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‘Remarkable’ seizure-free rates seen with adjunctive cenobamate
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
FROM LANCET NEUROLOGY
Benefits of focused ultrasound thalamotomy for essential tremor persist for 3 years
, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.
“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
Long-term follow-up of a prospective trial
Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.
Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
Postural tremor was eliminated
The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.
Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.
For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.
Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.
The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
Reduction in improvement may have many causes
“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.
The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.
Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
Effect on axial tremor is unclear
The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.
“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”
Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.
“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”
SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).
, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.
“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
Long-term follow-up of a prospective trial
Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.
Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
Postural tremor was eliminated
The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.
Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.
For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.
Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.
The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
Reduction in improvement may have many causes
“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.
The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.
Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
Effect on axial tremor is unclear
The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.
“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”
Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.
“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”
SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).
, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.
“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
Long-term follow-up of a prospective trial
Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.
Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
Postural tremor was eliminated
The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.
Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.
For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.
Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.
The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
Reduction in improvement may have many causes
“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.
The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.
Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
Effect on axial tremor is unclear
The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.
“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”
Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.
“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”
SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).
FROM NEUROLOGY
Survey asks adults: How likely are you to develop dementia?
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
FROM JAMA NEUROLOGY
Insomnia symptoms increase likelihood of stroke and heart disease
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.
“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.
To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.
For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.
The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.
More than 16% had any insomnia symptom
Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.
After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.
In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”
Opportunity for intervention
Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”
The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.
The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.
This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
FROM NEUROLOGY
Key clinical point: The presence of insomnia symptoms increases the likelihood of cardiovascular or cerebrovascular disease during approximately 10 years of follow-up.
Major finding: After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13.
Study details: An analysis of data from 487,200 adults in China aged 30-79 years who completed a baseline survey during 2004-2008 and were followed through 2016.
Disclosures: This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.
Source: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.
Neurologists publish consensus statement on stridor in MSA
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
FROM NEUROLOGY
Increased Parkinson’s disease risk seen with bipolar disorder
Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.
Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.
“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”
Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.
One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.
Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”
Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.
SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.
Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.
Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.
“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”
Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.
One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.
Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”
Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.
SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.
Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.
Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.
“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”
Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.
One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.
Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”
Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.
SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.
FROM JAMA NEUROLOGY
Accounting for sex may improve diagnosis of amnestic MCI
, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.
A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
An examination of ADNI data
Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.
The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.
Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
Biomarker analysis supported the hypothesis
The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.
When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.
The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.
The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
Results have implications for treatment
“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”
Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.
Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.
, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.
A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
An examination of ADNI data
Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.
The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.
Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
Biomarker analysis supported the hypothesis
The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.
When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.
The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.
The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
Results have implications for treatment
“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”
Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.
Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.
, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.
A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
An examination of ADNI data
Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.
The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.
Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
Biomarker analysis supported the hypothesis
The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.
When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.
The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.
The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
Results have implications for treatment
“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”
Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.
Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.
FROM NEUROLOGY
How does alcohol intake affect dementia risk in older adults?
Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, , according to the study, which was published in JAMA Network Open.
“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”
Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).
“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”
GEMS data
To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.
In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.
During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.
Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
Trial excluded adults with excessive alcohol use
Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.
The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.
SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.
Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, , according to the study, which was published in JAMA Network Open.
“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”
Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).
“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”
GEMS data
To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.
In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.
During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.
Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
Trial excluded adults with excessive alcohol use
Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.
The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.
SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.
Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, , according to the study, which was published in JAMA Network Open.
“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”
Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).
“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”
GEMS data
To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.
In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.
During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.
Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
Trial excluded adults with excessive alcohol use
Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.
The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.
SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.
FROM JAMA NETWORK OPEN
Early infusion of mononuclear cells may benefit stroke patients
, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.
Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”
For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.
The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.
Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”
In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”
The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.
, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.
Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”
For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.
The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.
Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”
In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”
The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.
, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.
Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”
For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.
The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.
Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”
In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”
The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.
FROM STEM CELLS
Can a novel steroidal anti-inflammatory drug benefit patients with Duchenne muscular dystrophy?
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
FROM NEUROLOGY