User login
Rock Steady Boxing could prove beneficial for Parkinson’s patients
Exercise classes that focus on boxing movements such as punching a bag may help to improve motor learning patterns in patients with Parkinson’s disease, according to a new pilot study.
When presented with a computerized test in which study participants with Parkinson’s disease had to press buttons corresponding to patterns appearing on a screen, those who had been taking Rock Steady Boxing classes for at least 6 months demonstrated faster reaction time than did those who had never taken the classes, according to Christopher K. McLeod, a second-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Mr. McLeod, who worked with Adena Leder, DO, director of the Parkinson’s Disease Treatment Center at the college, will present his research findings Oct. 20 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
While the results were not statistically significant, and the number of participants (n = 28) was relatively small, said Mr. McLeod, “We think this is a good pilot study for research going forward, since there really isn’t anything in the literature right now about how procedural memory and learning could be addressed from a therapeutic standpoint in Parkinson’s disease patients.” Procedural learning is a means of acquiring a new skill through repeating the task, like learning to drive a stick shift by doing it.
The investigators used a serial reaction time test to assess procedural memory in 14 patients diagnosed with Parkinson’s disease who had been regularly attending Rock Steady Boxing classes and in 14 patients who did not go to the classes. The test featured a computer screen with four squares that would light up and a box with four corresponding buttons to push as each square lit up. There were seven time blocks in which patients were presented with a series of 10 stimuli. The first pattern was random to get participants accustomed to the task. The second, third, fourth, and fifth blocks had the same sequence, to assess participants’ ability to learn the pattern and respond more quickly. The sixth block again had a random pattern to see if participants slowed down to learn the new pattern, and the seventh block repeated the familiar sequence from the second to fifth blocks.
Experienced boxers generally demonstrated faster reaction time than did nonboxers, the researchers found. Statistical analysis of the four learning blocks (blocks 2-5) revealed a moderate effect (P = .19), indicating that experienced boxers tended to react faster than nonboxers.
Diminished reaction time is a hallmark symptom of Parkinson’s disease, often resulting in patients having to give up the ability drive as the disease progresses, Mr. McLeod said: “Reaction time is something that could eventually lead to falling or not being able to drive, which are huge lifestyle changes that affect these patients emotionally and impact their quality of life.”
The researchers also observed a visible difference in how the two groups tended to respond to the random sequence following the repetitive blocks. Experienced boxers slowed slightly, with a 27.3-ms increase in reaction time, while nonboxers got faster, with a 93.5-ms decrease in reaction time. One possible explanation is that nonboxers simply got better at reacting to the stimuli over time without actually learning the repeated sequence, Mr. McLeod said.
Rock Steady Boxing was founded in Indianapolis by Scott Newman, a former county prosecutor who was diagnosed with Parkinson’s disease at age 40 and experienced significant improvement in his health and agility by engaging in rigorous workouts, such as boxing. Dr. Leder became certified in Rock Steady Boxing and opened a chapter at the New York college in May 2016. The classes include group activities, games, and boxing exercises designed to improve patients’ physical and mental stamina.
Mr. McLeod and Dr. Leder reported no relevant financial disclosures.
Exercise classes that focus on boxing movements such as punching a bag may help to improve motor learning patterns in patients with Parkinson’s disease, according to a new pilot study.
When presented with a computerized test in which study participants with Parkinson’s disease had to press buttons corresponding to patterns appearing on a screen, those who had been taking Rock Steady Boxing classes for at least 6 months demonstrated faster reaction time than did those who had never taken the classes, according to Christopher K. McLeod, a second-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Mr. McLeod, who worked with Adena Leder, DO, director of the Parkinson’s Disease Treatment Center at the college, will present his research findings Oct. 20 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
While the results were not statistically significant, and the number of participants (n = 28) was relatively small, said Mr. McLeod, “We think this is a good pilot study for research going forward, since there really isn’t anything in the literature right now about how procedural memory and learning could be addressed from a therapeutic standpoint in Parkinson’s disease patients.” Procedural learning is a means of acquiring a new skill through repeating the task, like learning to drive a stick shift by doing it.
The investigators used a serial reaction time test to assess procedural memory in 14 patients diagnosed with Parkinson’s disease who had been regularly attending Rock Steady Boxing classes and in 14 patients who did not go to the classes. The test featured a computer screen with four squares that would light up and a box with four corresponding buttons to push as each square lit up. There were seven time blocks in which patients were presented with a series of 10 stimuli. The first pattern was random to get participants accustomed to the task. The second, third, fourth, and fifth blocks had the same sequence, to assess participants’ ability to learn the pattern and respond more quickly. The sixth block again had a random pattern to see if participants slowed down to learn the new pattern, and the seventh block repeated the familiar sequence from the second to fifth blocks.
Experienced boxers generally demonstrated faster reaction time than did nonboxers, the researchers found. Statistical analysis of the four learning blocks (blocks 2-5) revealed a moderate effect (P = .19), indicating that experienced boxers tended to react faster than nonboxers.
Diminished reaction time is a hallmark symptom of Parkinson’s disease, often resulting in patients having to give up the ability drive as the disease progresses, Mr. McLeod said: “Reaction time is something that could eventually lead to falling or not being able to drive, which are huge lifestyle changes that affect these patients emotionally and impact their quality of life.”
The researchers also observed a visible difference in how the two groups tended to respond to the random sequence following the repetitive blocks. Experienced boxers slowed slightly, with a 27.3-ms increase in reaction time, while nonboxers got faster, with a 93.5-ms decrease in reaction time. One possible explanation is that nonboxers simply got better at reacting to the stimuli over time without actually learning the repeated sequence, Mr. McLeod said.
Rock Steady Boxing was founded in Indianapolis by Scott Newman, a former county prosecutor who was diagnosed with Parkinson’s disease at age 40 and experienced significant improvement in his health and agility by engaging in rigorous workouts, such as boxing. Dr. Leder became certified in Rock Steady Boxing and opened a chapter at the New York college in May 2016. The classes include group activities, games, and boxing exercises designed to improve patients’ physical and mental stamina.
Mr. McLeod and Dr. Leder reported no relevant financial disclosures.
Exercise classes that focus on boxing movements such as punching a bag may help to improve motor learning patterns in patients with Parkinson’s disease, according to a new pilot study.
When presented with a computerized test in which study participants with Parkinson’s disease had to press buttons corresponding to patterns appearing on a screen, those who had been taking Rock Steady Boxing classes for at least 6 months demonstrated faster reaction time than did those who had never taken the classes, according to Christopher K. McLeod, a second-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Mr. McLeod, who worked with Adena Leder, DO, director of the Parkinson’s Disease Treatment Center at the college, will present his research findings Oct. 20 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
While the results were not statistically significant, and the number of participants (n = 28) was relatively small, said Mr. McLeod, “We think this is a good pilot study for research going forward, since there really isn’t anything in the literature right now about how procedural memory and learning could be addressed from a therapeutic standpoint in Parkinson’s disease patients.” Procedural learning is a means of acquiring a new skill through repeating the task, like learning to drive a stick shift by doing it.
The investigators used a serial reaction time test to assess procedural memory in 14 patients diagnosed with Parkinson’s disease who had been regularly attending Rock Steady Boxing classes and in 14 patients who did not go to the classes. The test featured a computer screen with four squares that would light up and a box with four corresponding buttons to push as each square lit up. There were seven time blocks in which patients were presented with a series of 10 stimuli. The first pattern was random to get participants accustomed to the task. The second, third, fourth, and fifth blocks had the same sequence, to assess participants’ ability to learn the pattern and respond more quickly. The sixth block again had a random pattern to see if participants slowed down to learn the new pattern, and the seventh block repeated the familiar sequence from the second to fifth blocks.
Experienced boxers generally demonstrated faster reaction time than did nonboxers, the researchers found. Statistical analysis of the four learning blocks (blocks 2-5) revealed a moderate effect (P = .19), indicating that experienced boxers tended to react faster than nonboxers.
Diminished reaction time is a hallmark symptom of Parkinson’s disease, often resulting in patients having to give up the ability drive as the disease progresses, Mr. McLeod said: “Reaction time is something that could eventually lead to falling or not being able to drive, which are huge lifestyle changes that affect these patients emotionally and impact their quality of life.”
The researchers also observed a visible difference in how the two groups tended to respond to the random sequence following the repetitive blocks. Experienced boxers slowed slightly, with a 27.3-ms increase in reaction time, while nonboxers got faster, with a 93.5-ms decrease in reaction time. One possible explanation is that nonboxers simply got better at reacting to the stimuli over time without actually learning the repeated sequence, Mr. McLeod said.
Rock Steady Boxing was founded in Indianapolis by Scott Newman, a former county prosecutor who was diagnosed with Parkinson’s disease at age 40 and experienced significant improvement in his health and agility by engaging in rigorous workouts, such as boxing. Dr. Leder became certified in Rock Steady Boxing and opened a chapter at the New York college in May 2016. The classes include group activities, games, and boxing exercises designed to improve patients’ physical and mental stamina.
Mr. McLeod and Dr. Leder reported no relevant financial disclosures.
REPORTING FROM ICPDMD 2018
Several PT modalities are useful in Parkinson’s, movement disorders
Sensory receptor stimulation therapy can help certain patients with Parkinson’s disease improve posture and gait issues, according to Ben Weinstock, DPT, who specializes in physical therapy for patients with movement disorders.
Dr. Weinstock will present an update on several physical therapy modalities that can be useful for patients with Parkinson’s disease on Oct. 19 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
“Up to 70% of people with Parkinson’s disease are exercise intolerant,” Dr. Weinstock said in an interview. “As such, we must provide interventions that can keep them moving and avoid sedentary behavior.”
Manual stimulation of points on the foot can improve freezing of gait as well as normalize stride length, according to research published by Italian investigators in 2015 (Int J Rehabil Res. 2015 Sep. doi: 10.1097/MRR.0000000000000120) while electrical stimulation of acupuncture points on the ear and body assisted with motor and nonmotor Parkinson’s symptoms, based on a 2017 study (Front Hum Neurosci. 2017. doi: 10.3389/fnhum.2017.00338).
Advances in manual pressure therapy as well as using Kinesio taping to improve posture also will be addressed by Dr. Weinstock, who is in private practice in New York.
Sensory receptor stimulation therapy can help certain patients with Parkinson’s disease improve posture and gait issues, according to Ben Weinstock, DPT, who specializes in physical therapy for patients with movement disorders.
Dr. Weinstock will present an update on several physical therapy modalities that can be useful for patients with Parkinson’s disease on Oct. 19 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
“Up to 70% of people with Parkinson’s disease are exercise intolerant,” Dr. Weinstock said in an interview. “As such, we must provide interventions that can keep them moving and avoid sedentary behavior.”
Manual stimulation of points on the foot can improve freezing of gait as well as normalize stride length, according to research published by Italian investigators in 2015 (Int J Rehabil Res. 2015 Sep. doi: 10.1097/MRR.0000000000000120) while electrical stimulation of acupuncture points on the ear and body assisted with motor and nonmotor Parkinson’s symptoms, based on a 2017 study (Front Hum Neurosci. 2017. doi: 10.3389/fnhum.2017.00338).
Advances in manual pressure therapy as well as using Kinesio taping to improve posture also will be addressed by Dr. Weinstock, who is in private practice in New York.
Sensory receptor stimulation therapy can help certain patients with Parkinson’s disease improve posture and gait issues, according to Ben Weinstock, DPT, who specializes in physical therapy for patients with movement disorders.
Dr. Weinstock will present an update on several physical therapy modalities that can be useful for patients with Parkinson’s disease on Oct. 19 at the International Conference on Parkinson’s Disease and Movement Disorders in New York.
“Up to 70% of people with Parkinson’s disease are exercise intolerant,” Dr. Weinstock said in an interview. “As such, we must provide interventions that can keep them moving and avoid sedentary behavior.”
Manual stimulation of points on the foot can improve freezing of gait as well as normalize stride length, according to research published by Italian investigators in 2015 (Int J Rehabil Res. 2015 Sep. doi: 10.1097/MRR.0000000000000120) while electrical stimulation of acupuncture points on the ear and body assisted with motor and nonmotor Parkinson’s symptoms, based on a 2017 study (Front Hum Neurosci. 2017. doi: 10.3389/fnhum.2017.00338).
Advances in manual pressure therapy as well as using Kinesio taping to improve posture also will be addressed by Dr. Weinstock, who is in private practice in New York.
REPORTING FROM ICPDMD 2018
3-D model neurovascular unit developed with working blood-brain barrier
The development of a 3-D brain organoid that contains all six of the major cell types found in adult human brain cortex will be the featured topic of a presentation at the Young Research Forum of the International Conference on Parkinson’s Disease and Movement Disorders in New York on Oct. 20.
Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., will give the presentation, titled “The development of a multicellular three dimensional neurovascular unit model with a functional blood-brain barrier” at 1:45 p.m.
In the study that Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine published in May in Scientific Reports, they noted that, in addition to the model’s use of all six of the major cell types found in adult human brain cortex (human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons), they found that it also promotes the formation of a blood-brain barrier that mimics normal human anatomy.
The researchers said their 3-D in vitro system could have potential applications in drug discovery, toxicity screening, and disease modeling for neurologic diseases such as Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. They demonstrated the model’s use in toxicity assessment studies for molecules that have the potential to cross or open the blood-brain barrier and also reported establishing a model of the blood-brain barrier during clinical ischemia “showing physiologic responses under hypoxic conditions.”
The development of a 3-D brain organoid that contains all six of the major cell types found in adult human brain cortex will be the featured topic of a presentation at the Young Research Forum of the International Conference on Parkinson’s Disease and Movement Disorders in New York on Oct. 20.
Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., will give the presentation, titled “The development of a multicellular three dimensional neurovascular unit model with a functional blood-brain barrier” at 1:45 p.m.
In the study that Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine published in May in Scientific Reports, they noted that, in addition to the model’s use of all six of the major cell types found in adult human brain cortex (human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons), they found that it also promotes the formation of a blood-brain barrier that mimics normal human anatomy.
The researchers said their 3-D in vitro system could have potential applications in drug discovery, toxicity screening, and disease modeling for neurologic diseases such as Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. They demonstrated the model’s use in toxicity assessment studies for molecules that have the potential to cross or open the blood-brain barrier and also reported establishing a model of the blood-brain barrier during clinical ischemia “showing physiologic responses under hypoxic conditions.”
The development of a 3-D brain organoid that contains all six of the major cell types found in adult human brain cortex will be the featured topic of a presentation at the Young Research Forum of the International Conference on Parkinson’s Disease and Movement Disorders in New York on Oct. 20.
Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., will give the presentation, titled “The development of a multicellular three dimensional neurovascular unit model with a functional blood-brain barrier” at 1:45 p.m.
In the study that Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine published in May in Scientific Reports, they noted that, in addition to the model’s use of all six of the major cell types found in adult human brain cortex (human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons), they found that it also promotes the formation of a blood-brain barrier that mimics normal human anatomy.
The researchers said their 3-D in vitro system could have potential applications in drug discovery, toxicity screening, and disease modeling for neurologic diseases such as Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. They demonstrated the model’s use in toxicity assessment studies for molecules that have the potential to cross or open the blood-brain barrier and also reported establishing a model of the blood-brain barrier during clinical ischemia “showing physiologic responses under hypoxic conditions.”
REPORTING FROM ICPDMD 2018
FDA review supports Nuplazid’s safety
Pimavanserin (Nuplazid) remains an acceptable treatment for the hallucinations and delusions associated with Parkinson’s disease, according to a statement issued by the Food and Drug Administration after the agency conducted a postmarketing review of deaths and serious adverse events associated with the drug.
“Based on an analysis of all available data, FDA did not identify any new or unexpected safety findings” associated with the drug, according to the Sept. 20 statement.
However, the FDA researchers identified prescribing patterns that might increase the risk of serious adverse events, such as the concomitant use of pimavanserin and other antipsychotic drugs or drugs that can cause QT prolongation. The QT prolongation risk is listed on the drug label, which also includes a Boxed Warning about increased mortality risk in elderly patients.
The FDA statement reminds clinicians to know the risks described in the label and to be aware that no other antipsychotics are currently approved for psychosis in Parkinson’s patients.
The review was prompted by the number of reports of serious adverse events and deaths associated with pimavanserin, based on data obtained from multiple sources including the FDA Adverse Event Reporting System (FAERS), drug utilization data, safety data from the new drug application, the sponsor’s Periodic Adverse Drug Experience Reports, the sponsor’s analysis of fatal adverse event reports, and data from published medical literature.
When conducting the review, the FDA considered several factors, including the fact that Parkinson’s disease patients have higher mortality in general because of older age, advanced disease, and other medical comorbidities. In addition, pimavanserin adverse events and deaths are more likely to be reported because the drug is distributed mainly through a patient-support program and specialty pharmacy. The FDA also found no pattern suggestive of a drug effect on causes of death in patients whose deaths were reported through FAERS.
“Overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis,” according to the FDA statement.
Pimavanserin (Nuplazid) remains an acceptable treatment for the hallucinations and delusions associated with Parkinson’s disease, according to a statement issued by the Food and Drug Administration after the agency conducted a postmarketing review of deaths and serious adverse events associated with the drug.
“Based on an analysis of all available data, FDA did not identify any new or unexpected safety findings” associated with the drug, according to the Sept. 20 statement.
However, the FDA researchers identified prescribing patterns that might increase the risk of serious adverse events, such as the concomitant use of pimavanserin and other antipsychotic drugs or drugs that can cause QT prolongation. The QT prolongation risk is listed on the drug label, which also includes a Boxed Warning about increased mortality risk in elderly patients.
The FDA statement reminds clinicians to know the risks described in the label and to be aware that no other antipsychotics are currently approved for psychosis in Parkinson’s patients.
The review was prompted by the number of reports of serious adverse events and deaths associated with pimavanserin, based on data obtained from multiple sources including the FDA Adverse Event Reporting System (FAERS), drug utilization data, safety data from the new drug application, the sponsor’s Periodic Adverse Drug Experience Reports, the sponsor’s analysis of fatal adverse event reports, and data from published medical literature.
When conducting the review, the FDA considered several factors, including the fact that Parkinson’s disease patients have higher mortality in general because of older age, advanced disease, and other medical comorbidities. In addition, pimavanserin adverse events and deaths are more likely to be reported because the drug is distributed mainly through a patient-support program and specialty pharmacy. The FDA also found no pattern suggestive of a drug effect on causes of death in patients whose deaths were reported through FAERS.
“Overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis,” according to the FDA statement.
Pimavanserin (Nuplazid) remains an acceptable treatment for the hallucinations and delusions associated with Parkinson’s disease, according to a statement issued by the Food and Drug Administration after the agency conducted a postmarketing review of deaths and serious adverse events associated with the drug.
“Based on an analysis of all available data, FDA did not identify any new or unexpected safety findings” associated with the drug, according to the Sept. 20 statement.
However, the FDA researchers identified prescribing patterns that might increase the risk of serious adverse events, such as the concomitant use of pimavanserin and other antipsychotic drugs or drugs that can cause QT prolongation. The QT prolongation risk is listed on the drug label, which also includes a Boxed Warning about increased mortality risk in elderly patients.
The FDA statement reminds clinicians to know the risks described in the label and to be aware that no other antipsychotics are currently approved for psychosis in Parkinson’s patients.
The review was prompted by the number of reports of serious adverse events and deaths associated with pimavanserin, based on data obtained from multiple sources including the FDA Adverse Event Reporting System (FAERS), drug utilization data, safety data from the new drug application, the sponsor’s Periodic Adverse Drug Experience Reports, the sponsor’s analysis of fatal adverse event reports, and data from published medical literature.
When conducting the review, the FDA considered several factors, including the fact that Parkinson’s disease patients have higher mortality in general because of older age, advanced disease, and other medical comorbidities. In addition, pimavanserin adverse events and deaths are more likely to be reported because the drug is distributed mainly through a patient-support program and specialty pharmacy. The FDA also found no pattern suggestive of a drug effect on causes of death in patients whose deaths were reported through FAERS.
“Overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis,” according to the FDA statement.
Huntington’s progression tracks with levels of mutant huntingtin, neurofilament light
Concentrations of mutant huntingtin protein and neurofilament light proteins in cerebrospinal fluid and blood may be the first signs of progression in Huntington’s disease, according to a paper published online Sept. 12 in Science Translational Medicine.
In a cohort of 40 Huntington’s mutation carriers with manifest disease, 20 carriers without clinical symptoms, and 20 healthy controls, researchers examined levels of mutant huntingtin (mHTT) and neurofilament light (NfL) protein in biofluids, in parallel with clinical evaluations and MRI imaging.
They found that concentrations of mHTT in the cerebrospinal fluid (CSF) and concentrations of NfL proteins in the CSF and plasma were significantly higher in participants with manifest Huntington’s disease (HD) than in those without manifest disease or in controls.
Researchers also saw that CSF concentrations of mHTT showed the earliest detectable change in progression of the disease, followed by plasma and CSF levels of NfL. After that came changes in caudate and global brain volume, motor score, word reading, and other clinical measures.
“These results suggest that as our understanding grows further, analysis of mHTT and NfL might be useful for developing HD therapeutics and for clinical management,” wrote Lauren M. Byrne of the Huntington’s Disease Centre at the University College London Institute of Neurology and her coauthors.
Plasma concentrations of NfL showed the strongest association with clinical severity, even after adjusting for the number of CAG (or cytosine, adenine, and guanine) repeats – a measure of disease severity – and age.
“Our previous work suggests that NfL is a dynamic marker of ongoing neuronal damage in HD that predicts subsequent progression,” the authors wrote. “This perhaps reflects that NfL, as a marker of axonal damage, has a more direct relationship with the development of clinical manifestations and brain atrophy.”
NfL concentrations in CSF more closely predicted brain volume than did plasma NfL or CSF concentrations of mHTT.
In participants who carried the Huntington’s mutation, CSF concentrations of mHTT and NfL were strongly correlated. Researchers also noted that mutation carriers had a significantly higher CSF-to-plasma ratio of NfL than did controls.
The study also showed that mHTT in the CSF and NfL in the cerebrospinal fluid and plasma, were very stable within individuals over 4-8 weeks.
“The very high intraclass correlation values of the three markers revealed them to be highly stable, suggesting that intraindividual variation in these analytes is likely to be a minimal source of noise in natural history and therapeutic studies,” the authors wrote.
This work was supported by the Medical Research Council U.K., the CHDI Foundation, the Wellcome Trust, the U.K. Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme, the U.K. Dementia Research Institute, F. Hoffmann-La Roche, the Horizon 2020 Framework Programme, and the Engineering and Physical Sciences Research Council. A number of authors disclosed consulting or serving on advisory boards for F. Hoffmann-La Roche and/or other companies. Three authors are full-time employees of F. Hoffmann-La Roche.
SOURCE: Byrne L et al. Sci Transl Med. 2018;10:eaat7108. doi: 10.1126/scitranslmed.aat7108.
Concentrations of mutant huntingtin protein and neurofilament light proteins in cerebrospinal fluid and blood may be the first signs of progression in Huntington’s disease, according to a paper published online Sept. 12 in Science Translational Medicine.
In a cohort of 40 Huntington’s mutation carriers with manifest disease, 20 carriers without clinical symptoms, and 20 healthy controls, researchers examined levels of mutant huntingtin (mHTT) and neurofilament light (NfL) protein in biofluids, in parallel with clinical evaluations and MRI imaging.
They found that concentrations of mHTT in the cerebrospinal fluid (CSF) and concentrations of NfL proteins in the CSF and plasma were significantly higher in participants with manifest Huntington’s disease (HD) than in those without manifest disease or in controls.
Researchers also saw that CSF concentrations of mHTT showed the earliest detectable change in progression of the disease, followed by plasma and CSF levels of NfL. After that came changes in caudate and global brain volume, motor score, word reading, and other clinical measures.
“These results suggest that as our understanding grows further, analysis of mHTT and NfL might be useful for developing HD therapeutics and for clinical management,” wrote Lauren M. Byrne of the Huntington’s Disease Centre at the University College London Institute of Neurology and her coauthors.
Plasma concentrations of NfL showed the strongest association with clinical severity, even after adjusting for the number of CAG (or cytosine, adenine, and guanine) repeats – a measure of disease severity – and age.
“Our previous work suggests that NfL is a dynamic marker of ongoing neuronal damage in HD that predicts subsequent progression,” the authors wrote. “This perhaps reflects that NfL, as a marker of axonal damage, has a more direct relationship with the development of clinical manifestations and brain atrophy.”
NfL concentrations in CSF more closely predicted brain volume than did plasma NfL or CSF concentrations of mHTT.
In participants who carried the Huntington’s mutation, CSF concentrations of mHTT and NfL were strongly correlated. Researchers also noted that mutation carriers had a significantly higher CSF-to-plasma ratio of NfL than did controls.
The study also showed that mHTT in the CSF and NfL in the cerebrospinal fluid and plasma, were very stable within individuals over 4-8 weeks.
“The very high intraclass correlation values of the three markers revealed them to be highly stable, suggesting that intraindividual variation in these analytes is likely to be a minimal source of noise in natural history and therapeutic studies,” the authors wrote.
This work was supported by the Medical Research Council U.K., the CHDI Foundation, the Wellcome Trust, the U.K. Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme, the U.K. Dementia Research Institute, F. Hoffmann-La Roche, the Horizon 2020 Framework Programme, and the Engineering and Physical Sciences Research Council. A number of authors disclosed consulting or serving on advisory boards for F. Hoffmann-La Roche and/or other companies. Three authors are full-time employees of F. Hoffmann-La Roche.
SOURCE: Byrne L et al. Sci Transl Med. 2018;10:eaat7108. doi: 10.1126/scitranslmed.aat7108.
Concentrations of mutant huntingtin protein and neurofilament light proteins in cerebrospinal fluid and blood may be the first signs of progression in Huntington’s disease, according to a paper published online Sept. 12 in Science Translational Medicine.
In a cohort of 40 Huntington’s mutation carriers with manifest disease, 20 carriers without clinical symptoms, and 20 healthy controls, researchers examined levels of mutant huntingtin (mHTT) and neurofilament light (NfL) protein in biofluids, in parallel with clinical evaluations and MRI imaging.
They found that concentrations of mHTT in the cerebrospinal fluid (CSF) and concentrations of NfL proteins in the CSF and plasma were significantly higher in participants with manifest Huntington’s disease (HD) than in those without manifest disease or in controls.
Researchers also saw that CSF concentrations of mHTT showed the earliest detectable change in progression of the disease, followed by plasma and CSF levels of NfL. After that came changes in caudate and global brain volume, motor score, word reading, and other clinical measures.
“These results suggest that as our understanding grows further, analysis of mHTT and NfL might be useful for developing HD therapeutics and for clinical management,” wrote Lauren M. Byrne of the Huntington’s Disease Centre at the University College London Institute of Neurology and her coauthors.
Plasma concentrations of NfL showed the strongest association with clinical severity, even after adjusting for the number of CAG (or cytosine, adenine, and guanine) repeats – a measure of disease severity – and age.
“Our previous work suggests that NfL is a dynamic marker of ongoing neuronal damage in HD that predicts subsequent progression,” the authors wrote. “This perhaps reflects that NfL, as a marker of axonal damage, has a more direct relationship with the development of clinical manifestations and brain atrophy.”
NfL concentrations in CSF more closely predicted brain volume than did plasma NfL or CSF concentrations of mHTT.
In participants who carried the Huntington’s mutation, CSF concentrations of mHTT and NfL were strongly correlated. Researchers also noted that mutation carriers had a significantly higher CSF-to-plasma ratio of NfL than did controls.
The study also showed that mHTT in the CSF and NfL in the cerebrospinal fluid and plasma, were very stable within individuals over 4-8 weeks.
“The very high intraclass correlation values of the three markers revealed them to be highly stable, suggesting that intraindividual variation in these analytes is likely to be a minimal source of noise in natural history and therapeutic studies,” the authors wrote.
This work was supported by the Medical Research Council U.K., the CHDI Foundation, the Wellcome Trust, the U.K. Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme, the U.K. Dementia Research Institute, F. Hoffmann-La Roche, the Horizon 2020 Framework Programme, and the Engineering and Physical Sciences Research Council. A number of authors disclosed consulting or serving on advisory boards for F. Hoffmann-La Roche and/or other companies. Three authors are full-time employees of F. Hoffmann-La Roche.
SOURCE: Byrne L et al. Sci Transl Med. 2018;10:eaat7108. doi: 10.1126/scitranslmed.aat7108.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: Cerebrospinal levels of mutant huntingtin could be earliest sign of Huntington’s disease progression.
Major finding: Changing levels of mutant huntingtin in the cerebrospinal fluid are the first sign of disease progression.
Study details: Cohort study in 60 Huntington’s disease mutation carriers and 20 controls.
Disclosures: This work was supported by the Medical Research Council U.K., the CHDI Foundation, the Wellcome Trust, the U.K. Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme, the U.K. Dementia Research Institute, F. Hoffmann-La Roche, the Horizon 2020 Framework Programme, and the Engineering and Physical Sciences Research Council. A number of authors disclosed consulting or serving on advisory boards for F. Hoffmann-La Roche and/or other companies. Three authors are full-time employees of F. Hoffmann-La Roche.
Source: Byrne L et al. Sci Transl Med. 2018;10:eaat7108. doi: 10.1126/scitranslmed.aat7108.
Huntington’s Disease Symptoms Vary by Age of Onset
Earlier age of onset may be associated with higher severity of behavioral symptoms.
MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.
Examining Enroll-HD Data
A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease. 
Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.
Motor Symptoms More Common in Late-Onset Disease
Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.
A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.
At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.
“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”
—Erik Greb
Earlier age of onset may be associated with higher severity of behavioral symptoms.
Earlier age of onset may be associated with higher severity of behavioral symptoms.
MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.
Examining Enroll-HD Data
A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease.
Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.
Motor Symptoms More Common in Late-Onset Disease
Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.
A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.
At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.
“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”
—Erik Greb
MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.
Examining Enroll-HD Data
A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease.
Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.
Motor Symptoms More Common in Late-Onset Disease
Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.
A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.
At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.
“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”
—Erik Greb
How Does Fear of Falling Affect People in Middle Age?
Fear of falling may have less of an effect on gait and balance in adults younger than 65.
MIAMI—Healthy, middle-aged adults may have a fear of falling, but unlike in older adults, this fear does not appear to affect gait and balance, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. 
Since ptophobia, the fear of standing or walking, was described in the 1980s, “fear of falling has gained recognition as a health problem of older adults,” said Maria Sheila G. Rocha, MD, PhD, a researcher at Hospital Santa Marcelina in São Paulo, Brazil, and colleagues. In adults older than 65, fear of falling increases the likelihood of falls and injury and limits daily activities. The incidence and impact of fear of falling in younger adults is not known, however.
Dr. Rocha and colleagues aimed to evaluate the prevalence of fear of falling among urban, middle-aged, healthy adults, as well as associated risk factors and fear of falling’s impact on gait and balance in this population.
Their study included 111 healthy participants ages 18 to 95 who lived in São Paulo. The investigators assessed fear of falling using the following four variables from the Brazilian version of the Falls Efficacy Scale-International: history of falls, functional dependency in activities of daily living, cognitive screening test, and activity level. The researchers assessed gait and balance using the Berg Balance Scale, Dynamic Gait Index, Short Physical Performance Battery, and the Performance Oriented Mobility Assessment.
Of the 111 participants, 52.2% were female, mean age was 51.8, and mean Mini-Mental State Examination score was 29.5. Fear of falling was present in 25.2%, and prevalence increased with age. Fear of falling was present in 18.4% of adults younger than 65 and in 48% of those 65 and older.
Fear of walking on an uneven surface and fear of going up or down a slope were the most common fear of falling variables. Being female and older were the main risk factors associated with fear of falling.
Participants with fear of falling performed worse on the Berg Balance Scale and Short Physical Performance Battery than those without. Those younger than 65, however, “had similar gait and balance performance despite the presence of fear of falling,” Dr. Rocha and colleagues said. In addition, physically active participants had less fear of falling.
“Fear of falling creates a psychologic barrier to performing activities for many older adults,” Dr. Rocha and colleagues said. The results suggest that physical activity is a protective factor against fear offalling, the researchers concluded.
Fear of falling may have less of an effect on gait and balance in adults younger than 65.
Fear of falling may have less of an effect on gait and balance in adults younger than 65.
MIAMI—Healthy, middle-aged adults may have a fear of falling, but unlike in older adults, this fear does not appear to affect gait and balance, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
Since ptophobia, the fear of standing or walking, was described in the 1980s, “fear of falling has gained recognition as a health problem of older adults,” said Maria Sheila G. Rocha, MD, PhD, a researcher at Hospital Santa Marcelina in São Paulo, Brazil, and colleagues. In adults older than 65, fear of falling increases the likelihood of falls and injury and limits daily activities. The incidence and impact of fear of falling in younger adults is not known, however.
Dr. Rocha and colleagues aimed to evaluate the prevalence of fear of falling among urban, middle-aged, healthy adults, as well as associated risk factors and fear of falling’s impact on gait and balance in this population.
Their study included 111 healthy participants ages 18 to 95 who lived in São Paulo. The investigators assessed fear of falling using the following four variables from the Brazilian version of the Falls Efficacy Scale-International: history of falls, functional dependency in activities of daily living, cognitive screening test, and activity level. The researchers assessed gait and balance using the Berg Balance Scale, Dynamic Gait Index, Short Physical Performance Battery, and the Performance Oriented Mobility Assessment.
Of the 111 participants, 52.2% were female, mean age was 51.8, and mean Mini-Mental State Examination score was 29.5. Fear of falling was present in 25.2%, and prevalence increased with age. Fear of falling was present in 18.4% of adults younger than 65 and in 48% of those 65 and older.
Fear of walking on an uneven surface and fear of going up or down a slope were the most common fear of falling variables. Being female and older were the main risk factors associated with fear of falling.
Participants with fear of falling performed worse on the Berg Balance Scale and Short Physical Performance Battery than those without. Those younger than 65, however, “had similar gait and balance performance despite the presence of fear of falling,” Dr. Rocha and colleagues said. In addition, physically active participants had less fear of falling.
“Fear of falling creates a psychologic barrier to performing activities for many older adults,” Dr. Rocha and colleagues said. The results suggest that physical activity is a protective factor against fear offalling, the researchers concluded.
MIAMI—Healthy, middle-aged adults may have a fear of falling, but unlike in older adults, this fear does not appear to affect gait and balance, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
Since ptophobia, the fear of standing or walking, was described in the 1980s, “fear of falling has gained recognition as a health problem of older adults,” said Maria Sheila G. Rocha, MD, PhD, a researcher at Hospital Santa Marcelina in São Paulo, Brazil, and colleagues. In adults older than 65, fear of falling increases the likelihood of falls and injury and limits daily activities. The incidence and impact of fear of falling in younger adults is not known, however.
Dr. Rocha and colleagues aimed to evaluate the prevalence of fear of falling among urban, middle-aged, healthy adults, as well as associated risk factors and fear of falling’s impact on gait and balance in this population.
Their study included 111 healthy participants ages 18 to 95 who lived in São Paulo. The investigators assessed fear of falling using the following four variables from the Brazilian version of the Falls Efficacy Scale-International: history of falls, functional dependency in activities of daily living, cognitive screening test, and activity level. The researchers assessed gait and balance using the Berg Balance Scale, Dynamic Gait Index, Short Physical Performance Battery, and the Performance Oriented Mobility Assessment.
Of the 111 participants, 52.2% were female, mean age was 51.8, and mean Mini-Mental State Examination score was 29.5. Fear of falling was present in 25.2%, and prevalence increased with age. Fear of falling was present in 18.4% of adults younger than 65 and in 48% of those 65 and older.
Fear of walking on an uneven surface and fear of going up or down a slope were the most common fear of falling variables. Being female and older were the main risk factors associated with fear of falling.
Participants with fear of falling performed worse on the Berg Balance Scale and Short Physical Performance Battery than those without. Those younger than 65, however, “had similar gait and balance performance despite the presence of fear of falling,” Dr. Rocha and colleagues said. In addition, physically active participants had less fear of falling.
“Fear of falling creates a psychologic barrier to performing activities for many older adults,” Dr. Rocha and colleagues said. The results suggest that physical activity is a protective factor against fear offalling, the researchers concluded.
High autonomic dysfunction distinguishes persistent posttraumatic headache
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: New evidence that patients with persistent posttraumatic headache have high levels of autonomic dysfunction could open the door to novel treatments.
Major finding: Scores on the COMPASS-31 questionnaire, a measure of autonomic dysfunction, averaged 37.22 in patients with persistent posttraumatic headache, indicative of significantly greater impairment than the 27.15 in migraine patients and 11.67 in healthy controls.
Study details: This cross-sectional cohort study included 56 patients with persistent posttraumatic headache, 30 with migraine, and 36 healthy controls.
Disclosures: The study was sponsored by the Department of Defense and presented by an active duty military physician.
Source: Howard L et al. AHS 2018, Abstract FHM03
Sublingual Apomorphine Effectively Manages Off Episodes in Parkinson’s Disease
The treatment significantly improves motor function at 30 minutes after dosing, compared with placebo.
MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.
Evaluating the Efficacy and Safety of APL
To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.
Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.
Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.
The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.
Treated Patients Were More Likely to Be On
A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.
In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.
The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).
In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.
—Erica Tricarico
The treatment significantly improves motor function at 30 minutes after dosing, compared with placebo.
The treatment significantly improves motor function at 30 minutes after dosing, compared with placebo.
MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.
Evaluating the Efficacy and Safety of APL
To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.
Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.
Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.
The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.
Treated Patients Were More Likely to Be On
A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.
In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.
The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).
In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.
—Erica Tricarico
MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.
APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.
Evaluating the Efficacy and Safety of APL
To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.
Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.
Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.
The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.
Treated Patients Were More Likely to Be On
A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.
In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.
The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).
In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.
—Erica Tricarico
Droxidopa May Reduce Neurogenic Orthostatic Hypotension Symptoms in Patients Taking DDCIs
The number of patients experiencing falls significantly decreased after six months of droxidopa treatment, regardless of whether patients were on dopa decarboxylase inhibitors.
MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.
Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls. 
Droxidopa, a prodrug of norepinephrine, is approved to treat symptomatic neurogenic orthostatic hypotension. Droxidopa is converted to norepinephrine by dopamine decarboxylase, which also converts levodopa to dopamine. Patients with Parkinson’s disease are commonly treated with DDCIs in conjunction with levodopa treatment. DDCIs did not appear to interfere with the therapeutic efficacy of droxidopa in clinical studies, but “high doses of DDCIs (8- to 10-fold higher than clinical doses) have been shown to blunt the effects of droxidopa,” said Steven Kymes, PhD, Director of Health Economics and Outcomes Research at Lundbeck in Deerfield, Illinois, and colleagues.
A Post Hoc Analysis
To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.
Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.
Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.
Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.
Droxidopa Treatment Was Associated With Reduced Falls
A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).
“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.
The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.
Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.
In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.
“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.
—Erica Tricarico
The number of patients experiencing falls significantly decreased after six months of droxidopa treatment, regardless of whether patients were on dopa decarboxylase inhibitors.
The number of patients experiencing falls significantly decreased after six months of droxidopa treatment, regardless of whether patients were on dopa decarboxylase inhibitors.
MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.
Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls.
Droxidopa, a prodrug of norepinephrine, is approved to treat symptomatic neurogenic orthostatic hypotension. Droxidopa is converted to norepinephrine by dopamine decarboxylase, which also converts levodopa to dopamine. Patients with Parkinson’s disease are commonly treated with DDCIs in conjunction with levodopa treatment. DDCIs did not appear to interfere with the therapeutic efficacy of droxidopa in clinical studies, but “high doses of DDCIs (8- to 10-fold higher than clinical doses) have been shown to blunt the effects of droxidopa,” said Steven Kymes, PhD, Director of Health Economics and Outcomes Research at Lundbeck in Deerfield, Illinois, and colleagues.
A Post Hoc Analysis
To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.
Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.
Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.
Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.
Droxidopa Treatment Was Associated With Reduced Falls
A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).
“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.
The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.
Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.
In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.
“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.
—Erica Tricarico
MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.
Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls.
Droxidopa, a prodrug of norepinephrine, is approved to treat symptomatic neurogenic orthostatic hypotension. Droxidopa is converted to norepinephrine by dopamine decarboxylase, which also converts levodopa to dopamine. Patients with Parkinson’s disease are commonly treated with DDCIs in conjunction with levodopa treatment. DDCIs did not appear to interfere with the therapeutic efficacy of droxidopa in clinical studies, but “high doses of DDCIs (8- to 10-fold higher than clinical doses) have been shown to blunt the effects of droxidopa,” said Steven Kymes, PhD, Director of Health Economics and Outcomes Research at Lundbeck in Deerfield, Illinois, and colleagues.
A Post Hoc Analysis
To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.
Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.
Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.
Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.
Droxidopa Treatment Was Associated With Reduced Falls
A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).
“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.
The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.
Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.
In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.
“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.
—Erica Tricarico