be relatively increased release of Ab into the [interstitial fluid]. However, as OSA severity worsens, pressure effects of obstructive respiratory events impede the clearance of Ab and tau out of the interstitial space, resulting in lower levels in the CSF and an inverse U-shaped curve. In this model, a small improvement in OSA may result in an increase in Ab or tau, whereas a larger improvement in OSA – that ameliorates both SWA and clearance mechanisms – will result in a decrease in Ab and tau.”
The project was funded in part by Philips-Respironics, which provided the devices, and by the National Institutes of Health. Philips-Respironics had no input or role in any other part of the study. The authors had no financial disclosures.
SOURCE: Ju YS et al. Ann Neurol. 2018 Dec 31. doi: 10.1002/ana.25408.
Soluble amyloid-beta in cerebrospinal fluid (CSF) decreased when subjects with obstructive sleep apnea used a positive airway pressure device with good adherence, suggesting that improving sleep could reduce the risk of Alzheimer’s disease in this population.
The small decrease in cerebrospinal amyloid-beta 40 (Ab40) and Ab42 hints at decreased neuronal release of the neurotoxic protein, wrote Yo-El S. Ju, MD, and her colleagues. The report was published online in Annals of Neurology.
Alzheimer’s disease (AD) biomarker studies typically find decreased CSF levels associated with increased Ab brain plaques. But before plaques form, increased soluble Ab in CSF is a risk factor for aggregation. Thus, higher soluble Ab levels in mid-life may suggest a risk of later Ab pathology, wrote Dr. Ju of Washington University, St. Louis.
“We tested individuals without any AD pathology as assessed by Ab42 [in CSF], a highly sensitive biomarker of amyloid plaques,” Dr. Ju and her coauthors wrote. “This means our study findings can be extrapolated to the large population of people with OSA [obstructive sleep apnea], many of whom are middle-aged or younger, and have many years to accrue benefit from AD risk reduction ... The effect of OSA on SWA [slow wave activity], Ab, and possibly tau, is a probable proximal step in a cascade whereby OSA increases the risk of AD.”
The researchers recruited 35 subjects with mild to severe OSA and without abnormal Ab levels in CSF. Subjects used auto-titrating positive airway pressure (PAP) for 1-4 months; 18 were sufficiently compliant to be included in the analysis (more than 4 hours on more than 70% of 30 preceding nights as recorded by the machine). CSF was obtained after a baseline polysomnogram and after the treatment period lasting 1-4 months.
Of the 18 analyzed patients, 7 had mild OSA and 11 had moderate to severe OSA. They were an average of nearly 57 years old with a mean body mass index of 30.4 kg/m2; 7 patients had hypertension.
PAP treatment was effective, indicated by a normalized apnea-hypopnea index and decreased time in hypoxemia. Total sleep time and sleep efficiency were unchanged, but slow-wave activity did increase. As expected, hourly arousals and time in hypoxemia decreased, and hypoxic nadir shifted from an oxygen saturation of 82.5% to 91%.
“As a group, there was no significant change in Ab with treatment,” the researchers wrote. But a correlational analysis found that “greater improvement in OSA was associated with greater decrease in Ab40 and Ab42. Additionally, we found that change in tau negatively correlated with OSA improvement.”
The team suggested a two-factor model to explain the relationship between OSA and Ab levels. “Due to decreased SWA, there would be relatively increased release of Ab into the [interstitial fluid]. However, as OSA severity worsens, pressure effects of obstructive respiratory events impede the clearance of Ab and tau out of the interstitial space, resulting in lower levels in the CSF and an inverse U-shaped curve. In this model, a small improvement in OSA may result in an increase in Ab or tau, whereas a larger improvement in OSA – that ameliorates both SWA and clearance mechanisms – will result in a decrease in Ab and tau.”
The project was funded in part by Philips-Respironics, which provided the devices, and by the National Institutes of Health. Philips-Respironics had no input or role in any other part of the study. The authors had no financial disclosures.
SOURCE: Ju YS et al. Ann Neurol. 2018 Dec 31. doi: 10.1002/ana.25408.
FROM ANNALS OF NEUROLOGY
Key clinical point:
Major finding: After treatment, a correlational analysis found decreases in amyloid-beta 40 and 42.
Study details: The prospective, interventional study comprised 18 subjects.
Disclosures: The project was funded in part by Philips-Respironics, which provided the devices, and by the National Institutes of Health. Philips-Respironics had no input or role in any other part of the study. The authors had no financial disclosures.
Source: Ju YS et al. Ann Neurol. 2018 Dec 31. doi: 10.1002/ana.25408.
AAN publishes position statement on brain death
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
In a position statement published online ahead of print Jan. 2 in Neurology, Such uniformity would reduce uncertainty and improve patient care, according to the authors. The statement, which was drafted by the AAN’s Brain Death Working Group, also supports the development of uniform policies regarding brain death and its determination within American medical institutions. Finally, the document provides neurologists with guidance for responding to requests for accommodation, including objections to the determination of brain death and to the withdrawal of organ-sustaining technology.
The AAN defines brain death as death resulting from irreversible loss of function of the entire brain. The Uniform Determination of Death Act of 1981 held that brain death and circulatory death (that is, death resulting from irreversible loss of function of the circulatory system) are equivalent, and the AAN acknowledges this equivalence.
The two current medical standards for brain death are the AAN’s 2010 Evidence-Based Guideline Update: Determining Brain Death in Adults and the 2011 Guidelines for the Determination of Brain Death in Infants and Children, which was published by the pediatric section of the Society of Critical Care Medicine, the sections of neurology and critical care of the American Academy of Pediatrics, and the Child Neurology Society. “The AAN is unaware of any cases in which compliant application of the brain death guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes, or ventilatory effort,” according to their 2019 statement.
The only jurisdiction with laws that specifically defer to these standards, however, is Nevada. The vagueness of most states’ laws has contributed to divergent legal interpretations and idiosyncratic standards for determining brain death, according to the statement.
“The AAN believes that a specific, uniform standard for the determination of brain death is critically important to provide the highest quality patient-centered neurologic and end-of-life care,” said James Russell, DO, MS, a neurologist at Lahey Hospital and Medical Center in Burlington, Mass., and lead author of the position statement. “The AAN supports the development of legislation in every state modeled after the Nevada statute, which specifically defers to these current adult and pediatric brain death guidelines and any future updates.”
In addition to uniform institutional policies for determining brain death within U.S. medical facilities, the AAN calls for the development of training programs and credentialing mechanisms for physicians who determine brain death, regardless of their specialties. The association also supports research that enhances understanding of brain death and enhanced professional and public education.
While expressing respect and sympathy for requests for limited accommodation, the AAN asserts that these requests “must be based on the values of the patient, and not those of loved ones or other surrogate decision makers.” The association further observes that physicians have no ethical obligation to provide medical treatment to a deceased patient. New Jersey is the only state that legally obliges physicians to provide indefinite accommodation and continued application of organ-sustaining technology.
“The AAN believes that its members have both the moral authority and professional responsibility, when lawful, to perform a brain death evaluation, including apnea testing, after informing a patient’s loved ones or lawful surrogates of that intention, but without obligation to obtain informed consent,” according to the statement. “This position is analogous to the authority and responsibility historically granted to the medical profession to determine circulatory death without the requirement for additional informed consent.”
If a dispute about indefinite accommodation cannot be resolved, it is acceptable for a physician to withdraw organ-sustaining technology unilaterally over the objection of loved ones when legally permitted, according to the AAN. Such unilateral action is a measure of last resort and does not apply when the patient is a pregnant woman, said the authors. In the latter case, the ethical analysis should focus mainly on the welfare of the fetus.
The AAN provided financial support for the Brain Death Working Group’s efforts. The statement’s authors reported no relevant disclosures. The American Neurological Association and the Child Neurology Society have endorsed the AAN’s position statement.
SOURCE: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
FROM NEUROLOGY
Key clinical point: The AAN calls for uniform brain death laws, policies, and practices.
Major finding: The association published a position statement online on January 2.
Study details: The AAN’s Brain Death Working Group drafted the statement.
Disclosures: The authors reported no relevant disclosures, and the American Academy of Neurology funded their work.
Source: Russell JA et al. Neurology. 2018 Jan 2. doi: 10.1212/WNL.0000000000006750.
Researchers exploring ways to mitigate aging’s impact on diabetes
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
Nuedexta mainly prescribed for dementia, Parkinson’s
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.
Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.
The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.
To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.
Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.
“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.
Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112
FROM JAMA INTERNAL MEDICINE
Key clinical point:
Major finding: Only 8.4% of patients had a diagnosis of multiple sclerosis and only 6.8% had amyotrophic lateral sclerosis, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis.
Study details: Population-based cohort study of 12,858 patients prescribed dextromethorphan-quinidine between 2010 and 2017.
Disclosures: Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.
Source: Fralick M et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112.
